Alzheimer

ALZHEIMER UPDATE

DR. JAMAL AL-KHATIB

Alzheimer Update Diagnosis: 1Diagnosis Scandal Threatens Alzheimer's Diagnostic Test January 18, 1999 Last April, an expert panel of the National Institutes of Health declared that the Alzheimer's diagnostic test developed by Athena Neurosciences, Inc., of South San Francisco, California, was significantly better than rival tests. The announcement spurred sales of the test, which rose 28 percent during 1998. Athena's test analyzes blood for the various forms of the gene for apolipoprotein E, some of which have been linked to an increased risk of Alzheimer's. But last month, the Wall St. Journal reported that five of the expert panel's eight members had financial ties to Athena, possibly tainting their conclusion about the company's Alzheimer's test. In addition, Athena gave a $100,000 grant to the nonprofit Alzheimer's Association, the nation's leading Alzheimer's organization to organize the panel for the NIH. Since the cozy relationship between the experts and Athena was divulged, the Alzheimer's Association has said that it regrets having used the funds to support the panel's work. The panelists insist that the conclusion of their report is scientifically solid, that Athena's test is better than the competition's. Their endorsement was not unqualified. Athena's test does not provide a definitive diagnosis of Alzheimer's. That can still not be determined until autopsy. But Nymox Corporation, which makes a competing test, has cried foul, saying that the panel had a conflict of interest and that the Alzheimer's Association and the NIH should have taken action, but did not. Experts familiar with the workings of government expert panels say that it's not unusual for some experts to have some ties to companies whose products they evaluate, but they concede that five of eight raises questions about credibility.

1

Most physicians have not jumped to perform tests for Alzheimer's--Athena's, Nymox's, or any other. The current flap will probably reinforce physician reluctance to use any of these tests.

Source: Wall St. Journal

2Brain Scans Detect Earliest Signs of Alzheimer's Disease February 1, 1999 In an advance that may provide a way to definitively diagnose early Alzheimer's--possibly even before any memory loss occurs--a key memory center in the brain shrinks substantially in those with very mild Alzheimer's, a new study shows. Researchers at New York University School of Medicine used MRI scans to measure anatomical changes in an important memory center, the entorhinal cortex. They discovered that this area shrinks substantially in those with very mild Alzheimer's. MRI scans are a powerful imaging tool that can peer inside the head to create an anatomical snapshot of the brain. "We have found a way to measure what may be the earliest changes in the memory-processing areas of the brain," says Dr. Mony de Leon, professor of psychiatry at NYU School of Medicine. This technique can be performed rapidly and potentially may be used to monitor the effect of therapies on the course of Alzheimer's disease, says Dr. de Leon, who is Director of the NYU School of Medicine Neuroimaging Research Laboratory. Currently, physicians diagnose Alzheimer's by evaluating a person's performance on tests of memory and learning, taking a thorough medical and family history, and performing a physical examination. But the disease is difficult to diagnose in its initial stages because there are no definitive laboratory tests. The new study extends previous findings by Dr. de Leon and other researchers that the hippocampus, another region of the brain associated with memory and learning, diminishes in size as Alzheimer's progresses.

2

The progressive damage and loss of neurons is one of the hallmarks of Alzheimer's disease. Previous studies by a German research team indicated that the damage begins in the entorhinal cortex as early as age 30 and spreads to the hippocampus. However, without MRI, this deterioration has been impossible to monitor. "The entorhinal cortex is the gateway to the hippocampus and is central to all memory functions in the brain," explains Dr. de Leon. "It is a memory distribution and processing center and if its gate is broken, then new memories cannot be made and old memories cannot be retrieved." In the new study, Dr. de Leon and co-workers developed a new method of measuring the size of the entorhinal cortex based on structural landmarks visible on MRI. The researchers used autopsied brain tissue from Alzheimer's sufferers and from control subjects who died of conditions unrelated to the brain to establish that the landmarks could be used to define the boundaries of the entorhinal cortex, providing a valid tool for measuring its surface area. The landmark-measurement technique revealed that the entorhinal cortex was reduced by 45 percent among Alzheimer's patients. Next, the researchers used the landmark technique to distinguish those with very mild Alzheimer's from healthy volunteers. They found that the entorhinal cortex was 27 percent smaller in patients with very mild Alzheimer's. Moreover, the damage to the entorhinal cortex was greater than to the hippocampus and it proved a more reliable disease marker.

Source: NYU Medical Center, Lancet

3Is It? Diagnosis Alzheimer's Diagnosis: Why All the Delays? April 19, 1999 It takes an average of 30 months from the time family members notice the initial symptoms of dementia for the person to be diagnosed with Alzheimer's, according to a new study by Linda Boise, Ph.D., M.P.H., and colleagues at the Oregon Health Sciences University in Portland.

3

The researchers conducted in-depth interviews with 244 primary caregivers and other close family members in order to understand why the diagnostic process takes so long. The single biggest reason, cited by 72 percent of caregivers, was that they knew very little about Alzheimer's disease, and for a long time simply did not imagine that the person's changing behavior and deteriorating cognitive abilities were manifestations of an illness. Half of caregivers said they thought the changes were a normal part of aging. Here are selected other reasons for delay of diagnosis: • I didn't know what kind of doctor to see (44%). • I felt overwhelmed by the increasing burden of caregiving (42%). • I didn't know how to explain the problems to my doctor (38%). • My doctor did not take my concerns seriously (29%). • I didn't have a chance to talk to the doctor in private (27%). • The doctor said my loved one's problems were a normal part of aging (25%). • I did not want to know that the illness was Alzheimer's (20%). The caregivers also said that during the period before the diagnosis, they became increasingly anxious as the person deteriorated. When the diagnosis was finally made, most caregivers said they felt relieved.

Source: American J. of Alzheimer's. Disease

Urine may be used to diagnose Alzheimer's disease

4

NEW YORK, Aug 02 (Reuters Health) -- A new urine test that can assist in the diagnosis of Alzheimer's disease has been developed, according to researchers reporting last week at the 51st annual meeting of the American Association for Clinical Chemistry in New Orleans. The AD7C neural thread protein urine test measures urine concentrations of the protein, which is elevated in patients with Alzheimer's disease. In their study of more than 200 patients with Alzheimer's, Dr. Michael Munzar and colleagues at Nymox Pharmaceutical Corp. of Montreal, Canada, found that the average level of neural thread protein was 2.3 ng/ml compared with levels of less than 1.5 ng/ml for patients with other types of neurological diseases, and 0.83 ng/ml for healthy "control" subjects. Munzar, medical director of the company, presented his group's findings at the meeting. In an interview with Reuters Health, he said that the test has been accurately picking up Alzheimer's in about 80% of cases and has been correctly negative about 90% of the time. The test has been made available commercially, he noted. "Samples are sent to our reference laboratory in Kensington, Maryland. It's new, but physicians are using it." Munzar added that "it's not a predictive test... it's a state marker, a biochemical marker." He said that preliminary evidence indicates a correlation between level of elevation of neural thread protein and severity of Alzheimer's disease, "but we're very cautious about that. People are beginning to do baseline tests in (high-risk subjects) with family histories of Alzheimer's disease.... In patients with subtle, marginal symptoms, you may get elevations (of AD7C)." Nymox is in the process of developing a 7C assay, which is a quicker, more advanced test compared with AD7C. "It can be turned into a kit for direct use by physicians, without having to go through our reference laboratory," Munzar explained.

Rule Out These Drugs Before Diagnosing Alzheimer's August 18, 1998

5

Some physicians are not sufficiently informed about the large number of medications that can cause drug-induced dementia. They may diagnose Alzhiemer's when a drug reaction is actually the cause, says Bruce Robinson, M.D., a professor and chief of the division of geriatric medicine and the University of South Florida in Tampa. The list includes such drugs as aspirin and Motrin, which in large doses over long periods of time, for example, in treatment of arthritis, can impair cognition. Other drugs that may cause enoughtcognitive impairment to raise suspicion of Alzheimer's include: Nonsteroidal Anti-Inflammatory Drugs (NSAID's): Advil, Nuprin, ibuprofen, Naprosyn, naproxen, Indocin, indomethicin, Clinoril, sulindac. Antihistamines and Decongestants: Found in cold and allergy forumlas, for example, Sudafed, Chlor-Trimeton and Tavist products. Benzodiazepines: Valium, Xanax, Librium, Serax, Oxazepam, Ativan, Lorazepam, Alprazolam, Diazepam,Tranxene. Antidepressants: Prozac, Paxil, Zoloft, Elavil, Tofranil, Norpramin. Anticonvulsants: Dilantin, Depakene, Depakote, valproic acid, Tegretol, Depitol, phenobarbitol. High blood pressure medication: Atenolol, Tenormin, Brevibloc, Kerlone, Catrol, Zebeta, Prindolol, Visken, Lopressor, Toprol, Blocadren, Timolol, Betapace, Corgard, Nadolol, Acebutolol, Inderal, propranolol, Calan, Isoptin, verapamil. Ulcer/Stomach medication: Tagamet, cimetidine, Zantac, ranitidine

6

Antibiotics: Keflex, Keflin, Flagyl. Antiparkinson's drugs: Larodopa, Dopar, Parlodel, Permax Heart failure medication: Digoxin Corticosteroids: Prednisone Narcotics: Codeine, Percodan, Percocet

Source: Geratrics (1997) 52:12:30

Pathology 7

1Brain Cell Snapshots Provide Clues to Alzheimer's Disease Process October 26, 1998 A new imaging technology allows scientists to take genetic "snapshots" of brain cells affected by Alzheimer's. The new technology, developed at the University of Rochester, enables researchers to assess the activity of 20 genes simultaneously. The genes under investigation are believed to play a role in the Alzheimer's disease process. In Alzheimer's, brain cells die, but not all cells in any given area are affected. Healthy cells and Alzheimer's-affected cells are remarkably interspersed. The new technology allows scientists to analyze their activity, which, they hope, will shed new light on how the disease progresses, and how healthy cells resist it. Of the 20 genes tested, five showed significant differences between healthy cells and Alzheimer's-affected cells. The five genes all play a role in regulating cell division and telling the cell when to die. Many of these genes also play a role in cancer, raising the possibility that Alzheimer's might be a special, unique form of brain cancer, according to Paul Coleman, principle investigator. Now Coleman's team is comparing the activity of up to 100 genes in healthy and diseased brain cells using the new technology that combines laser microdissection with genetic analysis techniques. His team hopes that by studying thousands of genes, they will eventually be able to create a genetic map showing which genes are involved in Alzheimer's, and in what sequence.

Source: American Journal of Alzheimer's Disease Scientists Uncover Possible Trigger for Alzheimer's Disease June 23, 1998 Researchers may have uncovered one of the first links in the long chain of biological events that cause Alzheimer's disease.

8

Dr. Mary P. Lambert, of Northwestern University, and colleagues studied how toxic proteins known as amyloid beta-derived diffusible ligands, or ADDLs, interact with nerve cells in laboratory animals. ADDLs were discovered only recently and have been found in the brains of people with Alzheimer's disease in the form of long fibers. Scientists had thought that these weed-like fibers somehow choked off the growth of nerve cells, causing them to die away. When this happened, many scientists believed, symptoms of dementia would begin to occur. But Lambert and her colleagues discovered that ADDLs may gum up the nerve cells' chemical machinery much earlier, long before they begin to die off, and in the process prevent the cells from carrying out activities needed for learning and memory. The finding may give scientists a way to intervene in the Alzheimer's disease process before it damages the nerve cells, said researcher Dr. Grant A. Krafft of Evanston Northwestern Healthcare. "The implication of this work is that if Alzheimer's disease symptoms are caught at early stages, they potentially could be reversed," said Krafft.

Source: Proceedings of the National Academy of Sciences (1998) 95:64486453 Who Becomes Agitated? Who Becomes Verbally Abusive? November 3, 1998 When institutionalized, demented elderly often become physically agitated and verbally abusive/aggressive. But it's been hard to predict who will develop which problem. Researchers from the University of Pennsylvania, the Medical College of Georgia, and Wilkes University in Wilkes-Barre, PA believe they have solved this puzzle. Over 12 months, the researchers studied 586 nursing home residents with either agitated behavior (AB) or verbally aggressive behavior (VAB), along with 184 controls who displayed neither syndrome. Agitation turned out to be closely related to cognitive impairment. Compared 9

with cognitively normal elders, those with cognitive impairment were more likely to display AB. In those with severe cognitive decline, AB was four times more likely. On the other hand, verbal aggression was more related to use of drugs aimed at controlling unruly behavior. As drug use increased, residents were less able to act out physically, so they became more likely to resort to VAB. The best predictor of AB and VAB was previous similar behavior. Some people, it seems, gravitate toward verbal aggression while others tend toward physical outbursts.

Source: American Journal of Alzheimer's Disease

Age-Related Brain Cell Loss Reversed In Animals By Pam Harrison NEW YORK, Sep 20 (Reuters Health) -- For the first time, scientists have shown that brain cell changes associated with aging and memory loss are potentially reversible in animals. The findings may lead to therapies that fight age-related loss of brain cells. Drs. Heather A. Cameron and Ronald D.G. McKay from the National Institutes of Health, Bethesda, Maryland, surgically removed the adrenal glands in a group of aged rats to see if reducing stress hormones normally produced by these glands might restore nerve cell growth in the hippocampus, a part of the brain responsible for certain types of learning and memory. In a report of their findings published in the October issue of Nature Neuroscience, the researchers explain that it is believed that high levels of corticosteroids or adrenal stress hormones either cause or accelerate damage to this particular area of the brain, resulting in decreased cell production and memory loss associated with normal aging. The investigators found that by surgically reducing stress hormone production, the growth of new nerve cells was restored in the brains of aged rats to the same extent as it occurs in younger rats. These findings indicate that the ability of the brain to generate new nerve cells continues into old age, but that it is slowed down by high levels of stress hormones, they note. In an interview with ReuHealth, McKay noted that his team needs to generate more data to support the idea that high levels of corticosteroids are an important regulator of memory loss in humans, as they are in rats. "If it holds true, then we need to exploit our pharmacological skills to specifically target this particular aspect of corticosteroid action and leave the other, beneficial actions of stress hormones intact," he said. This is not as difficult as it might seem, he added. Right now, a class of drugs already exists that can turn on estrogen in specific parts of the body but not, desirably, in the breast or the uterus. McKay also noted that steroid receptors, proteins on cells that interact with the hormones, also "come in different flavors, and it is quite possible to target receptors in the hippocampus by making a drug that binds only to receptors in this part of the brain but not to others." Once inhibited by such a drug, corticosteroid levels in the brain could be controlled, and nerve cell growth may thus continue into old age, thereby preventing memory loss, McKay suggested.

10

SOURCE: Nature Neuroscience 1999;2:894-897.

Head Trauma Linked To Degenerative Brain Changes NEW YORK, Aug 31 (Reuters Health) -- Trauma to the head may trigger a cascade of biochemical events in the brain, in time resulting in neurodegenerative changes similar to those found in patients with Alzheimer's disease, report researchers at the University of Pennsylvania in Philadelphia. The findings back previous studies that suggested brain trauma increases the risk of Alzheimer's disease, a leading cause of dementia, later in life. In a statement, the researchers say that they hope their study will lead to a renewed commitment to educate the public about behaviors that reduce the risk of head injury, such as wearing seatbelts while traveling in an automobile and helmets while riding bicycles or motorcycles. Dr. Douglas H. Smith, who led the research effort, told Reuters Health that these findings support "several epidemiologic reports (that have suggested) a link between a single episode of brain trauma and the development of Alzheimer's disease later in life." Smith's team induced brain injury in anesthetized pigs via very rapid acceleration/deceleration of the animals' heads without direct impact, similar to what humans often experience in an automobile accident. They describe their experiments in the September issue of the Journal of Neuropathology and Experimental Neurology. "Brain trauma is the only environmental risk factor for Alzheimer's disease, so there is something about brain trauma that might initiate these insidious neurodegenerative cascades," Smith said in the interview with Reuters Health. Analysis of brain tissue from the animals revealed diffuse axonal pathology, the scientists report. "The most remarkable and consistent finding," they write in the paper, "was extensive (amyloid beta) and tau accumulation in damaged (brain cells) following trauma." Amyloid beta protein is a characteristic finding in the brains of patients with Alzheimer's disease. In the study animals, these changes were evident as early as 3 to 10 days post-injury. Smith said that some of the brain-injured animals, his group also observed plaque formation, another typical finding in Alzheimer's disease. The team conclude that microscopic injury to the brain caused by trauma can be linked to the development of Alzheimer's disease many years after the injury. The finding may also lead to new drugs aimed at preventing the process. "This study adds to the body of knowledge that might aid us in the development of an anti-plaque-making compound," Smith said in a statement.

SOURCE: Journal of Neuropathology and Experimental Neurology 1999;58:982-992.

11

Alzheimer’s disease Steve Simpson and Alistair Burns Current Opinion in Psychiattry 1996. 9:89-92

Introduction This review focuses on clinical research into Alzheimer’s disease, the commonest form of degenerative dementia. Although in recent years there have been developments in the treatment of the cognitive impairment [1,2], this year more progress has been made in the genetics of Alzheimer’s disease. In particular, a gene (S182) responsible for an estimated threequarters of presenile familial Alzheimer’s disease has been located on chromosome 14 (14q24.3). Other studies, including Alzheimer’s disease with depression and extrapyramidal signs in Alzheimer’s disease, are discussed.

Genetics Early onset Alzheimer’s disease is generally considered to be geneticallly determined. The evidence that late onset Alzheimer’s disease is familial is less strong and when no family history exists patients are diagnosed as having sporadic Alzheimer’s disease. At least three different genes have been identified that confer susceptibility; previous molecular genetic studies have implicated chromosomes 19, 21 and 14. (1) The e4 (112 Cys-Arg) allele of apolipoprotein E4 is associated with as much as 50% of all cases of Alzheimer’s disease. Apolipoprotein E4 is a plasma protein involved in the metabolism of cholesterol and triglycerides and its gene is linked to chromosome 19 [3]. (2) On chromosome 21, several missense mutations in the beta-amyloid precursor precursor protein represent a proportion of both familial Alzheimer’s disease and sporadic Alzheimer’s disease [4]. (3) Genetic linkage studies have mapped a third locus associated with susceptibility to an aggressive form of Alzheimer’s disease, to chromosome 14; the elucidation of the gene is anticipated [5]. This year a missense mutation was reported [6**]. In a genetic mapping study of 21 pedigrees, segregating Alzheimer’s disease as a putative autosomal dominant trait, one of the transcripts on the Alzheimer’s disease

12

gene (S182) corresponded to a novel gene, the product of which is predicted to contain multiple transmembrane domains and to resemble an integral membrane protein. Strong evidence now exists that mutations in the S182 gene are the cause of early onset familial Alzheimer’s disease in some pedigrees. The S182 protein is most homologous to another protein called SPE-4, found in the sperm of the round worm. SPE-4 is a membranous protein involved in intracellular transport or interactions with fibrillar proteins [7], which are relevant in the cytopathological mechanisms in Alzheimer’s disease [3,8]. S182 is envisaged to be involved in aberrant transport and processing of beta-amyloid precursor protein at a cytoskeletal level or to interact with cytoskeletal proteins such as microtubule Tau. Abnormalities in the intracellular, and ultimately, extracellular disposition of both these proteins are an integral part of the neuropathology of Alzheimer’s disease. How S182 interacts with beta-amyloid precursor protein or apolipoprotein in the pathogenesis of Alzheimer’s disease remains to be found; further research will determine its clinicopathological significance. The clinicopathological correlates of aplipoprotein e4 were studied by Zubenko et al. [9], who found no association between the allele and cerebrovascular disease in Alzheimer’s disease. The group suggested that the apolipoprotein e4 allele may contribute more to the formation (or decreased resorption) of senile plaques, the defining lesions in Alzheimer’s disease, than to the formation of neurofibrillary tangles. The authors also suggested that amyloid angiopathy may be a more central feature of a form of familial Alzheimer’s disease associated with the apolipoprotein e4 allele. The predicative effect of possessing the allele has received attention. In a Dutch male population, it was well charted in a 3-year prospective study [10**]. A random sample of normal elderly men (n = 538, aged 65-84 years) was examined. The rate of cognitive decline was greatest for men who were homozygous for e4 and intermediate for heterozygous patients. Using odds ratio statistic to calculate attributable risk, 22% of the risk of developing impaired cognitive function was attributed to the e4 allele, predicting that elderly men with this allele are at twice the risk of developing cognitive impairment. In another prospective study, apolipoprotein E4 status was the strongest predictors of the development of Alzheimer’s disease [11].

13

Clinical studies Noncognitive features Noncognitive features of dementia (that is, psychiartic symptoms and behavioural disturbances) continue to be the focus of research with increasing recognition that neuropsychological impairment is only one part of the clinical spectrum and even the early manifestations of Alzheimer’s disease are often noncognitive [12]. One of the most common psychiatric associations of Alzheimer’s disease is depression and the estimated prevalence varies from 0 to 86% [13]. The variation presumably reflects different methods of measurement, different sample selection and, perhaps, stage of illness. Establishing depression in dementia is problematic [14]; the measures used need to be designed for specialist use in dementia, such as the Cornell Scale for Depression in Dementia (CSDD). Vida et al. [15] found that a cutoff of seven points on the CSDD had a sensitivity of 0.9 and a specificity of 0.75 for depressive illness (using Research Diagnostic Criteria for depressive illness as the gold standard). The under-reporting of depressin will clearly affect prevalence rates [16] and carer-based assessments, such as those used in the CSDD, may be more sensitive. The finding that care givers can reliably act as surrogate reporters for depression in Alzheimer’s disease [17**] may be of practical help in the detection of depression in dementia. In this study [17**] of 76 patients with Alzheimer’s disease, the carers completed measures of depression on behalf of the patients. The surrogate assessments included a modified Beck Depression Inventory, the Geriatric Depression Scale and the Centre for Epidemiological Studies Depression Scale. The interview depression measures included the Hamilton Depression Rating Scale and the CSDD. The CSDD was found to be the most sensitive measure of depression and the Hamilton Depression Rating Scale the least. The authors concluded that care givers were able to act reliably as surrogate reporters for depression in Alzheimer’s disease. The wide range in quoted prevalence of depression in Alzheimer’s disease was discussed by Weiner et al. [18*] who examined two cohorts of patients with Alzheimer’s disease. The authors found a low prevalence and incidence (1.5% prevalence and no incident patients in one cohort and a 1.3% incidence over 2 years in the other). This suggests that established Alzheimer’s disease did not predispose to depressive illness, at least as defined in DSM-III-R, and major depression may herals the onset of 14

dementia. Migliorelli et al. [19*] differentiated dysthymia from major depression and found 28% prevalence for dysthymia for major depression. (Women were over-represented in both groups). Dysthymia was associated with the early stages of dementia and with low scores of anosagnosia compared with the group with major depression. In contrast, patients with major depression had an early onset of depression often before the diagnosis of dementia and its prevalence was similar across progressing stages of the illness. Major depression was not associated with anosagnosia and the authors postulated that, compared with dysthymia, major depression was less related to emotional factors. In another study of depression in Alzheimer’s disease, albeit with small numbers [20*], no difference was found in depression between two groups with and without anosagnosia.

Neuropsychology The differentiation of depression and dementia is a common clinical problem and Lacher and Engel [21], in a meta-analysis of 16 publications, found that a delayed retrieval memory task with distraction gave the best discrimination. In a study of major depression [22], with an average of 59 years and severity of 30 on the Hamilton Depression Rating Scale, the authors were unable to recommend clinical neuropsychology tests that could differentiate depression from early Alzheimer’s disease, despite the fact that the two groups posed no particular diagnostic difficulty. The differentiation of depression from early Alzheimer’s disease by neuropsychology is probably more difficult than previous research suggests.

Extrapyramidal signs These are a recognized feature of Alzheimer’s disease [23]. Investigators have estimated their prevalence at 56% they were identified as parkinsonism in 23% [24**]. Alzheimer’s disease with extrapyramidal signs has distinguishing clinical features characterized by a greater rate of cognitive decline [25], depression [24**] and deficits in executive function [24**, 26]. Patients extrapyramidal signs deteriorate by an additional 1.3 points on the Mini-Mental State Examination every 6 months [25]. Higher education, younger age and agitation are also risk factors for more rapid decline in Alzheimer’s disease [27]. Merello et al. [24**] found depression to be associated with extrapyramidal signs, in terms of both diagnosed depression (DSM-III-R) and severity, using the Hamilton Depression Rating Scale. In the depressed group, the accompanying neuropsychological impairments

15

were predominantly frontal with deficits measured on tests such as verbal fluency, Wisconsin card sort test and abstraction.

Neuroimaging Magnetic resonance imaging has focused on temporal lobe structures in the radiological diagnosis of Alzheimer’s disease. The appearance of medialtemporal lobe atrophy has been used to differentiate Alzheimer’s disease reliably from depressive illness [28*]. Forty-three patients with Alzheimer’s disease were compared with 32 patients with depression using a visual rating of hippocampal atrophy; 89% of patients were correctly diagnosed. Furthermore, the comparison of Alzheimer’s disease with individuals suffering from the dementia syndrome of depression resulted in correct discrimination in 84% of patients. Authors of T1 study [29] of temporal lobe structures concluded that hippocampal and parahippocampal atrophy were more useful than necortical atrophy in the earliest detection of Alzheimer’s disease. The radiological diagnosis of clinical Alzheimer’s disease based on temporal lobe measures appears to be reliable and this has been substantiated by neuropathological studies [30]. Bennett et al. [[31] reported on a number of studies looking at white matter changes found by magnetic resonance imaging in Alzheimer’s disease and Binswanger’s disease. The authors concluded that Binswanger’s disease, compared with Alzheimer’s disease. The radiological diagnosis of clinical Alzheimer’s disease based on temporal lobe measures appears to be reliable and this has been substantiated by neuropathological studies [30]. Bennett et al. [31] reported on a number of studies looking at white matter changes found by magnetic resonance imaging in Alzheimer’s disease and Binswanger’s disease, compared with Alzheimer’s disease, was associated with episodic memory defects, more depressive features, gait disturbance and more variable cognitive decline. In Alzheimer’s disease, some of the white matter lesions were associated with incontinence and gait disturbance but did not contribute to the severity of dementia. In a single photon emission computerized tomography study of delusions in Alzheimer’s disease, decreased regional cerebral blood flow bilaterally in the temporal lobes characterized the psychotic group but they had no differentiating neuropsychological profile [32]. Anosagnosia in Alzheimer’s disease has been studied because of its possible relation to depression. 16

However, in one study [20*], although anosagnosia was not associated with depression, it did correlate with blood flow deficits in the frontal inferior and superior (dorsal) areas in the right hemisphere. This region of interest was not found to be associated with any particular neuropsychological profile.

Conclusion Progress in the field of Alzheimer’s disease has been rapid over the past 12 months, the most dramatic findings being genetic. Further research into the S182 gene will follow the directions taken after the discovery of the first beta-amyloid precursor protein mutation on chromosome 21. More useful treatment may follow from a better understanding of the influence of susceptibility genes on the pathogenesis of Alzheimer’s disease. Noncognitive complications continue to be of prime interest and a number of significant contributions have been made to understanding depression. Extrapyramidal signs appear to be an important accompaniment of Alzheimer’s disease in terms of predictors of cognitive decline. Currently, the benefits of cognitive enhancing drugs are modest but further trials are being evaluated.

Treatment Until recently, nothing seemed to slow the inexorable mental decline of people with Alzheimer's disease. Until recently, nothing seemed to slow the inexorable mental decline of people with Alzheimer's disease. But recently, as researchers have learned more about the development of Alzheimer's, several promising treatments have been identified, two have been approved, and many more are in development. Treatment of Alzheimer's disease is still in its infancy, and experts are quick to concede that they have a long way to go. But today, for the first time, researchers have become cautiously optimistic that in the not-too-distant future, new treatments should be able to delay the onset Alzheimer's disease, and slow the mental deterioration it causes. Many predict that within the next decade or so, it will become a reasonably manageable chronic illness, rather like diabetes or asthma.

17

2-

"Safe" Doesn't Always Mean Safe When the FDA approves a drug as "safe and effective," it does so based on data obtained from clinical trials involving several thousand individuals. Trials involving a few thousand people are a good way to pick up common side effects, the kind that happen to, say, one user in 10, or 20, or 100. But many drugs have side effects -- some potentially quite serious -- that occur much less frequently. If a side effect happens to one user in 10,000 or 50,000, it may not turn up at all during the drug's clinical trials. It may take several years after the drug has been approved for researchers to realize that the drug has additional rare side effects. All drug use should be monitored closely. But the newer the drug, the closer this surveillance should be because chances are that one or more side effects remain to be discovered. 3-

Drug Slows Alzheimer's Decline June 5, 1998 Evidence is mounting that the new Alzheimer's drug, metrifonate, stems mental decline in those with mild to moderate Alzheimer's disease, a new study shows. In a 26-week study, researchers at the Washington University School of Medicine in St. Louis gave 334 Alzheimer's sufferers either metrifonate or a placebo. Comparing the groups' cognitive abilities, daily function, and behavior, those who took the drug remained stable during the study's 6 months, while those taking the placebo declined, said researcher John C. Morris. Metrifonate also helped control the hallucinations and agitation many people with Alzheimer's experience. Metrifonate, from Bayer Pharmaceutical Division, is not yet approved as an

18

Alzheimer's treatment, but the company has filed an approval petition with the Food and Drug Administration based on previous studies that showed a similar slowing of mental decline. Previous studies have also shown that metrifonate helps control the behavior problems associated with Alzheimer's.

Source: Neurology (1998) 50:1222-1230

4Who Chooses Alzheimer's Drugs? Those in the Earliest Stages September 8, 1998 The drug, donepezil (Aricept), and vitamin E both do a fairly good job of slowing the progression of Alzheimer's disease. Some people with Alzheimer's and their caregivers are eager to use them. Others are not. Paul Kettl, M.D., acting chair of psychiatry at Penn State University surveyed 60 people with Alzheimer's admitted to Hershey Medical Center about their use of these treatments. He found that 28 took the drugs while 32 did not. There were no differences in decision-making based on the affected individual's age or sex. The only thing that mattered was how far the disease had progressed. People in the earliest stages of Alzheimer's were much more likely to be treated than those with more advanced disease. In the early stages of Alzheimer's, affected individuals almost always live at home or with a caregiver. Treatment helps preserve their remaining cognitive function and makes life easier for their caregivers. But once people with Alzheimer's have more advanced disease, they have less cognitive function left to preserve and are more likely to live in residential care. The benefits of treatment decline, and they are less likely to be treated.

19

Source: American Journal of Alzheimer's Disease

5Newly Discovered "Parent" Brain Cells Raise Hope for Alzheimer's Treatment March 24, 1999 Swedish scientists have discovered the "parent" brain cells that give rise to all other brain cells. These "neural stem cells" hold tremendous interest for researchers because, if they could be manipulated, it's possible that they might be used to repair a broad range of neurological conditions, among them: Parkinson's disease, spinal cord injuries, and Alzheimer's. The Swedish biologists at the Karolinska Institute in Stocholm worked with rat brains. But now that the hiding place for neural stem cells has been discovered in a lower mammal, researchers voice confidence that they can be found in the same place in humans, or close by. Until recently, researchers believed that the brain did not add new cells after becoming mature, and therefore, had no stem cells. But in the last few years, studies have shown that the brain is much less static. Brain cells can be coaxed into dividing, and even changing into different types of brain cells. These findings strongly implied that the brain must have parent stem cells. The Swedish team is the first to find them. The scientists hope to develop methods to develop the stem cells into mature cells that can replace damaged cells in the brain. If this works, it would be possible in the future to reseed damaged brains with cells from the person's own brain, thus eliminating all transplant-rejection problems.

Source: New York Times

20

Treatment A New Alzheimer's Drug Shows Promise for Tasks of Daily Living May 16, 1999 A new Alzheimer's medication appears to outperform the two currently approved medications in supporting patients' ability to perform routine tasks of daily living, according to a new report. The drug, eptastigmine, was recently tested by researchers with the company that makes it, Mediolanum Farmaceutici, of Milan, Italy. Eptastigmine was given to 491 people with Alzheimer's for 24 weeks through study centers in Europe and the United States. All of them met standard diagnostic criteria for "probable Alzheimer's disease." Eptastigmine slowed cognitive deterioration about as well as the two approved drugs, tacrine (Cognex) and donepezil (Aricept). But eptastigmine showed greater benefit than the other two drugs in helping people with Alzheimer's maintain their ability to perform tasks of daily living: dressing, washing, eating, etc. It's not yet clear why eptastigmine preserves these abilities, and the study must be replicated by independent researchers before it can be considered valid. Nonetheless, if this report is correct, eptastigmine could prove a valuable addition to current drugs.

Source: Lancet, Oct 24, 1998; 352:1347.

Antioxidants We humans need oxygen to live, but oxygen also has a downside. In the body, some oxygen molecules become so highly chemically reactive that they disrupt other body processes. These troublemaker molecules are called "free radicals," and many scientists believe that the damage they inflict (oxidative damage) is at the root of both cancer and heart disease. (Smoking and a high-fat diet greatly increase the number of free radicals in the blood.) Free radicals also contribute to the development of Alzheimer's disease. The destructive action of free radicals fits neatly with two other risk factors for 21

Alzheimer's -- one form of the gene for apolipoprotein E (ApoE4) and betaamyloid. The ApoE gene controls synthesis of apolipoprotein, which transports cholesterol in the blood. People with two copies of the ApoE4 variety of this gene have higher concentrations of low-density lipoprotein, (LDL, so-called "bad cholesterol" because it increases risk of heart attack). High LDL levels have also been linked to Alzheimer's risk. In addition, high LDL levels also seem to favor deposition of beta-amyloid, the major component of the senile plaques characteristic of Alzheimer's. Beta-amyloid appears to react with the cells that line blood vessels in the brain to produce excessive quantities of free radicals, which damage brain tissue even more. Brain tissue is highly susceptible to free radical damage because, unlike many other tissues, it does not contain significant amounts of protective antioxidant compounds. (Lancet, 349:1189, 4-26-97) Fortunately, certain nutrients -- antioxidants -- can prevent the oxidative damage free radicals cause. Antioxidant nutrients include:vitamin A, vitamin C, vitamin E, the mineral selenium, and vitamin A's close chemical relatives, the carotenoids, among them beta-carotene. These nutrients are abundant in plant foods, and many studies show that as fruit and vegetable consumption increases, risk of cancer decreases. A few studies have investigated the effects of antioxidants on Alzheimer's disease. Results to date have been intriguing: • Czech researchers gave the antioxidant drug selegiline to 173 people with mild to moderate Alzheimer's disease. After six months, their memory improved significantly. • In another study, selegiline enhanced the benefits of tacrine (Cognex), one of the two drugs currently approved for Alzheimer's treatment.

Estrogen Compared with men, women are at greater risk of developing Alzheimer's disease. But recent studies show that they also have a treatment option unavailable to most men -- the female sex hormone estrogen, which helps prevent, delay, and treat Alzheimer's disease. Several studies show that women who take estrogen after menopause have an unexpectedly low incidence of Alzheimer's disease. Among women with Alzheimer's, those taking estrogen suffer less severe symptoms and slower

22

mental deterioration. In addition, animal studies show that estrogen improves blood circulation through the brain, and stimulates nerve cell growth in areas of the brain affected by Alzheimer's. These findings are summarized in a report published in the July 1996 Journal of the American Geriatric Society by Stanley Birge, M.D., a geriatrician at the Washington University School of Medicine in St. Louis. Birge calls these estrogen findings "terribly exciting" and potentially "among the most promising recent discoveries about treating Alzheimer's." Estrogen boosts the production of acetylcholine, a key chemical (neurotransmitter) involved in the transmission of nerve impulses across the tiny gaps between nerve cells (synapses). Estrogen also impedes the deposition of beta-amyloid, the protein involved in the characteristic plaques of Alzheimer's disease. In addition, estrogen improves blood flow through the brain, and enhances verbal abilities of postmenopausal women who take hormone replacement therapy. Estrogen also helps maintain the integrity of the hippocampus, a structure in the brain involved in memory. (Kawas, C. et al. "Treating Alzheimer's Disease: Today and Tomorrow," Patient Care, Nov. 15, 1996, 62-83.) Several lines of evidence show that estrogen helps both prevent and treat Alzheimer's disease: • Several epidemiological studies show that taking estrogen reduces women's risk of Alzheimer's disease. (Paganini-Hill, A. et al. " Estrogen Deficiency and Risk of Alzheimer's Disease," American Journal of Epidemiology (1994) 140:256.) Notably, New York City researchers investigated Alzheimer's risk among 1,124 elderly women. During the follow-up period, the disease developed in 14.9 percent of them. Among women who had never used estrogen, the figure was 16.3 percent, while only 5.8 percent of estrogen users developed Alzheimer's. Among estrogen users, risk decreased with hormone use longer than one year. (Tang, MX et al. "Effect of Estrogen During Menopause on Risk and Age at Onset of Alzheimer's Disease," Lancet (1996) 348:429.) • In a 30-week study of 318 women with mild to moderate Alzheimer's disease, all participants took tacrine (Cognex), one of only two drugs currently approved to treat the disease, and some also took estrogen

23

replacement therapy. Compared with those on tacrine only, the women taking tacrine plus estrogen fared better on a number of cognitive measures. (Schneider, LS et al. "Effects of Estrogen Replacement Therapy on Response to Tacrine in Patients with Alzheimer's Disease," Neurology (1996) 46:1580.) • In an eight-week study of 12 Tacoma, Washington, women with mild to moderate Alzheimer's, all the women received skin patches -- half that released estrogen into the blood, and that contained a placebo. "The estrogen had a rapid effect," said Sanjay Asthana, M.D., who presented the results at a meeting of the Society for Neuroscience. "Within a week, the women on estrogen showed improvement." By the end of the study, the estrogen users' cognitive test scores had almost doubled. The more estrogen the women absorbed, the greater their mental improvement. (New York Times, Nov. 21, 1996) • Finally, as part of the 38-year Baltimore Longitudinal Study of Aging, researchers from the National Institute on Aging assessed 16 year's worth of medical records for 514 postmenopausal women. They found that compared with women who had never taken estrogen, those who had were 54 percent less likely to develop Alzheimer's disease. (Stephenson, J. "More Evidence Links NSAID, Estrogen Use with Reduced Alzheimer's Risk," Journal of the American Medical Association (May 8, 1996) 275:1389.) In addition to helping prevent and treat Alzheimer's disease, a great deal of research shows that the sex hormone also helps prevent heart disease, women's leading cause of death, and osteoporosis, bone-thinning that can lead to serious fractures. But for all its benefits, estrogen also carries some risks. It increases breast cancer risk an estimated 20 to 30 percent, and also increases uterine cancer risk if the woman takes it without another sex hormone, progesterone.

Cholinesterase Inhibitors Most people think of the nervous system as the body's electrical wiring. This is correct -- but only up to a point. Nerve cells transmit impulses much like wires transmit electricity. But unlike wires, which are continuous filaments, nerve fibers are discontinuous. Nerve cells do not touch one another. They have microscopic gaps between them called synapses. Nerve impulses must

24

jump these gaps to proceed on their way. They do it with the help of special chemicals called neurotransmitters. As a nerve impulse passes through a nerve cell, it activates the release of neurotransmitters into the cell's synapses, allowing the impulse to jump the gap, and proceed on its way. Once the impulse crosses the synapse, special enzymes eliminate the neurotransmitter, leaving the cell and synapse ready to react to the next impulse. One important neurotransmitter is acetylcholine (a-SEE-tull-KOHleen). During the late 1970s, researchers discovered that people with Alzheimer's disease suffer a loss of acetylcholine from their synapses. This observation fueled theories that Alzheimer's might disrupt the synthesis of acetylcholine, or that the disease triggers overproduction of the enzyme that eliminates it, acetylcholinesterase -- generally known as cholinesterase. Scientists speculated that drugs that either increased acetylcholine or inhibited cholinesterase might help treat Alzheimer's disease. Cholinesterase inhibition has yielded the most promising results so far. The two drugs currently approved for treatment of Alzheimer's -- tacrine (Cognex) and donepezil (Aricept) -- are both cholinesterase inhibitors. They do not cure Alzheimer's disease, but when they work, they slow its cognitive decline. Several additional cholinesterase inhibitors are also being developed, and a few, for example, Promem (metrifonate from Bayer Corporation Pharmaceutical Division), are close to Food and Drug Administration (FDA) approval. (Bayer Corporation Pharmaceutical Division is the provider of an unrestricted educational grant to Alzheimers.com). • Promem (metrifonate from Bayer Corporation). ProMem is currently under review by the FDA for the treatment of mild to moderate Alzheimer's disease. In addition to improving cognition and the performance of activities of daily living, clinical trials have shown that it also helps minimize the disruptive behavior common among Alzheimer's sufferers. In a six-month study by researchers at the University of California, at Los Angeles, Alzheimer's Disease Center, 408 people with mild-tomoderate Alzheimer's were given either a placebo or metrifonate (30 to 60 mg once a day based on their weight). Cognition tests showed

25

that those taking the drug improved significantly. In addition, they also experienced significantly fewer typical Alzheimer's psychiatric and behavior problems, notably less depression, lethargy, and apathy, and fewer hallucinations. Researchers at the Washington University School of Medicine in St. Louis confirmed those results in a six-month study involving 334 Alzheimer's sufferers who took either metrifonate or a placebo. In the placebo group, cognitive function declined significantly, but among those taking metrifonate, it remained stable. In addition, metrifonate users suffered less agitation and few hallucinations. Metrifonate is given once a day. Common side effects include: nausea, diarrhea, and leg cramps. Bayer petitioned the FDA to approve metrifonate in 1997. The application is still pending. • Tacrine (Cognex, from Parke-Davis). Tacrine is one of only two drugs currently approved for treatment of Alzheimer's disease. The FDA approved it largely because a 30-week study showed that high doses improve cognition in people with mild to moderate Alzheimer's disease (Knapp, MJ et al. "A 30-Week Randomized Controlled Trial of High-Dose Tacrine in Patients with Alzheimer's Disease," Journal of the American Medical Association. (1994) 271:985). It has also shown some benefit for those with advanced Alzheimer's. But since its approval, clinical experience has been disappointing. Depending on the study, tacrine helps only 20 to 40 percent of those who take it (Kawas, C. et al. "Treating Alzheimer's Disease: Today and Tomorrow," Patient Care, Nov. 15, 1996, 62-83.) At this point, doctors cannot predict who will respond to tacrine, to what extent, and for how long. Tacrine may help somewhat, but only for a minority of people with Alzheimer's diseases. People taking tacrine typically start with 40 milligrams per day (md/d), with dosage rising incrementally at six-week intervals to 80, 120, and 160 mg/d. However, some clinicians say the dose can be

26

increased more rapidly. Tacrine has significant side effects, including nausea and vomiting. But the one that has caused the most concern is the possibility of liver damage. Tacrine substantially increases levels of the liver enzyme, alanine transaminase (ALT) -- to three to five times normal levels. The rise in ALT typically begins about six weeks into treatment. The long-term effects of high ALT levels remain unclear, but doctors prescribing tacrine generally advise blood tests to assess ALT level every two weeks, with a reduction in dose if levels rise beyond about five times normal. The person with Alzheimer's may resist the periodic blood tests that the use of the drug requires. Finally, the cost of tacrine is an issue. The drug costs about $125 a month. However, a recent study by the San Francisco-based Technology Assessment Group (TAG) shows that despite its limited effectiveness, tacrine is cost-effective for those who respond to it. TAG estimated that the lifetime cost of tacrine plus medical monitoring of its use would be around $2,600. However, the drug is estimated to save an estimated $9,300 in lifetime medical costs ($114,500 with tacrine, $123,800 without it). Finally, to the extent that a good response to tacrine keeps people functional longer, it also shortens nursing home stays. Without tacrine, the typical Alzheimer's sufferer spends 2.7 years in a nursing home; with it, 1.5. Tacrine may be cost-effective for the minority of people who respond to it, but because of its limited effectiveness and side effects, the enthusiasm that greeted its approval has cooled considerably. • Donepezil (Aricept, from Pfiser-Eisai). The FDA approved this cholinesterase inhibitor in November 1996, based in part on a study reported at the spring 1996 meeting of the American Academy of Neurology in San Francisco. In the 24-week study, 450 Alzheimer's sufferers were divided into two groups. One received a placebo; the other either 5 or 10 mg/d of donepezil. Compared with the placebo group, those taking donepezil showed significant improvement in cognitive skills and dailfunctioning.

27

Donepezil is better targeted than tacrine. It affects only acetylcholine in the brain, preventing its breakdown, while tacrine affects related compounds throughout the body, according to Dr. Sharon Rogers, research chief at the drug's manufacturer, Easai America. Donepezil's more targeted action means fewer side effects. Like tacrine, donepezil possible side effects include: nausea, vomiting, and diarrhea. But unlike tacrine, donepezil does not cause liver enzyme abnormalities. Users need not have regular liver-function tests. In addition, donepezil is taken only once a day. Tacrine must be taken four times a day. Like tacrine, donepezil does not work for everyone who uses it. As of February 1997, the response rate remains unclear. • ENA-713 (from Sandoz). A study of this cholinesterase inhibitor was presented at the Fifth International Conference of Alzheimer's Disease and Related Disorders in Osaka, Japan, in July 1996. The six-month trial involved 699 people with Alzheimer's, half of whom took the drug and half a placebo. Those on ENA-713 showed significant cognitive improvement. Side effects included: nausea, vomiting, diarrhea, and loss of appetite, but no liver-enzyme abnormalities. • Other cholinesterase inhibitors in development include: physostigmine SR (from Forest), NXX-066 (from Astra Arcus), and galanthamine (from Janssen). • Meanwhile, drugs that boost levels of acetylcholine are also in development, among them: xanomeline (from Eli Lilly), milameline (from Parke-Davis), SB-202026 (from SmithKline Beecham), AF102B (from Snow Brand Products), and ABT-418 (from Abbott).

Other Treatments WARNING: These treatments have not been approved by the U.S. Food and Drug Administration (FDA), and have not undergone FDA-approved double-blind studies.

28

Ginkgo Ginkgo (Ginkgo biloba), a living relic of the Dinosaur Age, is the oldest surviving species of tree on Earth. Poetically, it helps the oldest surviving people. An extract of ginkgo leaves helps prevent and treat many conditions associated with aging: stroke, heart disease, impotence, deafness, blindness, and memory loss. Recent studies show it also helps treat Alzheimer's disease. Available over-the-counter at health food stores, ginkgo is only starting to catch on in the U.S., and is not well-known among American physicians. But in Europe, where most of the research has taken place, ginkgo is widely prescribed for the elderly, accounting for sales of more than $500 million a year. Medical interest in ginkgo stems from the herb's ability to interfere with the action of a substance the body produces called platelet activation factor (PAF). Discovered in 1972, PAF is involved in an enormous number of biological processes. By inhibiting PAF, ginkgo has been shown to have enormous medical potential, particularly in conditions associated with aging. Unless otherwise noted, the information in this section comes from two European collections of ginkgo studies: Ginkgo Biloba Extract: Pharmacological Activities and Clinical Applications (Elsevier, Paris, 1991), and Rokan Ginkgo Biloba: Recent Results in Pharmacology and Clinic (Springer-Verlag, Berlin, 1988). Cerebral insufficiency/Memory. Whether or not people develop Alzheimer's disease, with age, blood circulation through the brain declines. When this becomes significant, the condition is known as cerebral insufficiency. It causes memory lapses, problem-solving difficulties, and other cognitive deficits, but does not progress to dementia. Dozens of European studies demonstrate that ginkgo extract helps restore blood flow through the brain and reverse cerebral insufficiency. In one 12-week, double-blind 1994 trial, conducted by researchers at the Humbloldt University of Berlin, German, 90 elderly people, average age 63, who had been referred by neurologists for cerebral insufficiency, were divided into two groups. One took a placebo, the other, a standardized gingko extract (50 mg three times a day). After three months, the placebo 29

takers showed only minor cognitive improvement, but those taking ginkgo showed significantly improved memory, concentration, and reaction time. The ginkgo extract caused no side effects. (Vesper, J. and KD Hansgen. "Efficacy of Ginkgo Biloba in 90 Outpatients with Cerebral Insufficiency," Phytomedicine (1994) 1:9.) Gingko improves memory not only in elderly with cerebral insufficiency, but also in younger people with normal brain function. British researchers at the University of Leeds gave memory tests to eight women (average age 32), and then gave them a variety of medications -- a placebo, and ginkgo extract in doses of 120 mg, 240 mg, and 600 mg. The placebo produced no improvement in memory, but the ginkgo did, with increasing doses showing increasing benefits. The women's memory improved "very significantly" after taking the 600 mg dose. Alzheimer's disease. In a 1996 study, German researchers recruited 156 people with either Alzheimer's disease or multi-infarct dementia, and gave half of them a placebo, and half a standardized ginkgo extract (120 mg twice a day). After 24 weeks, compared with the placebo group, those taking ginkgo showed significant improvement in cognitive function, as measured by a variety of standardized tests. About 6 percent of the ginkgo users reported minor side effects: allergic skin reactions, headache, and stomach upset (Kanowski. S. et al. "Proof of Efficacy of Ginkgo biloba Special Extract EGb 761 in Outpatients Suffering from Mild to Moderate Degenerative Dementia of the Alzheimer Type or Multi-Infarct Dementia," Pharmacopsychiatry (1996) 29:47.) In a report released in 1994, the German equivalent of the Food and Drug Administration endorsed ginkgo for early-stage dementias. Other uses. European physicians also prescribe ginkgo for: • Stroke recovery because it improves blood flow through the brain. • Coronary artery disease. This is the cause of heart attack. It involves the progressive narrowing of the arteries that nourish the heart. Gingko helps prevent arterial narrowing. • Intermittent claudication, similar narrowing of the arteries in the legs.

30

• Erection impairment caused by lack to blood flow to the penis. Two studies have shown "significant improvement" in erection capacity with ginkgo treatment. • Macular degeneration, deterioration of the retina, the nerve-rich area in the eye necessary for sight. A year-long double-blind study of 36 intermittent claudication sufferers showed ginkgo produced "significantly greater pain relief [than standard treatment]." • Cochlear deafness, hearing loss resulting from decreased blood flow to the nerves involved in hearing. A double-blind study comparing ginkgo to standard therapy showed "significant recovery in both groups, but distinctly better improvement in the ginkgo group." • Chronic ringing in the ears (tinnitus). A 13-month double-blind study of 103 chronic tinnitus sufferers showed ginkgo "conclusively effective." Ginkgo "improved all the patients" taking the herb. • Chronic dizziness (vertigo). Seventy people with chronic vertigo were treated for three months with either ginkgo extract or a placebo. At the conclusion of the trial, 18 percent of the placebo-takers no longer felt dizzy, compared with 47 percent of those who took ginkgo, a highly significant difference. Because ginkgo is not well-known among U.S. physicians, few recommend it. However, if you'd like to use it, or give it to a loved one, ginkgo extract is available at most health food stores and supplement shops. The medicinal chemicals in ginkgo leaves are too dilute to have any effect, so standardized extracts concentrate them by processing 50 pounds of leaves into 1 pound of extract -- a 50:1 extract. For dosage, follow package directions. Cognitive improvement may takes several months to become noticeable. Ginkgo side effects, if any, are typically minor -- stomach upset, headache, allergic skin reactions. If any develop, reduce the dose, or stop using ginkgo. Acetyl-L-Carnitine Alzheimer's disease is associated with decreased levels of the neurotransmitter, ac, in the brain. A key ingredient of acetylcholine is the amino acid, choline. But for reasons that remain unclear, choline

31

supplementation has little effect on Alzheimer's progression. However, another combination of amino acids, acetyl-L-carnitine, or carnitine for short, has shown some promise. Carnitine is a nutrient composed of two amino acids, lysine and methionine. Two studies have shown that carnitine slows cognitive deterioration in people with Alzheimer's disease. In a 1991 Italian study, researchers divided 130 people with Alzheimer's into two groups. One group took a placebo, the other, a daily dose of 2,000 mg of carnitine. After one year, both groups showed cognitive deterioration, but those taking carnitine showed significantly less decline in memory, logic, verbal skills, and attention to tasks. (Spagnoli, A. et al. "Long-Term AcetylL-Choline Treatment in Alzheimer's Disease," Neurology (1991) 41:1726) In 1992, Mary Sano, Ph.D., of the Neurological Institute in New York City, treated 30 people with mild to moderate Alzheimer's disease with either a placebo or acetyl-L-carnitine (2.5 g per day for three months, then 3 g/day for three months). At six months, compared with the placebo-takers, the carnitine group showed significantly less cognitive deterioration. (Sano, M. et al. "A Double-Blind Parallel Design Pilot Study of Acetyl-Levocarnitine in Patients with Alzheimer's Disease," Archives of Neurology (1992) 49:1137.) More recently, in a 1995 study, University of Pittsburgh researchers divided 12 Alzheimer's sufferers into two groups. Five received a placebo, while seven took 3,000 mg of carnitine daily for one year. Compared with the placebo group, those taking carnitine showed significantly less mental deterioration based on the Mini-Mental Status test and the Alzheimer's Disease Assessment Scale. (Pettegrew, JW, et al. "Clinical and Neurochemical Effects of Acetyl-L-Carnitine in Alzheimer's Disease," Neurobiology of Aging (1995) 16:1.) Ampakines Ampakines are a new class of drugs that improve memory. According to researcher Gary Lynch of the University of California at Irvine, who has studied ampakines since 1991, they increase cortical brain activity. Lynch and Gary Rogers, head of drug development at Cortex 32

Pharmaceuticals in Southern California, have developed an ampakine drug, Ampalex, that increases levels of a specific neurotransmitter in the brain, AMPA-glutamate. In a recent 16-day animal study, animals not taking Ampalex scored 50 percent on a variety of memory tests, while those taking the drug scored 85 percent. So far in humans, Ampalex has been tested in Germany and Sweden on 54 people, age 21 to 73, with normal brain function. Compared with those not taking the drug, those using Amaplex scored twice as well on short-term memory tests. In November, 1996, Cortex contracted with the National Institute on Aging to test Ampalex on a small group of people with Alzheimer's disease. Results are expected in 1998. Calcium Channel Blockers As nerve cells die, they lose the ability to regulate the flow of calcium across their cell membranes. Some researchers speculate that calcium channel blockers, drugs that effect this minerals flow in and out of cells, may prolong nerve cell life. Nerve Growth Factor This hormone stimulates the growth of the nerve cells that release acetylcholine, the neurotransmitter that declines in people with Alzheimer's disease. Some researchers believe that by introducing nerve growth factor -or a similar compound -- into the brains of people with early Alzheimer's, they may be able to slow or reverse cognitive deterioration. Unfortunately, nerve growth factor does not cross the blood-brain barrier, so the hormone cannot be given orally or by injection. Aromatherapy Massage Aromatherapy is an alternative healing art that uses fragrant plant oils (essential oils) to affect the body. Aromatherapy dates back to ancient Egypt, and is used today by real estate agents, who advise home sellers to bake cookies on days the home will be shown to fill the house with an inviting aroma that says "home."

33

Essential oils are small molecules that quickly reach the brain either by inhalation or through skin penetration in massage lotions. Their effects on the body remain largely unexplored, but the few studies that have been performed have documented a clear correlation between certain fragrances and mood enhancement. (Knasko, S. and A. Gilbert. "Emotional State, Physical Well-Being, and Performance in the Presence of Feigned Ambient Odor," J. of Applied Social Psychology, (1990) 20;1345.) In 1988, Megan Carnarius, R.N., a Colorado nursing home nurse who cared for people with Alzheimer's disease, began giving aromatherapy massages to six people with late-stage Alzheimer's who required antipsychotic medication to control their behavior problems. After five weeks of twice weekly, 40-minute massages, none of them needed antipsychotics any longer. In 1989, Carnarius became an Alzheimer's nurse at Manor Care Nursing Home in Boulder, Colorado, and expanded her aromatherapy program. She began using diffusers, special devices that broadcast fragrances, to spread a lemon scent around the Alzheimer's unit each morning. "Lemon is refreshing and helps everyone wake up," she explains. In the afternoon, she diffuses any of several calming oils around the unit -chamomile, germanium, lavender, marjoram, rosemary, or ylang-ylang. She has also recruited students from the nearby Boulder School of Massage Therapy to give people on the Alzheimer's unit aromatherapy massages using the calming essential oils. The aromatherapy program has not been evaluated in a rigorous scientific study, but Manor Care staff generally agree that it has had a significant positive impact on residents with Alzheimer's. Behavior problems have declined, and positive social interactions have increased. Recently, the program has been expanded to the Alzheimer's units of 13 additional Manor Care facilities, which house more than 450 Alzheimer's sufferers. In collaboration with Laraine Kyle, R.N., a founder of the Association for Holistic Aromatherapy, Carnarius has developed an aromatherapy massage kit containing five calming oils and instructions for their use.

34

Aromatherapy massage does not improve memory nor slow cognitive decline, but it improves quality of life for people with Alzheimer's, and as a result, can play a supportive role in treatment. (Flanagan, N. "Essential Oils and Aromatherapy for Alzheimer's Patients," Alternative and Complementary Therapies, Nov.-Dec. 1995, pp. 377-380.) Even without the use of essential oils, massage helps minimize disruptive behavior in people with Alzheimer's disease. In a study in three Alzheimer's care units in British Columbia, 57 people with the disease were divided into two groups. One received two six-minute massages a day for three days; the other did not. Despite the brevity of the massages and the short duration of the study, compared with the control group, the people who received the massages became less disruptive and wandered less. (Woods, DL et al. "Effect of Therapeutic Touch on Disruptive Behaviors of Individuals with Dementia of the Alzheimer's Type," Alternative Therapies, July 1996, 2:4:95.)

Many Caregivers Try Alternative Therapies on Loved Ones With Alzheimer's Fifty-five percent of caregivers give at least one alternative therapy to loved ones with Alzheimer's disease, according to a survey of 101 caregivers by researchers with the Program on Aging at the University of North Carolina School of Medicine. (Coleman, LM et al. "Use of Unproven Therapies by People with Alzheimer's Disease," Journal of the American Geriatric Society Among the various alternative approaches: • 84 percent of caregivers gave vitamins to Alzheimer's sufferers. • 22 percent fed them health foods. • 11 percent tried herbal medicines • 9 percent tried so-called "smart pills," over-the-counter products available at health food stores that claim to aid brain function. • One caregiver in five had tried three or more alternative treatments. Two-thirds of the caregivers, who werecruited from the North Carolina chapters of the Alzheimer's Association, reported that the alternative treatments produced no improvement in their loved ones, while one-third said the unconventional approaches had helped "a little." However, a one-third response rate is what could be expected from treatment with any placebo. These results suggest that the alternative approaches used 35

in this study have no value in treating Alzheimer's disease. But the researchers noted that they were not surprised by the popularity of alternative approaches because conventional medicine currently has so little to offer in the way of Alzheimer's treatment.

IPA CONGRESS: Aricept Effective, Well-Tolerated For LongTerm Alzheimer's Treatment

VANCOUVER, BC -- Aug. 17, 1999 -- Study results evaluating patients with mild to moderately-severe Alzheimer's disease (AD) found that Eisai Co., Ltd.’s and Pfizer Inc.’s once-daily treatment, Aricept(R) (donepezil hydrochloride) had beneficial effects on global and cognitive functioning and activities of daily living over one year. Researchers presented the results of this randomised, double-blind, placebocontrolled trial today at a poster presentation at the ninth congress of the International Psychogeriatric Association. "This is good news for Alzheimer's disease patients and their caregivers world-wide," said Bengt Winblad, M.D., department of clinical neuroscience and family medicine, Karolinska Institute, Sweden. "Aricept offers hope to those looking for well-tolerated and effective, long-term treatment." Patients treated with Aricept showed statistically significant results in global functioning. The Aricept-treated group's mean change from baseline on the Gottfries, Brane and Steen scale (GBS) total score were statistically significantly better at Weeks 24, 36 and 52 compared to the placebo-treated group. Patients treated with Aricept also showed statistically-significant improvement in cognition and activities of daily living compared to placebo. When compared to the placebo-treated group's scores, the Aricept-treated group's average changes from baseline on the Mini-Mental State Examination (MMSE) were statistically significant at Weeks 24, 36 and 52 and Progressive Deterioration Scale (PDS) total scores at Week 52, respectively. This study evaluated the long-term clinical efficacy and tolerability of donepezil versus placebo over one year in patients (average age 72.5 years) with mild to moderately severe Alzheimer's disease (AD). The study recruited 286 patients with possible or probable AD from 28 sites in five Northern European countries (Denmark, Finland, The Netherlands, Norway and Sweden). They were randomised to receive either Aricept or placebo for

36

one year. In this trial, 66.9 percent of Aricept- and 67.4 percent of placebotreated patients completed the one-year study. Only seven percent of Aricept- and 6.3 percent of placebo-treated patients discontinued due to adverse events. Alzheimer's disease is a progressive, degenerative brain disease that results in cognitive decline, impaired memory, thinking, behaviour changes, loss of language, motor skills and activities of daily living (or selfmaintenance skills -- that is, grooming, etc.). Currently, approximately 15 million people suffer from AD world-wide. Aricept is indicated for the symptomatic treatment of mild to moderatelysevere dementia of the Alzheimer's type. Aricept is well-tolerated, with a low incidence of side effects, offers convenient, once-daily dosing and can be taken with or without food. In controlled trials that supported the approval of Aricept, it was found that the drug's most common side effects include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and anorexia. These effects were often mild, transient and resolved with continued treatment. People at risk for ulcers should inform their doctor when taking Aricept. In clinical trials, syncopal episodes have been reported in patients taking Aricept (two percent versus one percent for placebo). Aricept is clinically effective at the starting dose of 5-mg/day and the dose can be escalated to 10-mg/day after four to six weeks if clinically indicated.

IPA MEETING: Aricept Effective In Long-Term Treatment Of Alzheimer's VANCOUVER, BC -- Aug. 18, 1999 -- Cognition and functional abilities of patients with mild to moderate Alzheimer's disease (AD) treated with Aricept (donepezil) are enhanced over an extended period of time compared to patients treated with placebo, according to study results presented for the first time at the ninth International Psychogeriatric Association meeting being held in Vancouver this week. Aricept, the first and only medication approved in Canada for the treatment of mild to moderate AD, was also confirmed as having long-term beneficial effects on patients' activities of daily living over a one-year period. The long-term effects of Aricept were assessed during a 52-week multicentre, double blind, placebo-controlled trial, involving 286 patients with mild to moderate AD in five Northern European countries. These patients were randomly divided to receive once-a-day Aricept or placebo for 37

one year. The Aricept group received 5 mg of Aricept for 28 days followed by 10 mg daily for the remainder of the trial. “This study is unique in that Aricept efficacy and safety were measured against placebo for one year,” said principal investigator Dr. Bengt Winblad, professor, department of neuroscience and family medicine at the Karolinska Institute, Huddinge, Sweden. “These results advance the previously published data supporting the long term benefit of this drug. They confirm that the clinical benefits of Aricept are sustained over time and that treatment is also well tolerated over the long-term.” Key Results: -- The observed improvement over baseline in global function was significant among Aricept-treated patients at weeks 24, 36 and 52 as measured on the Gottfries, Brane and Steen (GBS) scale. -- Statistically significant improvement in cognition over baseline was observed at weeks 24, 36 and 52 weeks in patients receiving Aricept, as measured by the Mini Mental State Evaluation (MMSE) scores. -- After one year, at week 52, Aricept-treated patients showed less decline in activities of daily living (ADL) as measured by the Progressive Deterioration Scale (PDS) scores. “This is certainly more good news for Canadian Alzheimer's disease patients and their caregivers,” said Dr. Sandra Black, head of neurology at Sunnybrook and Women's College Health Sciences Centre of Toronto and an AD investigator. “Alzheimer's disease is not a normal part of ageing. It is a degenerative disease that can be kept in check or delayed for some time,” Dr. Black explained. “To give people the best chance to maintain their current level of activities, treatment should be considered as soon as you think a patient has AD and preferably early in the disease course.” “These results are encouraging to document the effects of Aricept over a longer time period,” said Dr. François Primeau, psychogeriatrician at St. Mary's Hospital, Montreal. “As with diseases like cancer, we can now provide patients and their caregivers with an extended quality of life by delaying or preventing deterioration of their condition. We may not have a cure but we can significantly impact on the cost of care by delaying institutionalisation.”

38

The annual cost of caring for patients with Alzheimer's disease in Canada increases with the severity of the disease. A 1998 study showed that patients in the early to mild stages of AD cost $9,451 CDN to treat and care for on an annual basis. In contrast, the cost to treat and care for patients with severe AD rises four-fold to $36,794 CDN. As a patient's condition deteriorates, institutionalisation becomes the largest cost component accounting for as much as 84 per cent of the cost of care, according to the study. Recently updated Canadian guidelines for the diagnosis and treatment of Alzheimer's disease recommend that a trial course of Aricept be prescribed to informed and willing patients with mild to moderate dementia due to probable AD, whethere is no contraindication.

IPA CONGRESS: Aricept Effective, Well-Tolerated For LongTerm Alzheimer's Treatment

VANCOUVER, BC -- Aug. 17, 1999 -- Study results evaluating patients with mild to moderately-severe Alzheimer's disease (AD) found that Eisai Co., Ltd.’s and Pfizer Inc.’s once-daily treatment, Aricept(R) (donepezil hydrochloride) had beneficial effects on global and cognitive functioning and activities of daily living over one year. Researchers presented the results of this randomised, double-blind, placebocontrolled trial today at a poster presentation at the ninth congress of the International Psychogeriatric Association. "This is good news for Alzheimer's disease patients and their caregivers world-wide," said Bengt Winblad, M.D., department of clinical neuroscience and family medicine, Karolinska Institute, Sweden. "Aricept offers hope to those looking for well-tolerated and effective, long-term treatment." Patients treated with Aricept showed statistically significant results in global functioning. The Aricept-treated group's mean change from baseline on the Gottfries, Brane and Steen scale (GBS) total score were statistically significantly better at Weeks 24, 36 and 52 compared to the placebo-treated group. Patients treated with Aricept also showed statistically-significant improvement in cognition and activities of daily living compared to placebo.

39

When compared to the placebo-treated group's scores, the Aricept-treated group's average changes from baseline on the Mini-Mental State Examination (MMSE) were statistically significant at Weeks 24, 36 and 52 and Progressive Deterioration Scale (PDS) total scores at Week 52, respectively. This study evaluated the long-term clinical efficacy and tolerability of donepezil versus placebo over one year in patients (average age 72.5 years) with mild to moderately severe Alzheimer's disease (AD). The study recruited 286 patients with possible or probable AD from 28 sites in five Northern European countries (Denmark, Finland, The Netherlands, Norway and Sweden). They were randomised to receive either Aricept or placebo for one year. In this trial, 66.9 percent of Aricept- and 67.4 percent of placebotreated patients completed the one-year study. Only seven percent of Aricept- and 6.3 percent of placebo-treated patients discontinued due to adverse events. Alzheimer's disease is a progressive, degenerative brain disease that results in cognitive decline, impaired memory, thinking, behaviour changes, loss of language, motor skills and activities of daily living (or selfmaintenance skills -- that is, grooming, etc.). Currently, approximately 15 million people suffer from AD world-wide. Aricept is indicated for the symptomatic treatment of mild to moderatelysevere dementia of the Alzheimer's type. Aricept is well-tolerated, with a low incidence of side effects, offers convenient, once-daily dosing and can be taken with or without food. In controlled trials that supported the approval of Aricept, it was found that the drug's most common side effects include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and anorexia. These effects were often mild, transient and resolved with continued treatment. People at risk for ulcers should inform their doctor when taking Aricept. In clinical trials, syncopal episodes have been reported in patients taking Aricept (two percent versus one percent for placebo). Aricept is clinically effective at the starting dose of 5-mg/day and the dose can be escalated to 10-mg/day after four to six weeks if clinically indicated.

New Drug Holds Promise For Brain Disease NEW YORK, Aug 24 (Reuters Health) -- A new drug under investigation may one day prevent the death of brain cells due to head injury, Alzheimer's disease, Parkinson's disease, stroke and other neurologic disorders, according to preliminary research presented Tuesday at the annual meeting

40

of the American Chemical Society in New Orleans. Researchers at the Louisiana State University (LSU) Neuroscience Center of Excellence in New Orleans have discovered how to turn off the genetic switch that produces excessive amounts of cyclooxygenase-2 (COX-2), a protein which, in abundance, leads to death or damage in brain cells or neurons. "There is no comparable drug on the market. This is a totally new concept," lead researcher Dr. Nicolas G. Bazan, director of the LSU Neuroscience Center of Excellence, told Reuters Health. "We have found signals within brain cells that result in cell death (and) we have made a chemical that inhibits these signals," he added. "This chemical may become a drug applicable to diseases where injury-like processes take place, producing a damaging protein (that) induces damage and cell death," explained Bazan, an Argentine-born scientist. Basically, injury or disease such as head trauma or stroke triggers a chain reaction that signals the COX-2 gene to produce genetic material, which, in turn, produces an abnormally high amount of the COX-2 protein. "The new drug prevents the production of COX-2 and stops the signaling process before the genes can be overactivated," Bazan explained. But due to the testing required to ensure the drug's safety and effectiveness, it will be several years before the new drug reaches human patients, he noted. "In our experimental models, our drug is very effective in preventing the production of COX-2 and halting the signaling process before the genes can be overactivated," Bazan said. He added that the findings "may be applicable to neurodegenerative diseases such as Alzheimer's, Parkinson's, stroke and age-related macular degeneration" -- an age-related eye disease that is a common cause of blindness. "We are achieving a clearer understanding of the mechanisms underlying the consequences of brain injury. The brain is truly the last frontier of medicine - so complex," Bazan commented. "Yet neuroscience research is moving

41

forward at a rapid pace and, as we approach the new millennium, we are finding new approaches and ultimately cures for diseases, which only a couple of decades ago held no hope for cure," he added. Several new drugs on the market, known as super-aspirins, also target COX2. The drugs work by selectively blocking the COX-2 enzyme, which is thought to play a role in causing arthritis pain.

Alzheimer's Drug Helps Patients Maintain Abilities Longer NEW YORK, Sep 23 (Reuters Health) -- The drug Aricept (donepezil) helps patients with mild-tomoderate Alzheimer's disease maintain their ability to perform basic functions such as dressing and feeding themselves for longer, according to the results of a study. The one-year study -- the longest yet conducted with this drug -- was presented Thursday at the 12th annual European College of Neuropsychopharmacology meeting in London. In the study, 431 patients with mild-to-moderate Alzheimer's disease were randomly assigned to taking daily doses of either the drug or, for comparison purposes, a placebo ("dummy pill"). Investigators found that although the dementia continued to worsen in both groups of patients, patients taking Aricept functioned "highly significantly" better over a longer time than those on placebo. Patients on donepezil maintained functional status about 5 months longer than those on placebo, Pfizer, Inc., of New York and Esai Co, Ltd., announced in a release of the study's findings. "Results of this study confirm that treatment with the medication for up to one year allows patients to maintain their ability to perform activities of daily living such as dressing, eating meals, doing chores, and enjoying hobbies, and therefore helps them maintain their independence," according to a statement issued by the drug companies. Co-investigator Dr. John C. Morris of Washington University School of Medicine in St. Louis told Reuters Health that the findings "are clinically meaningful." He said that patients who took placebo during the study have now been switched to active treatment. A key point in treatment of patients with Alzheimer's might be the stage of disease when treatment begins, Morris said. There may be a point in the diseasat which the drug may no longer be effective. The big area of interest now is starting treatment at an even earlier stage of disease. A number of studies will be investigating that, Morris said. Adverse effects noted in patients taking Aricept included nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and anorexia. Effects were generally mild and transient, the makers say.

New drugs for Alzehimer’s disease Alistria burns, eve russell and sean page British journal of psychiatry (1999), 174, 476-479.

42

Alzheimer’s disease is the most common cause of dementia in older people, affecting up to 10% of the population over the age of 65 years and three times that figure in those over the age of 90 years (Hofman et al, 1991), with a total of about half a million people affected in the UK. The cause of Alzheimer’s disease is essentially unkonwn, there is no cure for the disease, the effect on sufferers and families is devastating in personal and emotional term and the annual cost in nearly 1 billion in the UK (Bosanquet et al, 1998). Based on this background, there should be understandable enthusiasm at the introduction of new drugs for the treatment of the core features of the disease (the cognitive deficits, predominantly memory loss) based on amelioration of the underlying pathophysiology.

Background A new class of agents, the cholinesterase inhibitors (or anticholinesterases because of their inhibiting action on acetylcholines-terase, the enzyme responsible for the breakdown of acetylcholine), is now available for the symptomatic treatment of Alzheimer’s disease. Other agents may influence disease progression, such as vitamin E (e.g. Sano et al, 1997) or are potentially active against both Alzheimer’s disease and vascular dementia (e.g. propentofylline; Rother et al, 1998). The purpose of this article is to review briefly these new drugs and outline the implications for psychiastrists, particularly old age psychiatrists, upon whom the burden of care is predictably falling. The clinical manifestations of dementia are threefold: cognitive impairment, non-cognitive features (psychiatric symptoms and behavioural distrubances), and activities of daily living (ADLs). Measurement of the effect of drugs has to take into account the changes is these domains and their relative importance traditionally has determined which scales are used to assess drug efficacy. It is widely accepted that cognitive impairment is the primary abnormality in dementia but the clinical and practical relevance of a numerical improvement in a memory test has been questioned, leading to the introduction of global assessments, the most commonly used being the clinician’s Interview Based Impression (CIBI), which is a simple sevenpoint scale measure based on the assumption that a clinician can detect change in a patient’s condition (Knopman et al, 1994, Schneider et al, 1997). Specific derivatives aimed at capturing change over time-the Clinicians’s Interview Based Impression of Change (CIBIC; Leber, 1990) and a scale

43

utilizing care-giver information (CIBIC Plus; Leber, 1990)-are now accepted as being an essential component of any drug trail. Non-cognitive features of dementia traditionally were regarded as epiphenomena (i.e. secondary to cognitive deficits), improvement in which would take place as a natural consequence of cognitive deficits and treatment of which was non-specific. For example, a positive effect by a drug being regarded as an antidepressant and not an antidementia drug, even if a positive effect on cognition was demonstrated. Problems in ADL are categorized as basic (e.g. eating, toiletting, washing/dressing) or instrumental (more complex, such as cooking, shopping and handling finances). The Committee for Proprietary Medicinal Products (CPMP, 1997) has produced guidelines recommending that two or three areas of dementia should be assessed to demonstrate efficacy-cognitive function and either a global rating or ADL.

Tetrahydroaminoacridine (Tacrine) Tetrahydroaminoacridine (tacrine) was the first of the new agents to be introduced and was licensed in the USA, Canada and parts of Europe in 1993. It improved cognitive function in up to 30% of people with Alzheimer’s disease tested over a six-month period in doses of up to 160 mg per day. Five crossover trials and five parallel group trials have been published on the efficacy of tacrine (Glennie, 1997) – modest efficacy overall and minor improvement in cognitive function were seen in only three. Preipheral cholinergic side-effects (such as nausea, vomiting and diarrhoea) were seen in one-fifth of patients but liver toxicity was more serious, with 40% of patients having raised hepatic transminase levels (severe in 2%) and necessitating blood monitoring of liver function tests for the first few months of treatment. In view of the high level of side-effects, tacrine cannot be recommended for routine use. The drug was not originally grated a licence in the UK but was approved at the same time as donepezil.

Donepezil hydrochloride The development of a drug with a similar efficacy profile to tacrine but free of side-effects was a waited and donepezil hydrochloride seemed to satisfy this criterion. As a piperidine-based anticholinesterase, is does have the same potential for liver toxicity as the acridine-based compound, tacrine. It was licensed for use in the symptomatic treatment of mild to moderate Alzheimer’s disease in the UK on 17 March 1997. At the time of writing, 44

there have been four published trials of donepezil a Phase II randomized controlled trial (Rogers & Friedhoff, 1996) with an open-label extension (Rogers et al, 1998a,b) – all of which have taken place in the USA. A European and Canadian based multi-country trial has been completed and the results are in the public domain. Donepezil was licensed at a stage when only the Phase II trial had appeared in a peer-reviewed journal, although data on the other trials were made available to the regulatory authorities. All three studies have demonstrated the benefits of denepezil compared to placebo. The Phase II study Rogers & Friedhoff, 1996) included 161 patients with mild to moderately severe Alzheimer’s disease prescribed 1, 3 or 5 mg of active drug or placebo and found a statistically significant improvement in the ADAS-Cog score (cognitive sub-scale of the Alzheimer’s Disease Assessment Scale; Rosen et al, 1984) in patients on 3 and 5 mg compared with placebo. No difference was found with the other measures. Rogers et al (1998a) reported that cognitive function (ADAS-Cog), ADL and global functioning (CIBIC) improved in 473 patients taking 5 or 10 mg compared with placebo, but with no difference between drug doses. The improvement returned to the level of the placebo group after a six-week washout. Rogers et al (1998b) reported a 12-week study on 468 patients and confirmed significant benefit of the drug over placebo; the European and Canadianbased multi-centre trial has produced similar positive results (Burns et al, 1999). Side-effect with donepezil are generally of moderate severity, trnasient and consist of diarrhoea, vomiting, fatigue, muscle cramps and dizziness. They affect less than 10% of people and are higher with the 10% of people and are higher with the 10 mg dose. The magnitude of change (similar all studies) seen with donepezil is an improvement of around three points on active drug compared with placebo on the ADAS-Cog scale, which is highly statistically significant (P<0.0001). to look at it another way, 42% of patients on placebo had worse cognitive function at the end-point compared with 20% on donepezil. An improvement of seven points on the ADAS-Cog scale is regarded as being of clinical significance; on this basis, 8% on placebo, 15% on 5 mg and 25% on 10mg improved. On the CIBIC, 11% improved in the placebo group compared with 25% on 5 mg and 25% on 10mg. The recommended drug dose is to start with 5 mg per day and titrate after a minimum of one month to 10mg. In the UK, the cost of the drug is 68.32 for 28 5 mg tablets and 95.76 for 28 10 mg tablets.

45

Rivastigmine Rivastigmine was licensed on 12 May 1998 in the European Community for the treatment of mild to moderately severe Alzheimer’s disease. Compared with donepezil, there is a larger patient database on which the introduction of the drug was based. A specific programme of studies (the ADENA programme; Anand & Gharabani, 1996; Novartis website (http://www.alzheimer-info.com/exelon), 1998) consisted of four pivotal trials aimed at overcoming the drawbacks of existing studies (i.e. small numbers of patients, short duration of treatment and restrictive entry criteria). Over 2000 patients have been examined with a dose range of 6-12 mg (twice daily administration), previous studies having shown that 4 mg was ineffective. The magnitude of the effect is similar to that seen with donepezil. Specific measures of ADL were included in the trials (the Progressive Deterioration Scale (PDS); de Jong et al, 1989). Compared with placebo, 21v. 12% improved on the CIBIC Plus and 26v. 17% improved on the PDS. Symptoms on rivastigmine included anorexia, nausea, dizziness, vomiting, appetite and weight loss. It is not, like donepezil, contraindicated in asthma. The recommended drug dose is to start at 1.5 mg twice daily with the therapeutic dose between 6 and 12 mg. In the UK, the cost of the drug is 31.50 for 28 tablets regardless of size (1.5, 3, 4.5 or mg), giving a monthly price of 63 for 12 mg per day.

Other drugs A dose-finding study of metrifonate (Morris et al, 1998) demonstrated the efficacy and safety of the drug in patients with Alzheimer’s disease, showing improvements in ADAS-Cog and the CIBIC. Morris et al (1998) description a 26-week double-blind treatment trial followed by an 8-week placebo extension on 408 patients with Alzheimer’s disease, of whom over 80% completed the trial in the active treatment was found in theADAS-Cog on an intention-to-treat basis. In addition, a specific beneficial effect was found in terms of non-cognitive features as measured by the Neuropsychiatric inventory (NPI; Cummings et al, 1994). The beneficial effect of the drug on non-cognitive features of dementia is novel. McKeith (1998) described an international study with 605 patients over 26 weeks in doses of 40-80 mg per day. On an intention-to-treat basis, the drug showed clear benefit over placebo on cognitive performance and global function. There are currently safety concerns about metrifonate.

46

Other anticholinesterase agents are being tested (such as galanthamine and slow-release physotigmine, eptastigmine, ibedenone, zifrosilone and quilostigmine), as are cholinergic muscarinic agonists (e.g. melamiline and xanomeline) and precursor loading agents (acetyl-l-cartinine). Noncholinergic treatments include; propentofylline, an endenozyne reuptake (phospho-diesterase) inhibitor that, it is climed, modulates mechanisms in Alzheimer’s disease and vascular dementia-cell activation, increased production of cytokines, free radicals and glutamate – with benefits seen in 901 patients with Alzheimer’s disease and 359 patients with vascular dementia (Rother et al, 1998); memantine, a modulator of the glutamatergic system that modulates the cytotoxic effects of excitatory amino acids and has been shown to be of benefit in both Alzheimer’s disease an vascular dementia (Gortelmeyer et al, 1993); vitamin E and selegiline (Sano et al, 1997), alone and in combination, which delay the progression of Alzheimer’s disease; Ginkgo biloba (Le Bars et al, 1997), which has been shown to produce benefit in one study; Cox-2 inhibitors (drugs with an antiinflammatory action), which are being tested; and calcium channel blockers (e.g. sabeluzole and nimodipine), which have been used. Qestrogenes also are being tested as potential agents for the prevention of Alzheimer’s disease (Burns & Murphy, 1996).

Managed introduction-clinical guidelines Guidelines have been used to manage the introduction of the new drugs for the treatment of Alzheimer’s disease (e.g. Lovestone et al, 1997). They define diagnostic criteria for Alzheimer’s disease, suggest clinically relevant inclusion and exclusion criteria based broadly, should be agreed locally with general practitioners, pharmacists, local purchasers of health care and specialists in the management of Alzheimer’s disease. Al with many other drugs, there is significant variation between different areas of the country and the implementation of guidelines (Harvey, 1999). Many purchasers of health care remain to be convinced of the usefulness of prescribing these drugs in dementia, and the tone of the two articles in the influential Drugs and Therapeutics Bulletin review of donepenzil reflects this attitude (Anonymous, 1998, 1999). The UK Government’s Standing Medical Advisory Committee (SMAC, 1998) has produced guidelines on the treatment of Alzheimer’s disease and recommends that treatment should be initiated and supervised by a specialist familiar with the management of Alzheimer’s disease and that, generally 47

speaking, the characteristics of patients selected for treatment should be the same as those in drug trials. Treatment should be assessed after 12 weeks and continued only if there is clear evidence of benefit, a judgement informed by the application of recognized objective tests.

Clinical Experience Our clinical experience in south Manchester is that the drugs were introduced without additional funding using a locally agreed protocol formulated by primary care, hospital specialists and pharmacists. The criteria are similar to those described in the SMAC guidelines. Prescribing is initiated by consultants in old age psychiatry in the setting of a specialist multi-disciplinary domiciliary clinic. Treatment is targeted towards patients with mild to moderate Alzheimer’s disease supported by radiological evidence of the absence of vascular disease. Measurements of efficacy in the three domains of cognitive function, ADL and non-cognitive features of Alzheimer’s disease are made before the start of treatment and at threemonthly intervals thereafter. Early experience of donepezil is similar to that of the drug trials in respect of the change in cognitive function, with about half of patients showing improvement at six months and two-thirds of the remainder failing to show the expected deterioration. Of more clinical importance are the striking improvements in non-cognitive features and ADL in some patients. Moreover, their carers describe marked changes to their own quality of life by no longer having to cope, for example, with a spouse or parent hallucinating or wandering at night. Many carers remark that patients appear brighter and more interested in their surroundings. The cost benefit of such changes has been questioned but the benefit to patients and carers is clear to them. As might be expected, when the drug is introduced into clinical practice with patients experiencing medical comorbidity, the adverse effect profile is worse than that seen in the trial data. Our initial protocol titrated all patients on donepezil up to 10 mg after a month and, perhaps as a result of this relatively quick titration (albeit that given in the data sheet), the frequency of adverse effect was high. Patients now receive 5mg and side-effects are usually mild and self-limiting.

48

Rivastigmine has been used less often but, as with donepezil, we have seen striking effects on non-cognitive features. Patients who have failed to tolerate donepezil appear to tolerate rivastigmine at a therapeutic dose and medical comorbidity seems to be less of a problem than with donepezil, particularly in relation to chronic obstructive airways disease and asthma. However, the twice daily dosage is a problem for patients without a carer, with whom we struggle to ensure compliance even on once daily donepezil. Overall, experience of these drugs has been very positive. Sixty-two patients have been started on treatment (3:1 in favour of donepezil) and approximately one-third (for each drug) have stopped treatment because of side-effects, intercurrent illness or lack of benefit. The changes seen in the ratings parallel those reported inclinical trials, although responses vary greatly between patients (Dening & Lawton, 1998). Early and frank discussion at the start of treatment with patients and carers, with an agreed trial of treatment and discussion of the results, has ensured that we have experienced no problems with stopping the drugs if patients are not receiving any benefit from them.

The Future New drugs for Alzheimer’s disease are not cures-their effects are probably best described as modest. However, for the first time, symptomatic improvement in cognitive function in Alzheimer’s disease is possible. Fear of the cost involved was calculated speedily in people’s minds simply by multiplying the numbers of patients with dementia in the UK (800.000) by the cost of the drug per year (1000); this prompted a knee-jerk reaction against these drugs, masquerading as protection of public funds in the face of minimal clinical improvement. More pragmatic trials are needed, emphasized by the recent call for proposals from the Health Technology Assessment programme. The AD2000 trial in the West Midlands is currently underway. In practice, not everyone with dementia has Alzheimer’s disease, not everyone with Alzheimer’s disease has mild to moderate disease and even then not everyone will be suitable. Patients and their families may not even want the drugs. Improvements in patients may cause problems of their own, such as the desire to drive again as a result of improved memory and concentration. All the thoughtful clinical would ask for would be that the medication be available and be introduced in a responsible fashion using agreed clinical guidelines and subject to audit. One would seek parity with the controls and restrictions placed on other newly introduced agents for 49

other conditions. The cost of the drugs may be high, but the human cost of dementia is infinitely higher.

50

MISCELLANEOUS Medical News August 1, 1999

Death Rate Higher for Alzheimer's Patients Living in Nursing Homes A new study concludes that Alzheimer's patients cared for in nursing homes have an increased risk of dying if they are older, male, malnourished, or are physically impaired. Researchers at Brown University in Providence, Rhode Island, examined data on nearly 10,000 Alzheimer's patients in Medicare/ Medicaid-certified nursing homes to reach their conclusions. The study found that roughly half of Alzheimer's patients in nursing homes died within two years of admission -- a rate about twice as high as elderly patients who do not have Alzheimer's. It was further found that being elderly and male increased the risk of death by over 80 percent, impaired basic functions (walking, eating, and self-care) increased the risk of death by 41 percent, and malnutrition increased the risk by 31 percent. Other factors less strongly linked to increased mortality risk in this patient population included: the presence of pressure sores, diabetes, or heart disease. Results of the analysis are reported in the "Journal of Neurology, Neurosurgery and Psychiatry" (1999;67:59-65). © Mediconsult.com 08/01/99

August 1, 1999

Demented Stroke Patients Less Likely to Receive Drug Therapy A recent report suggests that stroke patients with dementia are less likely than other stroke victims to receive standard clot- preventing medications such as aspirin or warfarin. (Note: such drugs can reduce the risk of stroke recurrence.) Researchers at the Columbia University College of Physicians and Surgeons, in New York, studied 272 ischemic stroke victims over the age of 60 to collect data. It was found, overall, that 11 percent of patients did not receive clot- preventing therapy by the time they left the hospital and that demented patients were 2.5-times more likely to not receive the drugs, compared to non-demented patients; about 36 percent of patients not given aspirin or warfarin had dementia, while only 16 percent of patients given the drugs were diagnosed with dementia. Authors note that the lack of anticoagulant therapy was also linked to discharge to a long-term care institution and to difficulty in walking. Reported in the "Journal of the American Geriatrics Society" (1999;47:824-829). © Mediconsult.com 08/01/99

August 1, 1999

Experimental Vaccine Shows Promise for Alzheimer's Victims Researchers have reported promising results from animal trials of an experimental vaccine against Alzheimer's disease. Researchers at Elan Pharmaceuticals, in South San Francisco, California, injected nine genetically engineered mice bred to develop Alzheimer's with a vaccine containing bits of the protein amyloid-beta to collect data. It was found the seven of the nine mice did not develop the amyloid plaques that characterize Alzheimer's and the vaccine appeared to prevent the nerve cell damage and brain inflammation typical of the disease. It was further found that administration of the vaccine appeared to reduce amyloid plaques in mice that had already developed them. Authors note that it is not yet clear exactly how the vaccine works, but speculate that it triggers the immune system to produce antibodies that attack the deposits of amyloid.

51

Officials at Elan Pharmaceuticals say they hope to begin safety tests of the vaccine in humans by the end of 1999. The findings are in the journal "Nature" (1999; 400:173-177). © Mediconsult.com 08/01/99

August 1, 1999

Other Factors May Influence Apo-E4-related Dementia Risk A new study says that the increased risk for Alzheimer's disease associated with the Apo-E4 gene mutation is more pronounced when other factors, such as diabetes, peripheral vascular disease and atherosclerosis are present. Researchers at the University of California School of Medicine, Davis, studied nearly 6,000 healthy people over age 65 during a 5 to 7 year period to collect data. The study found that those people with both atherosclerosis and the Apo-E4 mutation had more than an eight-fold increased risk for a decline in cognitive function, compared to those without the mutation or atherosclerosis. Those participants who carried the Apo-E4 mutation and had diabetes or circulation problems in their hands, feet or legs, had a much higher risk of a decline in memory and mental functioning during the study than those without the gene or these illnesses. Authors note, however, that 70 percent of participants experienced no decline in cognitive function during the study period and say the findings suggest that paying attention to diet and exercising regularly could mitigate many of the possible causes of dementia, even in individuals with the Apo-E4 mutation. The study is in the Journal of the American Medical Association (1999;282:40-45). © Mediconsult.com 08/01/99

July 12, 1999

Remember Your Estrogen A common complaint as we age is a loss of short-term memory. Where did I leave my car keys? Did I lock the front door? Researchers from Yale University recently released study findings indicating that this problem in women may be partially due to a drop in estrogen level, which occurs with menopause. Forty-six women, with an average age of 50, were divided into two groups. One group received estrogen for three weeks and the other a placebo. Then all the women received a functional magnetic resonance imaging (fMRI) test while performing simple verbal and nonverbal memory tasks. After a two-week break to allow the estrogen to dissipate from participants' systems, the groups were switched. After another 21 days of treatment had passed, another fMRI was done. The fMRIs showed that parts of the brain had increased activity in the women who were taking estrogen. The areas of increased activity included sections of the parietal and frontal lobes of the brain. Activity in specific parts of these lobes increased when information (stimuli) was being encoded or processed, when verbal information was being stored, and when information was being recalled. The activity pattern seen during the encoding process was very similar to the pattern seen in younger people. While brain activity increased in women taking estrogen, they didn't actually perform better on tasks. Researchers attributed this to the simplicity of the tasks used and recommended that future studies be done using more complicated tasks. Should further testing confirm the link between estrogen and memory, it would add to the hormone's already impressive list of benefits, which include prevention of osteoporosis, decreased risk of heart disease and colon cancer, and treatment of annoying menopause

52

symptoms like hot flashes and vaginal dryness. Several studies have linked estrogen to the prevention of Alzheimer's disease and to the metabolism of cholesterol in the liver. In addition to its benefits, remember that estrogen taken without progesterone seems to increase the risk of endometrial cancer, and controversy remains over estrogen's role in breast cancer. © Mediconsult.com 7/12/99

July 12, 1999

The Role Amyloids Play in Alzheimer's Disease During the progression of Alzheimer's disease, plaques form in the brain, taking the place of healthy, functional tissue. Researchers from the University of Washington report that they have found a structure that contributes to the formation of these plaques, which are made of thin strands (fibrils) of beta-amyloid protein. Understanding how these protein fibrils are made will hopefully lead researchers to find ways to block those formations, which could slow down the progression of Alzheimer's disease. The newly found structure is located in proteoglycans, large molecules made by almost all the cells in the body. In cartilage, proteogprovide stiffness and control the movement of fluid in the cartilage. They are the reason why some cushioning fluid remains in joints, even after you've been standing all day. In bone, they control what travels through the bone matrix. Unfortunately, proteoglycans also play an important role in the origins of many diseases in addition to Alzheimer's, including Down's syndrome, diabetes, cancer, arthritis, atherosclerosis, heart disease, and AIDS. In Alzheimer's and other disease processes involving amyloids, certain proteoglycans contribute to the production of amyloids and also interfere with the body's ability to remove excess accumulations. Once researchers decipher exactly how amyloids and amyloid fibrils are formed, the next step would be to isolate substances and produce medications to interrupt the processes. The National Institutes of Health (NIH) has recently funded two programs to investigate the role amyloid plaque formation plays in Alzheimer's disease. The first one is looking specifically at the mechanisms of plaque formation. What are the steps involved in their formation? The second study will focus on prevention of the amyloid deposits and possible treatments for deposits already present. Healthwire April 16, 1999 ) 1. Researchers Pinpoint Structure Within Proteoglycans Critical to Enhancement of Beta-Amyloid Protein Fibril Formation That Occurs in Alzheimer's Disease. 2. ProteoTech Receives Funding For Two NIH Research Grants to Study the Cause, Prevention and Treatment of Brain Amyloid Deposits Associated with Alzheimer's Disease © Mediconsult.com 7/12/99

July 9, 1999

Brain Protein Interaction May Lead to Alzheimer's Disease Researchers have reported findings suggesting that a certain protein interaction in the brain may play a role in the development of Alzheimer's disease. Researchers at the Gladstone Institute of Neurological Disease and the University of California-San Francisco studied the interaction of the

53

amyloid precursor protein (APP) and p53 proteins in mice to collect data; APP is associated with Alzheimer's disease in its mutated form and p53 is known to be associated with cell death. It was found that normal APP protected mice cells from the death-inducing effects of p53, but that the mutated APP offered no such protection. Authors say it was not previously known that APP can exert control over the cell death process and suggest that the failure of mutated APP to offer protection in the brain may lead to Alzheimer's and other neurodegenerative brain diseases. The findings are in the Proceedings of the National Academy of Sciences (1999;96:7547-7552). © Mediconsult.com 07/09/99

July 5, 1999

Prevention of Mental Decline in Elderly May Be Possible As we enter our senior years, it is inevitable that along with getting more wrinkles and gray hairs, our mental processes also deteriorate. Right? Maybe not. A study of nearly 6,000 senior citizens conducted by researchers at the University of California Davis School of Medicine, have shown that those with advanced atherosclerosis (narrowing of the blood vessels), peripheral vascular disease, or diabetes mellitus were at risk for a decrease in cognitive function as they aged. This risk, however, was substantially magnified if the subjects carried the apolipoprotein E4 (ApoE4) gene, a gene often linked with the development of Alzheimer's disease. Interestingly, 70 percent of the participants showed no significant reduction in cognitive function. This unaffected group had, in fact, two things in common: 1) they did not express the ApoE4 gene, and 2) they showed few, if any, signs of diabetes or atherosclerosis. Over the course of the study, subjects underwent a clinical assessment each year and answered basic questions about their health history. They also had to perform simple cognitive tasks such as recalling their birthdate, counting from one to five—both forwards and backwards and folding a piece of paper in half. Those who scored the worst on the test were people who had both atherosclerosis or diabetes and possessed the ApoE4 gene. These subjects were found be eight times more likely to develop an impairment in cognitive ability than those who had low levels of atherosclerosis and no ApoE4 predisposition. It was also shown that those with just the ApoE4 gene were three to four times as likely to have a loss in mental function than those who did have the ApoE4. Finally, seniors with advanced atherosclerosis were three times as likely to have a reduction in cognitive function as those who did not have atherosclerosis. This study sheds some positive light on individuals entering their senior years, because it suggests that the risk for developing cognitive impediments may be reduced, even in people with a genetic predisposition, by preventing atherosclerosis and/or diabetes. © 08/24/99 Mediconsult.com

June 28, 1999

Remember Your Estrogen A common complaint as we age is a loss of short-term memory. Where did I leave my car keys? Did I lock the front door? Researchers from Yale University recently released study findings indicating that this problem in women may be partially due to a drop in estrogen level, which occurs with menopause. Forty-six women, with an average age of 50, were divided into two groups. One group received estrogen for three weeks and the other a placebo. Then all the women received a functional magnetic resonance imaging (fMRI) test while performing simple verbal and nonverbal memory

54

tasks. After a two-week break to allow the estrogen to dissipate from participants' systems, the groups were switched. After another 21 days of treatment had passed, another fMRI was done. The fMRIs showed that parts of the brain had increased activity in the women who were taking estrogen. The areas of increased activity included sections of the parietal and frontal lobes of the brain. Activity in specific parts of these lobes increased when information (stimuli) was being encoded or processed, when verbal information was being stored, and when information was being recalled. The activity pattern seen during the encoding process was very similar to the pattern seen in younger people. While brain activity increased in women taking estrogen, they didn't actually perform better on tasks. Researchers attributed this to the simplicity of the tasks used and recommended that future studies be done using more complicated tasks. Should further testing confirm the link between estrogen and memory, it would add to the hormone's already impressive list of benefits, which include prevention of osteoporosis, decreased risk of heart disease and colon cancer, and treatment of annoying menopause symptoms like hot flashes and vaginal dryness. Several studies have linked estrogen to the prevention of Alzheimer's disease and to the metabolism of cholesterol in the liver. In addition to its benefits, remember that estrogen taken without progesterone seems to increase the risk of endometrial cancer, and controversy remains over estrogen's role in breast cancer. © Mediconsult.com 06/28/99

June 16, 1999

Is There A Way Around the Blood Brain Barrier? The blood brain barrier is both a blessing and a curse. Researchers at the Washington School of Medicine in St. Louis believe they may have found a way to remove the curse. As a blessing the blood brain barrier protects the brain from the many harmful substances circulating in our blood. As a curse, it prevents necessary drugs from reaching brain tissue. A protein called p-glycoprotein (Pgp), which prevents substances from entering the brain through blood vessels, guards the blood brain barrier. This substance seems to work with another protein MRP (multidrug-resistance associated protein) at a second brain barrier that lines the deep cavities within the brain called the choroid plexus. The researchers are hoping the choroid plexus will turn out to be a back door into the brain. The normal function of the choroid plexus is to keep foreign substances from entering the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. This is the fluid that is removed in a spinal tap. Researchers ahoping to figure out how to manipulate the protein that guards this back door. Research on how to cross the blood brain barrier has focused on blocking Pgp and hasn't been very successful. Scientists at Washington University are wondering if there would be more success if both proteins, Pgp and MRP, are blocked. They will continue their research using animal models to try to discover exactly where and how these two proteins guard the brain. Once this is known, the next step is to figure out how to use them to help certain medications get into the brain. If this method can be found, it could be used for the treatment of brain tumors, AIDS, depression,

55

and other diseases that hide behind the protective barriers that surround the brain. © Mediconsult.com 06/16/99

June 16, 1999

It's the Vitamin E in Food that Prevents Heart Disease If you're a woman who's passed through menopause, you're now more likely to develop heart disease, suffer a stroke, and develop certain types of cancer. Researchers at the University of Michigan have some advice for you. Increase your vitamin E, but do it with diet, not a pill. Until this study, the emphasis was that postmenopausal women needed more vitamin E, so physicians recommended they take a supplement. However, this study shows that the antioxidant properties of vitamin E may not be effective unless you get it in food. When low-density lipoproteins (LDL or 'bad' cholesterol) is oxidized, it can cause damage to your blood vessels. The damaged areas are then prone to inflammation and plaque buildup. The more plaque, the narrower and rougher the passageway becomes. All these conditions, which are called atherosclerosis, increase your likelihood of developing a blockage in blood vessels, which can lead to heart attack or stroke. Antioxidants work at the initial step, blocking the oxidation of LDL. Oxidation reactions are also linked to Alzheimer's disease, cancer, diabetes, cataracts, rheumatoid arthritis, skin disorders, and hemochromatosis (iron overload syndrome). Researchers at University of Michigan were looking for an explanation of a previous study showing that women who got their vitamin E from foods, rather than supplements, had a lower rate of cardiovascular disease (CVD). Their findings suggest that vitamin E in food blocks LDL oxidization. Women who got their vitamin E from supplements not only didn't get the beneficial antioxidant effects, they actually had increased LDL oxidation, which increased their risk for cardiovascular disease. The vitamin E supplement dose in this study was low, taken via a multivitamin. Researchers caution that the possibility that higher doses of vitamin E may be beneficial cannot be ruled out. They also note that they can't say for sure that it was solely the vitamin E in foods that was supplying all the antioxidant effects. However, they did rule out other known antioxidants— Vitamin C, beta-carotene, and folic acid—as sources of antioxidant benefits in this study. © Mediconsult.com 06/16/99

June 16, 1999

Why They Can't Find Their Way Home The memory loss associated with Alzheimer's disease has led to disorientation, with people suddenly finding themselves lost in their own home or neighborhood. Researchers at the University of Rochester have found another explanation for this problem, which they call "motion blindness". Motion blindness occurs in a very specific part of the brain that deals with interpreting motion, and it is different from the memory centers that are also affected by Alzheimer's disease.

56

When we move, whether it's walking, driving a car, or riding on a train, our changing environment is taken in by our senses and interpreted in our brains. The researchers use the example of driving through a snowstorm; our mind interprets that we are travelling forward through the snow, not that we are still and the snow is traveling at 60 mph past us. Our surroundings provide countless clues so we can determine where we are in relationship to our environment, and how we are moving through that space. As we age, we lose some of this motion detecting ability. When researchers brought a group of people through the winding corridors of the medical center, 88 percent of the young people correctly answered questions about the route they had taken. Seventy- three percent of the healthy elderly people answered correctly, but only 32 percent of the people with Alzheimer's disease could give the right answers. In the early stages of Alzheimer's disease not all patients experience severe motion blindness, which affects their sense of perception; some may exhibit extreme memory loss. Eventually, all Alzheimer's patients will have both problems as the disease destroys both areas of the cerebral cortex, but which aspect will show up first depends on which area is affected early on. Researchers are planning to continue their study of this aspect of the disease with the hope of being able to improve the quality of life for people with Alzheimer's disease and to further our knowledge about the disease process. © Mediconsult.com 06/16/99

May 7, 1999

Breakthrough Treatments Offer Hope for Victims of Neurological Disorders A U.S. pharmaceutical company recently received patents for new treatments that could help people with Alzheimer's disease, Parkinson's disease, multiple sclerosis, ALS (Lou Gehrig's Disease), and stroke—among others. The patents are for treatments involving neuroimmunophilin ligands, a complex name for a group of small molecules that can attach to other substances and, in animal subjects, have showed the capacity to regenerate nerves that have been injured by accident or disease. Not only do they have a positive effect on damaged nerves, but they show no effect on nerves that have not been damaged. This advancement could not only help those already stricken with these diseases, but also may help prevent those diseases from occurring in the first place. Neuroimmunophilin ligands are fairly new to the field of research. While they haven't yet been proven to be effective or safe for use in humans, neuroimmunophilin ligands have the potential for improving the lives of people who suffer from various chronic, degenerative, neurological conditions. A patent has also been granted for use of a group of enzymes called NAALADAse inhibitors, which stop the excessive release of glutamate without interfering with normal glutamate levels. Glutamate is a protein that acts as a neurotransmitter in the brain to excite neurons (nerve cells). Too much glutamate has been linked to many chronic and acute degenerative nerve disorders that with stroke, trauma, spinal cord injury, Parkinson's disease, and chronic pain. Experiments with these inhibitors have also shown them to interfere with prostate cancer cell growth. © Mediconsult.com 05/07/99

57

May 1, 1999

Researchers are Closing in on Alzheimer's One theory of the cause of Alzheimer's disease is over production of certain proteins in the brain. These proteins are believed to clump up and kill brain cells. A new study from the University of Minnesota shows how these same proteins might contribute to Alzheimer's disease in another way, by increasing production of oxygen radicals. These radicals interfere with the ability of small blood vessels in the brain to deliver blood to brain cells. Without an adequate blood supply, brain cells die. By now, you've probably heard of antioxidants, a term used to describe the action of certain vitamins such as Vitamin E. Antioxidants stop oxidation processes that damage blood vessels in the brain. In preventing damage, they also help prevent Alzheimer's disease. In fact, a 1997 study showed a slower progression of Alzheimer's disease in people treated with Vitamin E. The research used lab mice, which were studied before they showed any sign of Alzheimer's. Having oxygen radicals present seemed to cause a defect; the blood vessels couldn't dilate normally. When activity in a section of the brain increases, the blood vessels supplying that area should open up, or dilate, to provide the extra oxygen and nutrients needed. Oxygen radicals prevent this dilation,causing the cells to starve and become weakened. The study also found that if the mice's brains were bathed in an antioxidant, the radicals were rendered harmless. Another study at Tel Aviv University, claims that simply having the Alzheimer's gene may predispose you to poor recovery from a traumatic brain injury. Meanwhile researchers at Allegheny University, Wayne State University and Johns Hopkins University are working on the connection between bacterial and viral infections and Alzheimer's disease. Specifically, they are studying the Chlamydia bacteria, a common cause of respiratory infections. There are many new and exciting studies, research, and clinical trials currently going on for Alzheimer's disease. Hopefully, someone will soon find the key to treating or preventing this debilitating disease.

© Mediconsult.com 5/1/99

April 25, 1999

MRI Can Predict Alzheimer's Disease Before Symptoms Noticed A recent report suggests that it may be possible to use magnetic resonance imaging (MRI) to diagnose Alzheimer's disease before the onset of condition-related symptoms. Researchers at New York University (NYU) used MRI to measure glucose metabolism in the brain and the volume of various brain regions in elderly patients with progressive memory impairment to collect data. It was found that the brains of memory-impaired patients appeared to show that Alzheimer's disease progressed from shrinkage in the entorhinal cortex to atrophy of the hippocampus, and finally to changes in the cerebral cortex that cause the dementia and extreme memory loss characteristic of Alzheimer's. Authors say the stages of disease progression may occur over a period of up to 30-40 years and that MRI could be used to help diagnose the disease before the onset of clinical symptoms. The report was presented by NYU's Dr. Mony de Leon at the Experimental Biology '99 conference in Washington, DC (April 21, 1999).

58

© Mediconsult.com 4/25/99

April 15, 1999

Study Suggests Smoking May Protect Against Parkinson's Disease The more you smoke the less likely you are to develop Parkinson's disease. According to a study done at the Henry Ford Health Centers in Detroit, people who smoke the most are the least likely to develop this disease. Researchers have acknowledged the link between nicotine and Parkinson's disease for years, and it's been the focus of many studies-some of which have suggested that smoking protects against developing Parkinson's and others concluding that smoking worsens the symptoms. The latest evidence suggests that smoking less than 30 packs a year lowers the risk for Parkinson's disease by 40 percent, while smoking more than 30 packs lowers the risk by 90 percent. Researchers believe that nicotine protects by altering some types of receptors and chemical transmissions in the brain, avoiding the classic Parkinson's imbalance of the neurotransmitter dopamine. Some studies suggest that nicotine only provides this benefit in people with a certain gene. A study done at Salpetriere Hospital in Paris, France, correlated this benefit with age: Nicotine appeared to protect against Parkinson's in a younger age group but caused it in an older group. A few studies indicate that if researchers could discover how nicotine's protective mechanism works, it may have applications for Alzheimer's, schizophrenia, and addictions-all diseases which involve disorders or imbalances of the brain's neurotransmitters or receptors. While study conclusions vary, one thing the experts agree on is that more studies are needed to understand the relationship between nicotine and Parkinson's disease. Regardless of nicotine's role in preventing Parkinson's, smoking remains the leading cause of other serious fatal diseases, including: cancers of the lung, cervix, bladder, pancreas, kidney, larynx, esophagus and mouth; emphysema; hypertension; coronary artery disease; stroke; and heart attack. None of the studies suggest that any potential protection smoking may offer against Parkinson's disease outweighs the serious risk for developing any of these conditions. © Mediconsult.com 4/15/99

April 11, 1999

Gene Mutations Associated with Alzheimer's Disease Researchers have reported new findings concerning the increased risk of Alzheimer's disease among people who inherit mutations in the presenilin genes. Note: an estimated 40% of people with familial Alzheimer's disease have presenilin gene mutations. Researchers at Harvard Medical School report that alterations made in the presenilin-1 gene in cultured laboratory cells resulted in the inhibition of beta-amyloid precursor protein and in lower levels of amyloid-beta protein, which forms the brain lesions found in Alzheimer's patients. Authors say the findings suggest that presenilin may be the long-sought enzyme that is responsible for the overproduction of beta-amyloid in Alzheimer's patients. The findings are in the journal Nature (1999;398:466467).

© Mediconsult.com 4/11/99

59

April 7, 1999

Effects of Constant Caregiving on Immune System Function Researchers at the University of California, San Diego, have found that the stress of caring for a sick loved one can reduce a person's own ability to fight illness. The researchers measured immune system markers in the blood of 41 elderly men and women caring for spouses suffering from Alzheimer's disease and found that those who rarely got a break from caregiving had 60% fewer active CD8 T cells and significantly fewer active CD4 T cells compared to less-stressed caregivers. (T cells are white blood cells that help rid the body of invading pathogens.) Vulnerable caregivers also reported that their illnesses lasted three times longer than the non-vulnerable caregivers. Researchers further suggest that elevated levels of the stress hormone epinephrine may inhibit levels of active immune system cells. The findings are in the journal Psychosomatic Medicine (1999;61:168-174).

© Mediconsult.com 4/7/99

March 26, 1999

'Motion blindness' may cause Alzheimer's Patients to Lose Their Way A recent report suggests that vision problems may have more to do with Alzheimer's disease patients getting lost than confusion or memory loss. Researchers studied six healthy young people, 12 healthy elderly people, and 11 patients with Alzheimer's disease to collect data; participants were tested on their recall of a traveled route and were asked to determine the direction of movement in several computer simulations. It was found that Alzheimer's patients were significantly less likely than members of the other groups to be able to correctly answer questions about a route they had traveled and were found to have twice as much difficulty in determining direction of travel on computer simulations, compared to members of the other groups. Authors suggest that damage to the parieto-occipital cortex brain region in Alzheimer's patients may lead to "motion blindness," a condition in which the visual analysis of optic flow and spatial orientation are impaired. The report is in the journal Neurology (1999;52:958-965). © Mediconsult.com 3/26/99

March 19, 1999

Blood Protein Linked to Slowing Alzheimer's Disease Researchers have reported findings that suggest an association between the blood protein apoE and a slowing of the development of Alzheimer's disease. Researchers at the Washington University School of Medicine in St. Louis, Missouri, studied the effects of apoE on the development of Alzheimer's-related factors in mice to collect data. It was found that mice genetically engineered to produce human amyloid-beta peptide, which forms plaques in the brains of Alzheimer's patients, developed plaques by the age of nine months, but that those mice who were also engineered to produce human apoE did not develop the plaques by the same age. Authors suggest that apoE may remove amyloid from plaques and note that the increased risk of Alzheimer's previously found to be associated with one form of apoE (apoE-4) may be due to a decreased ability of that form to remove amyloid, compared to other variants. The findings are in the "Journal of Clinical Investigation" (March 15, 1999). © Mediconsult.com 3/19/99

60

March 19, 1999

Mild Memory Loss is Not an Indicator of Early Alzheimer's Disease A recent study sought to examine distinctions between age-related mild cognitive impairment (MCI) and the early stages of Alzheimer's disease. Researchers at the U.S. National Institute on Aging in Bethesda, Maryland, studied more than 400 people over a period of 10 years to collect data. The study found that MCI and early-stage Alzheimer's disease could be clearly differentiated using a battery of mental status tests. The report says that patients suffering from MCI have specific memory problem, but do not exhibit problems in other cognitive domains, such as language, judgement, and a variety of communication abilities, that are characteristic of Alzheimer's disease. Authors further note that those patients suffering from MCI appear to be at increased risk of developing Alzheimer's disease, compared to healthy people over the age of 65. The report is in the "Archives of Neurology" (1999;56:303-308). © Mediconsult.com 3/19/99

February 26, 1999

Alzheimer's-related Protein Linked to Learning Disabilities Recent study has found that mice genetically engineered to produce a protein associated with Alzheimer's disease show evidence of severe learning disabilities. Researchers at the University of Minnesota Medical School in Minneapolis engineered mice to produce a mutant version of the amyloid precursor protein (APP), which is found in Alzheimer's- related plaques in the brain in humans. The study found, as the mice developed APP brain plaques, that they began to poorly on learning and memory tasks, which researchers say appeared to be primarily based in impairments to forming nerve cell connections in response to cell activation. Authors say the findings suggest that new forms of treatment that concentrate on restoring proper nerve function, instead of replacing dead brain cells, could be used to treat Alzheimer's disease. The study is in the journal Nature Neuroscience (1999;2:271-276). © Mediconsult.com 2/26/99

February 26, 1999

Exercise May Stimulate New Cell Growth in Brain A new report suggests that vigorous exercise may stimulate the development of new cells in the hippocampus, a brain region known to play a key role in learning. Researchers at the University of Illinois in Urbana say they used fluorescent staining techniques to locate recently-formed cells in the hippocampi of mice that lived in various environments and performed specific tasks. It was found that those mice that engaged in voluntary exercise on a running wheel showed about double the level of new cell proliferation, compared to controls. Authors say the findings also suggest that exercise may help to prolong the life of already-established cells in the hippocampus. The findings are in the journal Nature Neuroscience (1999;2:203-205). © Mediconsult.com 2/26/99

February 26, 1999

Interesting Environment Linked to Changes in Brain 's Memory System

61

A new report concludes that environmental complexity appears to increase the production of adult-generated hippocampal neurons in mice. Researchers at Princeton University and Rutgers University studied the hippocampal regions of mice exposed to living spaces filled with interesting, varied objects and stimuli to collect data. It was found that mice exposed to the complex/stimulating environment showed increased production rates of neurons in the hippocampus, compared to mice not exposed to such an environment. Authors say the findings suggest that learning about space and environment has growth-inducing effects on hippocampal neurons and speculate that the hippocampus may have developed to aid the cerebral cortex "by adding neurons that can deal with new information while deleting those that encode obsolete information." The findings are in the journal Nature Neuroscience (1999;2:260-265).

© Mediconsult.com 2/26/99

February 26, 1999

Study Links Common Herbal Supplements With Infertility A new report suggests that high doses of several popular over-the- counter herbal supplements could impair fertility. Researchers at Loma Linda University School of Medicine in California studied the effects of high doses of St. John's Wort, echinacea, gingko, and palmetto on the ability of sperm to penetrate hamster eggs in a laboratory setting to collect data. It was found that high doses of St. John's Wort prevented sperm from penetrating eggs, while echinacea and gingko impaired such penetration; palmetto did not appear to effect penetration. Authors further note that sperm exposed to St. John's Wort for more than a week appeared to be damaged and say that further study is being planned to evaluate the actual effects of the herbs on fertility when taken by humans. Notes: St. John's Wort is marketed for treating depression and anxiety, gingko for improving memory and helping patients with Alzheimer's disease, palmetto for easing prostate problems, and echinacea for boosting the immune system. The report is in the journal Fertility and Sterility (February 22, 1999). © Mediconsult.com 2/26/99

February 19, 1999

Cognitive Decline Associated with Serious Head Injury A new study concludes that serious head injury may be associated with an increased risk of Alzheimer's disease and other age-related dementia in elderly patients. Researchers at the University of Oulu in Finland studied 588 Finns aged 70 and older, some of whom had suffered head injuries, over a 2.5-year period to collect data. The study found that those participants who showed the highest levels of decline in cognitive ability over the study period were about fourtimes as likely as others to have suffered a head injury and that, overall, about 20% of all head injuries were associated with later decline in mental ability. Authors note that minor head injuries did not appear to be associated with declines in cognitive function and that the findings suggest that both head injury and Alzheimer's disease may trigger neurological decline in similar ways. The study is in the journal Neurology (1999;52:557-562). © Mediconsult.com 2/19/99

February 8, 1999

Dental Mercury Does Not Cause Alzheimer's Disease

62

A recent study concludes that dental amalgam (silver dental fillings) and its mercury component do not appear to play roles in the development of Alzheimer's disease. Note: previous research has found imbalances of some metal elements, including mercury, in patients with Alzheimer's disease. Researchers at the University of Kentucky at Lexington studied 68 Alzheimer's patients and 33 control subjects to collect data; the dental histories of all patients were examined, as was information on their non-dental exposure to mercury. The study found no evidence of a link between dental amalgam and increased risk of Alzheimer's. Authors say the study is the thorough clinical pathological correlative study of humans to show that dental amalgam is not a neurotoxic factor in the development of Alzheimer's. The study is in The Journal of The American Dental Association (February, 1999). © Mediconsult.com 2/8/99

January 30, 1999

Alzheimer's Gene Associated With Poor Brain Injury Recovery A new report suggests that a gene previously linked to an increased risk of Alzheimer's disease may also be associated with poor recovery from traumatic brain injury. Researchers at Tel Aviv University, Israel, studied 69 patients with severe brain injuries to collect data. It was found that those patients who expressed the apolipoprotein E-4 (Apo E-4) gene were five-times more likely to spend seven or more days unconscious as a result of their brain injury than those without the gene; six months after brain injury, those patients with the gene were significantly more likely to be suffering form complications such as speech problems, behavioral abnormalities or difficulty in swallowing than those without the gene. Authors say that, overall, those with Apo E-4 were about 14-times more likely than others to have a less-than-optimal outcome following head injury and suggest that the findings could indicate a possible means of tailoring treatment to each patient following trabrain injury. The findings are in the journal Neurology (1999;52:244-248). © Mediconsult.com 1/30/99

January 14, 1999

Rate of Iatrogenic Disease-Related ICU Admissions Remains Unchanged A new report says the percentage of hospital intensive care unit (ICU) admissions due to prescription drug side-effects and complications from medical procedures has remained unchanged since about 1980. Note: illness from prescription drug side-effects and complications from medical procedures are collectively known as "iatrogenic disease." Researchers at General Hospital in Compiegne, France, examined the rate of iatrogenic disease-related ICU admissions over the course of a year at the hospital and compared the findings from a similar study from 1980 to collect data. It was found that about 11% of ICU admissions were related to iatrogenic disease in the current study, compared to 12.6% in the 1980 study. The report notes that 41 of the 68 iatrogenic disease- related admissions in the current study were linked to adverse drug effects, 15 to surgical complications, and 12 to complications from other medical procedures; 22 of the admissions were attributed to negligence on the part of healthcare staff The report is in the Archives of Internal Medicine (1999;159:71-78). © Mediconsult.com 1/14/99

January 8, 1999

New Screening Guidelines for High Risk Heart Disease 63

The American Heart Association has issued new guidelines on the screening of some patients for elevated homocysteine levels. Note: homocysteine is an amino acid that is used both in the production and maintenance of body tissues; elevated homocysteine levels can lead to the clumping of blood platelets, which can increase the risk of heart attack and stroke. The AHA science advisory says more than one in three people with heart disease experience high levels of homocysteine and that high-risk patients, including those with a personal or family history of heart disease be screened for high levels of the amino acid. Elevated homocysteine levels, which are generally correctable through dietary changes, have also been linked to Alzheimer's disease, chronic fatigue syndrome and rheumatoid arthritis. The AHA science advisory is in the journal Circulation (January 5, 1999).

© Mediconsult.com 1/8/99

January 7, 1999

Rate of Brain Tissue Loss No Different in the Elderly A recent report concludes that, despite long-held beliefs to the contrary, the natural loss of brain tissue over time does not accelerate during the last decades of life. Researchers at the Oregon Health Sciences University in Portland used magnetic resonance imaging (MRI) to study the volume of brain regions in 46 healthy volunteers, ages 65-95, to collect data. It was found that while the volumes of certain brain regions did decrease over time, the rate of such decreases remained relatively constant, even in the oldest patients. Authors say previous studies that suggested an accelera tion in brain tissue loss with age may have included patients in the earliest stages of diseases characterized by brain-tissue damage-related dementia, while the current study excluded all patients who showed signs of such conditions. The report is in the journal Neurology(1998;51:1-7).

© Mediconsult.com 1/7/99

December 22, 1998

Drug Treatment of Dementia Symptoms A new report concludes that Janssen Pharmaceutica, Inc.'s Risperdal(r) (risperidone) appears to be effective in reducing psychotic symptoms associated with dementia, schizophrenia and other forms of psychosis in elderly patients. Researchers randomized 330 Alzheimer's disease patients, with an average age of 82.7 years, to receive either a placebo or 0.96 mg/day of Risperdal daily for one year to collect data. It was found that patients treated with Risperdal showed significant reduction in both psychosis and aggressive behaviours, compared to placebo recipients. Authors further note that only one recipient of the drug developed tardive dyskinesia, a condition characterized by involuntary movements and uncontrolled facial grimacing that is a common side-effect of other anti-psychotic medications. The report was presented at the 37th annual meeting of the American College of Neuropsychopharmacology in San Juan, Puerto Rico (December 16, 1998). © Mediconsult.com 12/22/98

64

65