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Unraveling Alzheimers Disease

Unraveling Alzheimers Disease

I leave absolutely nothing out! Everything that I learned about Alzheimer’s I share with you. This is the most comprehensive report on Alzheimer’s you will ever read. No stone is left unturned in this comprehensive report.

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Alzheimers Disease And Atherosclerosis

There is some evidence that chronic activation of T cells, leading to increased proliferation and telomere shortening, may be involved in other age-related diseases as well. The etiology of Alzheimer's disease (AD) is not known, but our recent studies suggest a possible involvement of T cells. We observed that the telomere length of T cells, but not of B cells or monocytes, correlates with mental function tests in AD patients (Panossian et al., 2002). Those patients with lower Mini Mental Status Examination (MMSE) scores, which is a marker of disease status, had T cells with shorter telomeres than those persons with higher MMSE scores. These findings suggest that the immune system of AD patients is perturbed in some way and may not necessarily respond normally to therapeutic vaccines aimed at retarding AD disease progression. Interestingly, one such therapeutic vaccine trial was recently interrupted due to unanticipated brain inflammation in some participants (Nicoll et al., 2003).

Natural Models Of Alzheimerlike Pathology

Information on the neurobiology of aging in nonhuman primates has grown steadily over the past four decades (Hof et al., 2002). By far the most thoroughly investigated species are the rhesus monkey (Macaca mulatta) and the squirrel monkey (Saimiri spp), although there is a burgeoning literature on other nonhuman primate species, including great apes, marmosets (Saguinus jacchus), cynomolgus monkeys (Macaca fascicularis), green monkeys (Chlorocebus aethiops), baboons (Papio hamadryas), and mouse lemurs (Microcebus murinus). We will focus here primarily on rhesus monkeys and squirrel monkeys as natural primate models of Alzheimer-like pathology. Rhesus monkeys. Rhesus monkeys are Old World monkeys with a maximum life span of approximately 40 years they reach puberty at 3-4 years of age, and females go through menopause at approximately 25 years of age (Walker, 1995). Age-related cognitive decline is well-documented in rhesus monkeys, but a dementia-like state has not been reported....

Progress In Recapitulating Alzheimers Disease

The original models for AD attempted to mimic the neurochemical deficits, mainly in the cholinergic pathways. With a better understanding of the neuropatholog-ical lesions at a molecular level, transgenic models were devised that recapitulated a surprising degree of AD pathology. These include reasonably faithful age dependence, brain region specificity, and appropriate behavioral effects. There is evidence of neuroinflammation in microglial activation, even though many of the mouse strains are deficient in the inflammatory response (Schwab et al., 2004). There is also evidence of oxidative stress, and some of the neurochemical changes are similar to those in AD. Some of the behavioral changes in the APP overexpressing mice also resemble facets of early AD dementia.

Neuropsychological Dysfunction in Parkinsons Disease Without Dementia

In reviewing the PD literature, Lieberman (29) reported that 17 to 53 of treated and untreated PD patients without dementia demonstrate cognitive dysfunction. Unfortunately, few of the studies reported formal criteria for determining what did or did not constitute dementia, thus making it difficult to determine whether patients were in the early stages of dementia. As noted earlier, more recent studies suggest that formal neuropsychological testing may uncover mild cognitive deficits in 25 to 36 of PD patients at the time of diagnosis (22,23). When present in early PD, cognitive dysfunction is typically mild and most commonly involves bradyphre-nia (a slowness of thought) and subtle deficits in executive functions, recall, and or visuoperceptual spatial functions (30).

Neuropsychological Dysfunction in Parkinsons Disease with Dementia

The annual incidence of clinically diagnosed dementia in PD (PDD) is about 3 for individuals younger than 60 years and 15 or less for those 80 years and older (66,67). Estimates of dementia prevalence in patients with PD vary between 9 and 93 , depending on which diagnostic criteria, ascertainment methods, and sampling methods are implemented (24). The methodologically soundest studies yield prevalence estimates of about 25 (68). Dementia is very rarely present early in the disease course moreover, dementia that precedes or accompanies the evolution of motor symptoms should raise concern that the dementia might be related to factors other than PD, for example, AD, LBD, or depression. Recently revised diagnostic criteria for LBD (69) propose that the clinical diagnostic term PD with dementia be reserved for individuals who have a clinical diagnosis of PD and have had only motor symptoms for at least 12 months before developing fluctuating cognition and other neuropsychiatric symptoms...

Risk Factors for Dementia in Parkinsons Disease

TABLE 3 Risk Factors for Dementia in Parkinson's Disease Lower socioeconomic status Family history of Parkinson's dementia patients with PD on verbal fluency, attentional, and visuospatial tasks was associated with subsequent development of dementia. Woods and Tr ster (93) found that nondemented PD patients who met criteria for dementia at one-year follow-up evaluation demonstrated poorer baseline performance on measures of word-list learning and recognition, complex auditory attention, and executive function.

Pathophysiology of Dementia

There is controversy regarding which features are the primary contributors to dementia in PD. PD is characterized by cell loss in the substantia nigra pars compacta (SNc), resulting in loss of dopaminergic input into the striatum. Several pathological and functional imaging studies have shown that in PD, there is greater depletion in the lateral compartment of the SNc, which projects to the putamen, than in the medial compartment, which projects to the caudate (139-141). Cognitive impairment is associated with loss of dopaminergic projections to the caudate (142). This functional division of the striatum is, perhaps, the main reason for the predominance of motor, over cognitive symptoms in PD and is likely why dopaminergic agents do not markedly improve cognition in PD (143). A relationship between cholinergic deficiency and dementia in PD has also been reported (144). Striking cell loss is seen in the nucleus basalis of Meynert, which provides projections to the amygdala and...

Parkinsons Disease Dementia

Pathological findings considered to account for dementia in PD include severe pathology in monoaminergic and cholinergic nuclei that project to the cortex producing a subcortical dementia (39 ), coexistent Alzheimer's disease (AD) (29 ), and diffuse cortical Lewy bodies (26 ) (22). The basal forebrain cholinergic system is the subcortical region most often implicated in dementia, and neurons in this region are damaged in both AD and Lewy body dementia. Neuronal loss in the basal nucleus is consistently found in PD, especially PD with dementia (23). Cholinergic deficits are common in PD (24) and they may contribute to dementia in PD in those cases that do not have concurrent AD or cortical Lewy bodies. While virtually all PD brains have a few cortical Lewy bodies (22), they are usually neither widespread nor numerous in PD patients who were not demented. Several studies have shown, however, that cortical Lewy bodies are numerous and widespread in PD with dementia (25-27) and that the...

Gsk3 In Alzheimers Disease

GSK-3 has been associated with several neuropathological mechanisms involved in Alzheimer's disease. The postmortem diagnosis of Alzheimer's rests on the presence of two abnormal deposits extracellular plaques consisting of P-amyloid (AP), and intracellular neurofibrillary tangles (NFTs). Compared to age-matched control samples, increased levels of GSK-3 have been found in postmortem analysis of brains from Alzheimer's disease patients 8 . In addition GSK-3 has been shown to localize to pretangle neurons, dystrophic neurites, and NFTs in Alzheimer's disease brain 8 . Neurons actively undergoing granulovascular degeneration are also immunopositive for active GSK-3P 9 . A spatial and temporal pattern of increased active GSK-3P expression coinciding with the progression of NFT and neurodegeneration have been demonstrated. Taken together, these studies provide strong evidence that the active form of GSK-3 P is increased in Alzheimer's disease brain. Recently it has been demonstrated,...

Other genes for Alzheimers disease

There have been multiple strategies deployed to try to map these additional AD-susceptibility genes. Genetic linkage studies and family-based association analyses have been employed on datasets with pedigrees multiply affected with AD, and have led to the suggestion that there may be additional susceptibility loci in (1) the pericentro-meric region of chromosome 12 (Alzheimer Type 5) (Pericak-Vance et al., 1997 Rogaeva et al., 1998) and (2) the long arm and pericentromeric region of chromosome 10q (Alzheimer Type 6) (Bertram et al., 2000 Ertekin-Taner et al., 2000 Myers et al., 2000). However, to date, the exact genes in these regions that cause susceptibility to AD have not been identified. Weaker evidence, in single studies have also implicated chromosome 20p (Olson et al., 2002) 15q22 (Scott et al., 2003) and 9p (Pericak-Vance et al., 2000). The glutathione S-transferase omega-1 (GSTO1) gene on distal chromosome 10q has also been implicated as a gene modulating age-of-onset in both...

Familial nonspecific dementia

A small number of pedigrees have been described which segregate an autosomal dominant adult-onset disease characterized by early-onset dementia with non-specific neuropathological changes of neuronal loss, minor gliosis and some spongiform change (Gydesen et al., 1987). Completely absent are the typical findings of Alzheimer's disease (AD) or Pick's disease. Genetic linkage studies have mapped one such disease locus in one large Danish pedigree to a 12 cM region of chromosome 3 spanning the centromere between the markers D3S1284 and D3S1603 (Brown etal., 1995).

Familial British dementia FBD and familial encephalopathy with neuronal dementia with neuroserpin deposits

Recently, two very rare forms of inherited dementia (Familial British dementia and familial encepha-lopathy with neuroserpin inclusion bodies (FEN1B)) have been described which support the emerging concept that many of the inherited dementias are disorders of protein processing in which there is either intracellular or extracellular toxic accumulation of misfolded misprocessed proteins, a theme common to all of the diseases discussed here. Familial British dementia is characterized by spasticity, ataxia, and later progressive dementia accompanied by widespread demyelination, with distinctive perivascular fibrous deposits that are clearly different from the plaques of AD. A T > A transversion mutation in the stop codon of the BRI Missense mutations in neuroserpin, a neuron-specific serine protease inhibitor (serpin), have been described in two pedigrees with a familial dementia (Davis etal., 1999). In these families with FEN1B the mutant neuroserpin forms typical serpin loop-sheet...

Frontotemporal lobe dementia FTD

Fronto-temporal dementia is a pleomorphic neuro-degenerative illness which typically begins before the age of 65 years. In a minority of cases, the disease is inherited as an autosomal-dominant trait (Lynch et al., 1994 Wszolek et al., 1992). The disease often begins with personality and behavioral changes including disinhibition manifest by alcoholism, hyper-religiosity, hypersexuality, hyperphagia (elements of the Kluver-Bucy syndrome) and stealing. As the disease progressed in these families, further abnormalities in judgment, language and praxia developed. In addition to these cognitive changes, some patients also developed Parkinsonism and amyotrophy. However, presentations with primary progressive aphasia, Parkinsonism, dystonia and or oculomotor disturbances are not infrequent. Neuropathologically, the illness is typified by fronto-temporal atrophy with severe neuronal loss, spongiform change in the superficial layers Genetic linkage studies in the subset of FTD cases showing...

Psychological Functioning In People With Intellectual Disabilities Mental Illness And Dementia

'Dementia', on the other hand, usually occurs after a period of normal functioning and involves 'the global impairment of higher cortical functions' (Royal College of Physicians, 1981), affecting memory, thought, language, emotion, personality and behaviour, as well as motor and sensory abilities. Dementia may arise from a number of underlying conditions, but the most frequent causes in 'elderly' people (i.e. persons aged 65 years or more), such as Alzheimer's disease (the commonest form), are progressive and irreversible (see Jacoby and Oppenheimer, 2002 Gelder et al., 2000, for further details).

Gsk3 Regulation And Alzheimers Disease

Since its discovery, GSK-3 has been found to be involved in many physiological process. GSK-3 plays important roles in embryonic development, cell differentiation, microtubule dynamics, cell cycle division, cell adhesion, glucose metabolism, and apoptosis 19,20 . In addition, a growing amount of experimental data has demonstrated its involvement in some pathological processes as Alzheimer's disease.

Age Related Hippocampa Dysfunction Early Alzheimers Disease vs Normal Aging

As we age, all of us will experience an inexorable slide into forgetfulness. Age-related memory decline localizes, in part, to the hippocampal formation, a brain circuit made up of separate but interconnected hippocampal subregions. Human studies have established that Alzheimer's disease targets the hippocampal circuit early in its course, and since Alzheimer's disease affects older individuals it is one cause of age-related hippocampal dysfunction. Animal studies, however, have established that the aging process itself targets the hippocampal circuit, contributing to age-related hippo-campal dysfunction observed in all mammalian species. These independent observations have led to a continued debate among investigators of the aging human brain, summarized by the following questions Is age-related hippocampal dysfunction in humans etiologically homogeneous, or is age-related hippocampal dysfunction caused by both AD and by normal aging If age-related hippocampal dysfunction is caused...

Guam Parkinsondementia Complex

A characteristic parkinsonism with dementia Parkinson dementia complex (PDC) with a number of features that overlap with PSP (50) has been reported in the native Chamorro population of Guam since the 1950s (51). The frequency of PDC is declining in recent years for unknown reasons, and the etiology is unknown. The gross findings in PDC are notable for cortical atrophy affecting frontal and temporal lobes, as well as atrophy of the hippocampus and the tegmentum of the rostral brainstem (52). These areas typically have neuronal loss and gliosis with many NFTs in residual neurons.

Dementia

Cognitive impairment is common in PD, especially in the domain of executive function (28). Such deficits are usually the earliest cognitive signs in PD (117). Patients or caregivers often report difficulties with decision making, planning, and completion of goal-directed behaviors. When these cognitive deficits worsen, and patients have impairment of occupational or social functioning, a diagnosis of dementia is made (13). At this point, it is unclear whether the presence of early cognitive deficits leads to dementia. The rate of cognitive decline in PD can be variable depending upon the population subset. A recent community-based study estimated that the mean overall annual rate of cognitive decline in PD patients was one point on the Mini-Mental State Examination (MMSE) (118). However, patients with PD and dementia declined faster, at a rate of 2.3 points, whereas PD patients who did not develop dementia progressed at the same rate as age-matched controls. Complicating the picture...

Dementia Pugilistica

An akinetic-rigid syndrome with dysarthria and dementia is sometimes a long-term outcome of repeated closed-head trauma, as seen in professional boxers. The pathology on gross examination, other than lesions that can be attributed to trauma, for example, subdural membranes and cortical contusions, is nonspecific. The substantia nigra may also show pigment loss. Microscopically, there are NFTs similar to those in AD in the brainstem monoaminergic nuclei, cortex and hippocampus and some cases also have amyloid plaques (55,56). At the electron microscopic level, they are composed of paired helical filaments and biochemically composed of 68, 64, and 60 kDa forms (57).

Poststroke dementia

Post-stroke dementia (PSD) is currently defined as any dementia occurring after stroke. The overall statistic is striking as the incidence of stroke doubles the risk of dementia. There is also a direct link between stroke and development of Alzheimer's disease although the latter is responsible only for part of the eventually developed dementias the fraction of patients with Alzheimer's disease accounts for 20-60 per cent of those with PSD. A particular type of post-stroke dementia is represented by Binswanger's disease, (or subcortical dementia), which is a form of vascular dementia characterized by diffuse white matter lesions it leads to progressive loss of memory, cognition and behavioural adaptation. The infarct occurring in white matter triggers progressive death of oligodendrocytes, activation of microglia and degeneration of axons. The primary pathological steps most likely are associated with ischaemic death of oligodendrocytes.

Alzheimers disease

Alzheimer's disease (AD), together with multi-infarct dementia, is the main cause of senile dementia. AD, named after Alois Alzheimer, who was the first to describe this pathology in 1907, is characterized by profound neuronal loss throughout the brain which rapidly compromises memory and results in severe impairment of cognitive functions. Histological hallmarks of AD are represented by the formation of deposits of -amyloid protein (A ) in the walls of blood vessels, accumulation of A plaques in the grey matter and intra-neuronal accumulation of abnormal tau-protein filaments in the form of neuronal tangles. AD is also characterized by prominent reactive astrogliosis and activation of microglia (incidentally, the involvement of glial cells in pathogenesis of AD was initially suggested by Alois Alzheimer himself in 1910). In fact, AD plaques are formed by Ap deposits, degenerating neurites, astroglial processes and activated microglial cells. Figure 10.7 Possible role of astrocytes in...

Series Editors Introduction

Paul, Sacktor, Valcour, and Tashima have assembled an impressive international team of experts to summarize the current state of knowledge concerning brain function in AIDS. Early chapters review epidemiology, pathophysiology, neuropathology, neuroimaging, and HIV genetics followed by a series of chapters concerning the neuropsychological, behavioral, and neuropsychi-atric aspects of the disease. Finally, several chapters are devoted to examining the interaction of the aging brain on the expression of AIDS-related cognitive impairment. This volume is largely directed to a clinical audience with the hope of advancing multidisciplinary translational research that may serve to increase the understanding of how HIV affects the brain. The sobering statement by the editors that AIDS may be the most common cause of dementia among people under age 40 should lend impetus to the importance of more effectively dealing with this most dreaded complication of the disease.

The Importance Of Interval Timing In Memory And Attention

Human learning and memory is also highly sensitive to temporal factors, and oscillator-based models have been proposed for the coding of serial order in memory (e.g., Brown and Chater, 2001 Brown et al., 2000 McCormack and Hoerl, 2001). In addition, deficits in learning, memory, set shifting, and interval timing have been observed in a variety of patient populations with damage to the basal ganglia, including Parkinson's disease and Huntington's disease patients, as well as other cortical and subcortical brain structures affected by Alzheimer's disease, injury, and stroke (see Cronin-Golomb et al., 1994 Diedrichsen et al., this volume Gabrieli et al., 1996 Harrington and Haaland, 1999 Malapani and Rakitin, this volume Nichelli et al., 1993 Stebbins et al., 1999). Temporal bisection data obtained from age-matched controls (n 6), cerebellar lesion patients (n 3), Alzheimer's disease patients (n 4), and Parkinson's disease patients (n 4) tested off of their medication are presented in...

The Unusual Substrate Specificity Of Gsk3

Although GSK-3 was originally identified as a protein kinase involved in the regulation of glycogen metabolism, we now know that it participates in the control of many cellular processes, including embryonic development, where it is a key component of the Wnt signalling pathway, as well as gene transcription and neuronal cell function, which will be apparent from reading the chapters in this book. Undoubtedly, many more substrates for GSK-3 remain to be discovered in these and other processes. Another extremely exciting development in recent years has been has the advent of potent and specific inhibitors of GSK-3, which have not only become powerful pharmacological reagents with which to study its functions, but also have therapeutical potential for the treatment of diabetes, stroke, Alzheimer's and other diseases. These aspects are the major topic of Sections B and C of this book. However, these compounds are still at the preclinical stage and whether inhibitors of GSK-3 can be used...

Advantage of genetic animal models

Use of genetic model animals has at least two significant advantages. First, as described above, these will contribute to understanding of the pathology of the disease, including the course and mechanisms relevant to disease etiologies. Indeed, major genetic susceptibility factors for schizophrenia play key roles during early development, which suggests that these factors may be tightly associated with the cause of the disease. Second, such models can be utilized for translational means, such as compound screening for future therapeutic strategy toward schizophrenia. Therefore, high throughput readouts that reflect human pathology and phenotypes may be expected in animal models. Are behavioral assays, however, the most appropriate readouts to evaluate these models In genetic animal models for Alzheimer's disease, senile plaques or p-amyloid plaques are used as a major readout to evaluate the models. Considering this successful precedence, it may be important to consider objective...

Copper In Diseases And Genetic Diseases Of Copper Metabolism

Spongiform Encephalopathies and Alzheimer's Disease mulates and is resistant to proteolysis, probably normally functions in transport of copper at synapses and perhaps also (directly and or indirectly) in the scavenging of radicals. Lack of these normal activities appears to underlie some of the damage sustained by the brain in these diseases (see Section 2.1.8. for further details of PrPC function). The P-amyloid protein, which forms the damaging brain tangles in Alzheimer's disease, also has some connection to copper (185), although what this might be in the normal state is still far from clear. Copper (and zinc) are associated with the amyloid deposits of the disease (191). However, at least in vitro, zinc precipitates aggregation of the amyloid protein, and copper works against the effect of zinc (except at high concentrations) (192).

Vulnerable Population

Data from the National Nursing Home Survey provide a fairly illustrative picture of nursing home residents in the United States (Jones, 2000). More than 1.6 million persons 65 years and over reside in nursing homes. More than 90 are age 65 or over, and 46 age 85 or over. The current population has an average length of stay of 892 days. Those discharged from nursing homes have an average stay of 272 days. Many nursing home residents require help with basic needs such as bathing (94 ), dressing (87 ), toileting (56 ), and eating (47 ) 47.7 have an active diagnosis of dementia (U.S. Department of Health and Human Services, 1998).

Some Recommended Resources

Ethics in aging research is actually the intersection of three different studies, gerontology, ethics, and research methodology, each of which has its own literature. Among periodicals, consider the Hastings Center Report, IRB Ethics and Human Research, the Journal of the American Geriatric Society, and the American Journal of Bioethics. Disease-specific periodicals can be helpful as well. The Alzheimer's research community has sustained a long and fruitful discussion related to capacity for consent, much of which is in Alzheimer's Disease and Related Disorders. Consider also the work of associations with an interest in aging and research. Much of their contributions can be accessed through the respective websites of the Alzheimer's Association, the American Geriatric Society, and the Association for the Accreditation of Human Research Protection Programs. Websites for are listed in the References section.

Obtaining Informed Consent From Elderly Persons

Having a mental illness or an illness that affects cognition does not necessarily mean an individual lacks decision-making capacity (AGS Ethics Committee, 1998 Alzheimer's Association, 2004). Indeed, many elders with diminished cognition are not only legally competent, but also have decision-making capacity and can consent to participate in research. Capacity to consent need not be based on an overall state of competence. A patient can have diminished cognition (e.g., due to dementia) and still understand the purpose of the study (e.g., that it is research and may not provide a therapeutic benefit), the risks of participating in the study, and that he or she may refuse to participate. Instead, consent for participating in research studies of varying complexity requires varying levels of capacity. For example, a person may be able to effectively consent to participate in a minimal risk study (i.e., a study in which the risk and magnitude of harm to the subject are no greater than what...

Cognitive and Emotional Factors

By definition, the intellectual functioning of people with intellectual disabilities or dementia is impaired. Similarly, overall intellectual impairment may temporarily accompany mental illness, at least while there is evidence of psychotic symptoms. Over the last 10 years, however, it has become increasingly apparent that, even when a well-established, global, measure of overall intellectual ability is used (for example, the Wechsler Adult Intelligence Scale (3rd edition) Wechsler, 1999), it is an inadequate predictor of the ability to make a particular decision. Indeed, even the verbal parts of such assessments, though they normally correlate positively with judgements of capacity, do not accurately predict decision-making ability (Grisso et al., 1995 Wong et al., 2000). This is, perhaps, not surprising since each subtest normally reflects a variety of skills, including abstract ability, attention, motivation, and educational background (Kaufman and Lichtenberger, 1999). As a...

Conducting Research For The Good Of Elderly Persons

The principle of beneficence suggests that investigators avoid involving vulnerable elders in research. Yet, many elders suffer from conditions that not only leave them vulnerable, but also have a predilection for elders (e.g. dementia). Ideally, research of such conditions would involve subjects with those conditions. However, if vulnerable elders are excluded from research in order to avoid harm, then these elders would never benefit from research. Indeed, prohibiting research involving vulnerable elders may in fact cause significant harm by not allowing discovery of new knowledge that would help them (Ratzan, R., 1980).

Genetic Research Involving Elders

Genetic research (i.e., the identification of genetic variants) has the potential for discovering important preventive and therapeutic interventions for diseases associated with aging. For example, the identification of genetic mutations in familial Alzheimer disease and other diseases has yielded information regarding the mechanisms of the sporadic, yet more prevalent, forms of these diseases (Banks, D. and Fossel, M., 1997 Blacker, D., et al., 1997 Longo, V. and Finch, C., 2002). Hence, it is not surprising that the interest in and conducting of genetic research in elders are growing.

Alterations in Neurocognition in HIV Infection

Neurocognitive deterioration has been recognized in HIV-infected individuals since the year in which AIDS was first recognized as a clinical entity. Prior to the development of effective antiretroviral therapy, the AIDS dementia complex (ADC), in which impaired intellectual function, often associated with progressive vacuolar myelopathy, was a common finding. The ADC, characterized by poor concentration, diminished memory, motor dysfunction, and often social withdrawal and apathy, seldom if ever occurs in persons who begin antiretroviral therapy prior to developing moderately severe immunodeficiency (e.g., before the CD4 count falls below 350 cells mm3). It has rarely been recognized in patients in whom the CD4 count has never fallen below 200 cells mm3.

Assessment Of Disability

The assessment of PD is difficult, because it is expressed variably in an individual patient at different times and it is influenced by emotional state, response to medication, and other variables. Moreover, there is a marked interpatient variability of symptoms and signs. To study this heterogeneity and to determine possible patterns of clinical associations, we analyzed the clinical findings in 334 patients with PD and identified at least two distinct clinical populations of parkinsonian patients (104). One subtype was characterized by a prominent tremor, an early age at onset, and a greater familial tendency. Another subtype was dominated by postural instability and gait difficulty (PIGD) and was associated with a greater degree of dementia, bradykinesia, functional disability, and a less favorable long-term prognosis.

Reaching beyond Researchers

A number of Web sites aim to inform the general public, but prove useful for researchers. They can help with teaching or setting scientific work in a broader context. The American Federation for Aging Research's Info-Aging, for example, offers explanations of a number of topics under several headings. Topics in the ''Biology of Aging'' section include oxidative damage, telomeres, stem cells, and biomarkers of aging. Each one summarizes crucial issues, addresses basic questions, provides links to related research, and points readers toward other resources in addition, they are reviewed by experts in each field. The ''Disease Center'' similarly contains key information and questions on some age-related illnesses, such as Alzheimer's disease, macular degeneration, and osteoporosis, and the ''Healthy Aging Center'' discusses issues such as nutrition, stress, hearing, and immunization. The Merck Manual of Geriatrics provides detailed information and guidelines on the care of older people...

Mentation Behavior And Mood History

2 Moderate memory loss, with disorientation and moderate difficulty handling 3 Severe memory loss with disorientation for time and often to place. Severe 4 Severe memory loss with orientation preserved to person only. Unable to 2. Thought disorder (due to dementia or drug intoxication).

Organizations And Ethics

Much of the research on human subjects is sponsored by public and private organizations or foundations. For example, public support for research and training programs that benefit older Americans comes from federal agencies such as the Administration on Aging, the Office of Nursing Home Affairs, the National Institute on Aging, and the Department of Education. The National Institute on Aging (NIA), in particular, sponsors biological research on Alzheimer's disease, osteoporosis, drug reactions in older people, and prosthetic devices. In its research support functions, the NIA tries to strike a balance between medicine, biology, psychology, and other sciences concerned with aging. Basic research on aging conducted by specialists in geriatrics, gerontology, and other professions is also sponsored by the British Council on Aging and similar organizations in other countries.

Neuronal Polarity And Gsk30

It has been shown that GSK-3P plays a role in establishing and maintaining the axon-dendrite polarity. Interestingly, after the transition from st. 2 nonpolarized neurons to st. 3 polarized neurons, GSK-3P activity is higher in dendrites than in axons, which is critical for determining axon-dendrite polarity. A protein known as collapsin response mediator protein-2 (CRMP-2) has been described as crucial for axon outgrowth and determination of the fate of the axon and dendrites. CRMP-2 is therefore essential in the establishment and maintenance of neuronal polarity. Further it has been shown that GSK-3P phosphorylates CRMP-2 and inactivates its activity, participating in neuronal polarization through CRMP-2. Also NT-3 and brain-derived neurotrophic factor were shown to inhibit GSK-3P via PKB, reducing the phosphorylated levels of CRMP-2 at Thr514 and thus leading to axon elongation and branching 22 . Phosphorylation of CRMP-2 at Ser518 and Ser522 is implicated in the formation of...

Characteristics of AD

Alzheimer's disease (AD) is a progressive neurodegene-rative disorder that is characterized by the relentless decline of cognitive function, judgment, perception and personality, and ultimately the loss of the distinctive and shared qualities that define an individual's existence (Cummings, 2004). For unknown reasons, the full behavioral and neurodegenerative phenotype of AD is unique to humans, a characteristic that has hindered the Histopathologically, AD is characterized primarily by the presence of senile plaques and neurofibrillary tangles (NFTs) in specific brain regions (Figure 11.1) (see Hauw and Duyckaerts, 2001 Hardy and Selkoe, 2002 for review). Senile plaques are intricate lesions centered about a core of aggregated, fibrillar amyloid-p (Ap) peptide neurofibrillary tangles are intracellular inclusions comprised of aberrant, microtubule-associated protein tau. A variety of additional pathologic changes accompany plaques and tangles in AD, including cerebral p-amyloid...

T714i T714a W15m 1716v

Alzheimer's disease cascade (1) The large quantity of A deposits in the AD brain implicates the peptide in pathogenesis (2) the most common autosomal dominant forms of AD all involve mutations either in the -amyloid precursor protein ( APP) (Figure 11.2) (Revesz et al., 2003) or in the presenilins (PS1 and PS2, which form the probable catalytic subunit of the gamma-secretase complex that liberates A at its C-terminus (Marjaux et al., 2004) and (3) all known genetic and environmental risk factors for AD increase the production of A and or its tendency to aggregate (Hardy and Selkoe, 2002). According to the A -cascade hypothesis, the abnormal accumulation of multimeric A triggers a progression of events leading to amyloid plaques, neurofibrillary tangles, inflammation, neuron- and synapse loss, and dementia. In vitro and in vivo studies are beginning to implicate a prefibrillar, oligomeric form of A in this cascade (Kayed et al., 2003). Indeed, the major genetic risk factor for AD...

Modeling Other Behavioral Conditions

AD is characterized by a number of behavioral disturbances beyond cognitive function, particularly in the mid- to late stages of the disease. These include sleep disturbances, depression, wandering, and aggressiveness, which are frequently the cause of nursing home placement. These are conditions that also occur in the absence of AD symptoms. There is some question as to whether they are different in the presence and absence of dementia. This is an area in which better therapeutics could make a significant impact on quality of life for the patient and the caregivers. These behavioral problems are currently addressed by add-on medications, but the

Pathology Models Natural vs Engineered

AD symptoms are dominated by the progressive loss of cognitive function, although other modalities are affected, particularly in the later stages of the disease. Dementia, however, can result from multiple etiologies such as tumors, drugs, toxic agents, multiple cerebral infarcts, Lewy body disease, prionoses, and tauopathies, to name a few. Each disease generally presents a clinical picture that is distinct from the others, although areas of overlap are a persistent challenge for clinical diagnosis. The defining characteristic of AD is that the dementia develops in the context of the accumulation of -amyloid peptide in plaque structures and the development of neurofibrillary tangles. In the absence of these lesions, in particular the amyloid deposition, the dementia is not considered to be of the Alzheimer's type.

Amyloid Hypothesis And Aft Amyloidosis

The characteristic pathological signature of AD noted by Alzheimer is the presence of deposits of Aft peptide in extracellular plaques accompanied by tau deposits in intracellular tangles. The weight of the genetic evidence from familial forms of AD supports the Aft peptide as a

The Tau Hypothesis And Tau Pathology

Tau transgenics The discovery of mutations in the tau gene in fronto-temporal dementia-17 (FTDP-17) familial tauopathy opened up the possibility that similar advantage could be taken of tau mutants to model pathology as had been so useful with APP. There was also the chance to settle the long-standing debate over the primary insult in AD. Although familial forms of various tauopathies were mapped to the tau gene, no tau mutations have been linked to AD, despite ample tau deposition in neuro-fibrillary tangles in AD. Tau is expressed as multiple splice variants in humans such that up to six forms are produced in developmental-, tissue-, and cell-specific patterns. Abnormal polymerization of tau is caused by mutations in coding or intronic regions of the tau gene, each somehow resulting in a characteristic tangle morphology causing a recognizable clinical phenotype resulting in different diseases such as Pick's disease, progressive supranuclear palsy, and multiple system tauopathy. Both...

Human Studies Interrogating the Hippocampal Circuit in AD and Aging

As discussed above, variants of fMRI sensitive to basal correlates of neuronal function are well suited to aid in resolving this debate. In one study, an MRI measure sensitive to basal levels of deoxyhemoglobin was used to assess the hippocampal subregions in patients with AD dementia compared to age-matched controls (Small, Nava et al., 2000). This MRI measure has proven capable to detect cell sickness in individual hippocampal sub-regions. Univariate analysis revealed that normalized signal intensity was reduced in all hippocampal sub-regions in patients compared to controls. Nevertheless, when the hippocampus was analyzed as a circuit namely, using a multivariate model to analyze signals from all hippocampal subregions simultaneously the entorhinal cortex was found to be the primary site of dysfunction in AD (Small, Nava et al., 2000). This study suggests that the entorhinal cortex, not the CA1 subfield, is the hippocampal subregion most vulnerable to AD agreeing with some, though...

Research Vs Clinical Care Instruments

Delirium and dementia can also be barriers to pain assessment (14). An experience with an older adult who had early dementia with loss of some executive function demonstrated the shortcomings of the Visual Analogue Scale as the individual responded that his pain was not on the line, but in his shoulder.

Gsk3 In Neuronal Development

It is generally accepted that in many cell types, GSK-3 plays an important role in several critical physiological processes including the cell cycle, apop-tosis, and development. Indeed, in terms of neuronal physiology GSK-3 has been implicated in pathways that control morphogenesis, synaptogenesis 3 or survival 4 , and it has even been associated with pathological processes such as Alzheimer's disease (AD) 5,6 .

Neurocognition and Its Assessment

Patients who undergo neurocognitive testing may display a range of minor impairments across or even within any particular domain of function. Some patients may experience subtle decrements in cognitive function that are not of sufficient magnitude to qualify for diagnosis of a cognitive disorder. However, it is possible that these decrements remain noticeable or distressing to the patient. In contrast, other patients may experience declines that reach greater levels of clinical significance. For example, the diagnosis of mild cognitive impairment (MCI) is characterized as the presence of a significant deficit in one or more domains, though these impairments may not interfere with activities of daily living. However, more severe cognitive impairments, typically associated with pronounced functional limitations (e.g., caregiver dependence), may be indicative of a dementia diagnosis such as Alzheimer's disease (AD). Varying levels of dementia and impairment exist along the continuum...

Lesley R Brown and David A Harris

The prion disorders include Creutzfeldt-Jakob disease (CJD), kuru, Gerstmann-Straussler syndrome, and fatal familial insomnia in man, as well as scrapie and bovine spongiform encephalopathy (mad cow disease) in animals. In man, these diseases are characterized clinically by dementia and motor dysfunction and neuropathologically by neuronal loss, spongiosis, and amyloid deposition. Infectious, inherited, and sporadic forms of prion diseases have been described. Prion diseases are of now of enormous concern from a public health standpoint because of an epidemic of bovine spongiform encephalopathy in Britain and other European countries and recent evidence that this disease has already been transmitted to human beings by consumption of contaminated beef (1,2).

Neuropsychological Findings In Parkinsons Disease

Parkinson (20) contended that patients with shaking palsy did not exhibit significant intellectual changes however, by the late 1800s, investigators had begun to recognize the presence of cognitive deficits in patients with PD (21). Mild neuropsychological changes are widely accepted to occur in early PD. Increasingly, it is recognized that cognitive alterations, especially in executive functions and or memory, may already be present at the time of disease diagnosis. Recent studies estimate that one-quarter to one-third of patients may have deficits detectable on careful neuropsychological testing at the time of disease diagnosis (22,23). Cognitive declines early in the disease most often include deficient information processing speed, visuospatial abilities, verbal fluency, recall, and executive functions (24,25). The neuropsychological dysfunction associated with early PD is hypothesized to reflect nigrostriatal dopamine depletion and disruption of mesocortical and mesolimbic...

Contributors to Volume 404

Bacskai (50), Alzheimer's Disease Research Laboratory, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts Jesse Skoch (50), Alzheimer's Disease Research Laboratory, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts

Conclusion Policy Recommendation

Overt barriers to health care for minorities of color (e.g., racially segregated health clinics and hospitals) have largely disappeared. However, institutional discrimination remains. This ranges from the sharp underrepresentation of ethnic-minority physicians to informal norms and practices and official policies. This effectively restricts access for minorities, the poor, and the uninsured. Racial-discrimination barriers to health care are illegal. Nevertheless, barriers to equal access for the minority elderly persist. There is rationing of health care, for example, for such procedures as renal dialysis and heart transplant and a limit on the number of days for mental health services per year. There is also a preference for private-pay-insurance patients physicians claim that they do not profit off government-supported health care programs. Finally, there are restrictions on health care for the homeless and patients with a diagnosis of Alzheimer's disease or mental illness.

Prototypes Creating Representations of Illness and Targets for Management

Prototype checks are not only at the core of the intra-personal processes that give meaning to experience but also central for interpersonal communication. Once the opening niceties are completed (How are you ), a medical practitioner will address the presenting complaint with the same checks the patient uses What is bothering you Where is it How does it feel How long has it been going on Has it been getting worse What were you doing when it started Have you done anything to self-treat it What happened This exchange reinforces the check process and may or may not provide an alternative explanation for the presenting symptoms and physical and cognitive dysfunctions. An additional set of PCs emerge from social comparison processes. We assign meaning to symptoms and functional changes by checking for common exposure (e.g., exposure to someone with SARS), familial linkage (e.g., family member had breast cancer), similarities in physiognomy, temperament, and response to aging (e.g.,...

Putative Physiopathological Implications Of Gsk3 Activation

In certain neurodegenerative processes, such as Alzheimer's disease (AD), GSK-3 appears to be deregulated. Indeed, it is thought to be responsible for the aberrant phosphorylation that contributes to neurodegeneration and to augmenting the formation of neurofibrillar tangles, a pathological hallmark of AD. Furthermore GSK-3 is one of the kinases activated by pSAmyloid 6,28 or PrP 49 . It is for this reason that GSK-3 is emerging as a promising therapeutic target in neurodegenerative processes such as AD and ischemia 50 , as well as in psychiatric disorders. Thus understanding the regulatory mechanisms that control the activation and inhibition of GSK-3 is an increasingly more important issue.

Innate Immune Responses Friend or

Most studies consider the induction of innate immune responses such as cytokines, chemokines, oxidative stress, and proteases to be detrimental to the neuron. This concept has been applied to most neurodegenerative diseases, including HIV-associated cognitive impairment (Fig. 1). However there are reasons to believe that in the setting of viral infections, such responses may not always be hostile to the host. Organisms that lack a cellular immune response often use such innate immune responses to protect themselves from invading pathogens. For example, plants, without a specific adaptive immune system, may use metalloproteinases, along with other innate defense mechanisms, to combat infection. For example, the metallo-proteinases-2 gene of the soybean, Glycine max, is upregulated in response to a variety of infections (1). Thus in circumstances where the cellular immune responses fail to control the pathogen such as persistent HIV infection of the CNS, the innate immune responses get...

Concluding Remarks

Although for many years GSK-3 was believed to be a constitutively active kinase, it has since become apparent that the activity of GSK-3 may be regulated by several different pathways. As a general role many pathway control GSK-3 by inhibition, which in most cases correspond with a boots of survival. However, the transient activation, or a more persistent activation, appears not necessarily correlated with neuronal death. Even if we consider that data from many labs indicated that deregulation of GSK-3 it is associated with some pathological processes such as Alzheimer's disease (AD) or ischemia, the regulatory possibilities have to be fully clarified. While we have a good picture of this intriguing kinase, we feel that more is still to come.

Goals of complex disease trait mapping

Since the greatest public health benefit is expected to follow from the first aim, it will be important to identify and focus on key pathways. Single genes exerting large phenotypic effects, such as cell cycle and mismatch repair genes in colorectal cancer, are likely to be closest to the key, rate-limiting steps in the disease process. From this follows the need to give some priority to identifying moderate-to-large rather than average genetic effects, since these are likely to be concentrated in important pathophysiological pathways. In addition, the complexity of common late-onset disorders suggests that identifying genes with the largest effects, which contribute most to the extremes of the disease or trait distribution, may be the most robust approach, similar in principle to the methods successfully applied to monogenic disorders. For example, the identification of genetic variants accounting for rare monogenic forms of common disease (e.g. breast and colon cancer, Alzheimer...

Congenital General Anosmia

In addition to the human inter-individual diversity in perceiving specific odorants, humans also vary in their general olfactory capabilities. This covers a wide range of phenomena, from general anosmia through hyposmia (diminished sensitivity to smell). At the other end of the scale is general hyperosmia (enhanced smell sensitivity) (30). Moreover, during aging, a general olfactory loss occurs, which is also a feature of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases (31).

Immune Reconstitution Syndrome An Unrecognized Consequence of Antiretroviral Therapy

Histology shows massive infiltration of T cells in the brain in patients with CNS-IRIS, which leads to an increase in neuronal death, and break down of the blood-brain barrier (31-33). This impairment of the BBB can then in turn permit greater immune cell access to the brain. Importantly, studies have emerged that identify increased T cells in the brain of patients who came to autopsy or underwent a brain biopsy in the postcombined antiretroviral therapy era (33, 34). HIV dementia is largely driven by macrophage activation and HIV-infected macrophages, whereas T cells appear to mediate the detrimental effects of IRIS (34, 35) (Fig. 1).

Neuropsychological Aspects Of Parkinsonplus Syndromes And Essential Tremor

TABLE 4 Comparison of Neurobehavioral Features of Parkinson's Disease with Dementia, Lewy Body Dementia, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Multiple System Atrophy TABLE 4 Comparison of Neurobehavioral Features of Parkinson's Disease with Dementia, Lewy Body Dementia, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Multiple System Atrophy

Progressive Supranuclear Palsy

Prevalence rates of dementia in PSP range from 50 to 80 , but some authors contend that these numbers reflect over-diagnosis due to bradyphrenia, emotional problems, and visual dysfunction that accompany PSP. Cognitive deficits are seen in approximately 50 of patients with PSP (172), with the neuropsychological profile being typical of diseases with subcortical involvement, including slowed information processing, executive dysfunction, and information retrieval deficits (173). As compared to patients with PD, cognitive slowing and executive dysfunction in PSP emerges earlier in the disease course, is more severe, and progresses more rapidly (174-177), and this differential executive dysfunction may reflect radiographically demonstrated differences in frontal atrophy between the two conditions (178). Executive dysfunction in PSP may also differ qualitatively from that in PD (179). Memory and attention are relatively intact in PSP, although retrieval deficits and accelerated rates of...

Modulation of Neurogenesis in HIV infection A New Target for Neuroregenerative Therapies

Much attention has been focused on trying to protect the injured or dying neuron. Several detailed studies have clearly shown evidence of neuronal apoptosis and dendritic loss in the brain of HIV-infected patients, and experimental studies have implicated HIV proteins and substances released from activated glial cells in causing the damage. Despite this overwhelming evidence, to date all clinical trials with neuroprotective therapies have shown little or no improvement in cognitive function in patients with HIV infection (47). These observations are not unique to HIV dementia but in most neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis, neuroprotective therapies have been dismal failures. This has made us and others reevaluate the therapeutic targets. It is becoming abundantly clear that there is continuous replacement and regeneration of neurons during adulthood hence, any impairment of neurogenesis may have...

Multiple System Atrophies

The MSA nomenclature subsumes several different diseases, including olivoponto-cerebellar atrophy (OPCA), striatonigral degeneration (SND), and Shy-Drager syndrome (SDS). Cognitive deficits are relatively mild in most forms of MSA, and dementia is not a common feature of these conditions (183), except perhaps in OPCA, in which 40 to 60 of patients may develop dementia, which is more prevalent in familial forms of the disease (184). Mild executive and memory deficits have been reported in MSA (SND and SDS) (185), but are considered to be of similar severity

Corticobasal Degeneration

The prevalence of cognitive impairment and or dementia in CBD is not established. Neuropsychological functions appear to be relatively preserved in the early stages of CBD, at least within an average of five years of diagnosis (188), with dementia emerging as a more common feature later in the disease course (189). Although the neuropsychological profile of CBD reveals both cortical and subcortical features (190), it is possible to differentiate CBD from AD and PSP (176,191). The neuropsychological profile associated with CBD is marked by significant executive dysfunction, which is comparable in severity to PSP, but relatively milder than is observed in patients with AD. Also evident in CBD is asymmetric apraxia (not evident in PSP or AD), alienhand sign (not reported in PSP or AD), impairment in motor programming and speed (similar to PSP but unlike AD), attentional dysfunction, and deficits in verbal fluency (comparable to AD). When aphasia is present it is most often of the...

Role of Viral Strains and Clades in HIV Neuropathogenesis

As the virus has evolved and spread to different regions of the world, it has become apparent that there are clear geographical differences in the neurological manifestations of HIV infection. In regions of the world infected with HIV clade C, only milder forms of cognitive impairment have been recognized even in patients with advanced immunosuppression in the absence of antiretroviral therapy (28, 59). While it is possible that patient selection bias may in part be responsible for these differences, there is also evidence to suggest that genetic differences in the tat gene of the HIV clades may also alter the pathogenicity of the virus. For example, the cysteine in position 31 of clade B virus is mutated to a serine in clade C virus. This mutation results in decreased chemotactic properties of clade C virus and decreased neurotoxicity (60, 61). Studies from Uganda suggest that individuals infected with clade D virus are more likely to develop dementia compared with those infected...

Role of Host Genetic Factors in HIV Neuropathogenesis

The epidemiology of HIV dementia suggests that host genetic factors must contribute to the pathophysiology of HIV dementia. Some patients despite high viral loads and profound immunosuppression remain cognitively intact, while a smaller percentage of such patients develop a dementing illness. Despite this overwhelming evidence, only a handful of genes have been studied as a potential factor in HIV neuropatho-genesis. One reason is that such studies require large sample sizes. The Apo E genes have been best studied in this regard. Both population-based and experimental studies in vitro and in vivo suggest that individuals with ApoE4 gene are more likely to develop HIV dementia (63) in particular among older HIV+ individuals (64). Individuals with HIV infection and ApoE4 allele have increased oxidative stress in the brain and CSF (65, 66) and human neuronal cultures with the ApoE4 allele are more vulnerable to toxicity by HIV proteins (66). Further, human lipidated apoE3 greatly...

Crystal Structures Of Gsk30 Inhibitor Complexes

GSK-3 has been considered a target for adult onset diabetes 34-36 , stroke 37,38 , Alzheimer's disease 39,40 , bipolar disorder 41 , and schizophrenia 42,43 . The ATP binding site has been the preferred site for kinase drug design and the crystallization of inhibitors with GSK-3 P is relatively straightforward. Unphosphorylated protein and ligand readily form diffracting crystals when combined with a mixture of PEG and salt (e.g., 5 ). The PEGION screens from Hampton Research or Nextal Biotechnologies yield crystals under multiple conditions. The crystals typically have the same space group as the native unliganded protein, although exceptions have been observed (e.g., the GSK-3P complex with 6-bromoidurubin, PDB 1UV5 44 ). The space group is P212121 with unit cell dimensions 83, 86, and 127 A, and 90 angles, and there are two GSK-3P inhibitor complexes in the asymmetric unit. The Protein Data Bank contains seven crystal structures of GSK-3P in complex with non-ATP inhibitors, all of...

Protein misfolding and its consequences for disease

If proteins do not fold correctly they will not able to exercise their proper function such misfolded species are often degraded rapidly within the cell. Other (e.g. disorders associated with a1-anti-trypsin) result from the failure of proteins to be trafficked to the appropriate organs in the body (Carrell and Lomas, 2002 Powell and Zeitlin, 2002). In other cases, misfolded proteins escape all the protective mechanisms discussed above and form intractable aggregates within cells or in extracellular space. An increasing number of pathologies, including Alzheimer's and Parkinson's diseases, the spongiform encephalopathies and late onset diabetes, are known to be directly associated with the deposition of such aggregates in tissue, Table 7.2 (Dobson, 2001 Koo et al., 1999 Pepys, 1995 Selkoe, 2003 Thomas et al., 1995). Diseases of this type are amongst the most debilitating, socially disruptive and costly in the modern world, and they are becoming increasingly prevalent as our societies...

A generic description of amyloid formation

Of the polypeptide chain is minimal (Dobson, 1999b). Other familial diseases are associated with the accumulation of fragments of native proteins, produced by aberrant processing or incomplete degradation such species are usually unable to fold into aggregation-resistant states. Other pathogenic mutations act by enhancing the propensities of such species to aggregate, for example by increasing their hydrophobicity or decreasing their charge (Chiti et al., 2003). In the case of the transmissible encephalopathies, it is likely that ingestion of pre-aggregated states of an identical protein (e.g. by cannibalistic means or by contamination of surgical instruments) increases dramatically the rate of aggregation within the individual concerned, and hence underlies the mechanism of transmission (Chien et al., 2003 Harper and Lansbury, 1997 Prusiner, 1997). Such seeding phenomena may also be at least part of the reason why some deposition conditions such as Alzheimer's disease progress so...

The fundamental origins of amyloid disease

Despite our increasing knowledge of the general principles that underlie protein misfolding diseases, the manner in which improperly folded proteins and aggregated proteins can generate pathological behavior is not yet understood in detail. In the case of systemic disease, the sheer mass of protein that can be deposited may physically disrupt the functioning of specific organs (Pepys, 1995). In other cases it may be that the loss of functional protein results in the failure of some crucial cellular process (Caughey and Lansbury, 2003). But for neurodegenerative disorders, such as Alzheimer's disease, it appears that the primary symptoms arise from the destruction of cells such as neurons by a ''toxic gain of function'' that results from the misfolding and aggregation process (Caughey and Lansbury, 2003 Koo et al., 1999). It has recently become apparent ability to prolong life (Polverino de Laureto et al., 2003) is leading to the proliferation of these diseases as the limitations in...

Atypical Antipsychotics

Atypical antipsychotics are typically used to treat psychosis in PD. Table 1 provides a summary of atypical antipsychotic studies in PD. The United States Food and Drug Administration (FDA) recently asked all atypical antipsychotic manufacturers to add a boxed warning to their product labels, saying that atypical antipsychotics, when used in elderly patients with dementia, were associated with a higher risk of mortality (54). However, since the deaths were primarily due to cardiovascular or infectious causes, it is unclear how the atypical antipsychotics cause increased mortality. Since psychosis can be difficult to treat in PD, it is likely that these agents will continue to be utilized until a direct cause and effect relationship is uncovered.

Power Of Decision Making

Decisions when the patient has cognitive problems (such as dementia) are often extremely difficult to make. The possible scenarios are too numerous to mention here, but the following is an excellent example of one such scenario that could begin to occur more and more as the number of persons with Alzheimer's disease continues to increase Margo, when fully competent, had executed a formal document directing that if she developed Alzheimer's disease, she did not want treatment for any other serious life-threatening diseases she might contract. She even stated that if she contracted such a disease, she should be killed as soon and as painlessly as possible. A resident who was taking a gerontology elective began visiting Margo every day and learned about her life with dementia. She appeared happy, active in her painting, reading, and listening to music. According to the resident, ''Margo is undeniably one of the happiest people I have known.'' Ronald Dworkin offers a new way to interpret...

Approaches to therapeutic intervention in amyloid disease

For those types of amyloid disease that result not from the aggregation of intact proteins but of proteolytic fragments, resulting from natural processing or from incomplete degradation, that are unable to fold in the absence of the remainder of the protein. A possible therapeutic strategy for such diseases would be to reduce the levels of the aggregation-prone peptides by inhibiting the enzymes through whose action the fragments are generated. An extremely important example of this approach involves the 40 or 42 residue Ab-peptide derived from the amyloid precursor protein (APP) as the aggregation of this species is linked to Alzheimer's disease. Much is now known about the complex secretase enzymes whose role in processing APP gives rise to the Ab-peptide (Wolfe, 2002), and a number of potent inhibitors have already been developed as potential therapeutics for this debilitating neurodegen-erative disease (Vassar, 2002). Another way of reducing the levels of aggregation-prone species...

Neurophysiological Factors

As discussed in Chapter 3, organic brain disorders can have a pronounced effect on behavior and abilities. This is particularly evident in Alzheimer's disease, a disorder that afflicts approximately 20 of individuals in the 75- to 84-year age range and about 47 of those over 85 (Evans et al., 1989). An even greater percentage of older Americans suffer from hypertension, another disorder that is associated with reduced intellectual functioning (Hertzog, Schaie, & Gribbin, 1978 Sands & Meredith, 1992) and which can lead to cardiovascular disease and stroke. By interfering with the oxygen flow to the brain, a major stroke can affect not only intellectual abilities but also speaking, walking, and other skills. The brain's blood supply can also be temporarily reduced by emphysema, acute infection, poor nutrition, injuries, and surgery. The loss of neuronal tissue, changes in metabolic rate, and a decline in blood circulation also have depressing effects on cognitive functioning....

Cholinesterase Inhibitors

Fabbrini et al. (104) administered donepezil (5 mg qhs) to eight nondemented PD patients with visual hallucinations, with or without delusions. At the end of two months, subjects had decreased PPRS scores with hallucinations and paranoid ideation, being the most responsive. However, two patients experienced clinically significant motor decline. Another small open-label study enrolled six patients with PD, dementia, and psychotic symptoms and treated them with 10 mg d of donepezil (105). Five patients showed moderate-to-significant improvement in psychosis and one showed minimal improvement. None had worsening of motor symptoms. Finally, Kurita et al. (106) reported three PD patients who had improvement of visual hallucinations with 5 mg d of donepezil without worsening of motor function, but one patient had treatment emergent delusions that resolved, after donepezil was discontinued. Only one placebo-controlled trial of donepezil has been reported for PD psychosis (107). This was a...

Incidence Prevalence and Risk Factors

Estimates of incidence and prevalence of dementia in PD vary widely because of different definitions, methods of ascertainment, and study designs. Prevalence rates of dementia in hospital- or clinic-based cohort studies range from 11 to 22 (123-125), whereas population-based estimates are somewhat higher, ranging from 18 to 44 (9,126-129), perhaps reflecting referral bias. A recent systematic review of the literature estimated that the prevalence of dementia in PD ranges from 25 to 31 (130). This review also found that dementia in PD accounted for 3 to 4 of the total dementia population. Incidence rates for PD dementia range from 4 to 11 per year, with a relative risk for the development of dementia in PD of 2 to 6 (12,129,131-133). Age and severity of extrapyramidal symptoms were associated with an overall risk of developing dementia. One study demonstrated that age and severity of disease by themselves were not associated with a greater risk of dementia, but the combination of these...

Genes predisposing to exceptional longevity

It is practically intuitive to state that centenarians outlive those who are relatively predisposed to age-related fatal illnesses and that they are less likely to have environmental and genetic exposures that contribute to death at earlier ages. This selection phenomenon, called demographic selection, is exemplified by the fact that the apolipoprotein E e4 allele, associated with heart disease and Alzheimer's disease, is rare in centenarians, whereas the prevalence of an alternative allele, e2, is relatively high (Schachter et al., 1994). Along the same lines, it is likely that there are certain environmental exposures that are rare among centenarians as well, such as tobacco, obesity and bullets. Richard Cutler, in what is now a classic paper in gerontology, proposed that persons who achieve extreme old age do so in great part because they have genetic variations that affect the basic mechanisms of aging and that result in a uniform

Inducible expression of mutant DISC1

As the breakpoint is in the middle of open reading frame, the translocation is hypothesized to produce the truncated N-terminus product, mutant DISC1 (Millar et al., 2001). The identifiable mutation that is strongly associated with major mental diseases makes DISC1 and the mutant protein product interesting and attractive candidates for studying the neurobiology of psychiatric disorders (Ross et al., 2006). There are several examples of how similar functional mutations have helped to shed light on the molecular mechanisms of neurodegen-erative diseases, including familial forms of Parkinson's disease and Alzheimer's disease (e.g., Davidzon et al., 2006 Piscopo et al., 2008).

Other Pharmacologic Agents

Few other pharmacologic strategies for specifically treating dementia in PD have even been reported. Because noradrenergic depletion could contribute to executive dysfunction in PD, Bedard et al. (170) conducted a trial of naphtoxazine (SDZ-NVI-085), a selective noradrenergic alpha 1 agonist, versus placebo in nondemented patients with PD. The results of the study demonstrated improved performance on tasks of set-shifting and cognitive flexibility, such as the Stroop and Odd-Man-Out tests. Furthermore, specific evoked potentials (Nd1 and Nd2 curves), thought to reflect attentional processes and known to be affected in PD, were improved with naphtoxazine. Memantine, an N-methyl-D-aspartate antagonist, has been approved for AD but to date there are no published studies of memantine for PD dementia. Estrogen replacement therapy (ERT) may be a reasonable protective strategy for the development of dementia in women who have PD. The effect of ERT on the risk of development of dementia was...

Neuropathological Findings in the PostHAART

Although the incidence of HAD has decreased since the introduction of HAART, there has been a rise in reports of more minor cognitive dysfunctions (63, 64). In addition clinical reports suggest that the regions of the brain maximally affected in HIV have altered (65). In the pre-HAART era subjects with HAD displayed primarily sub-cortical symptoms that correlated well with pathological findings of damage and inflammation in the basal ganglia. Post-HAART, clinical symptomatology in some studies points towards damage in the hippocampus and temporal lobe, although sub-cortical neurodegeneration characteristic of the pre-HAART era is still noted in some studies (66, 67). Dementia is reported as more common in older HIV-positive individuals, suggesting they are more at risk of this complication (68). It has been postulated for some time that those who survive long term with HIV in the HAART era will be predisposed to the early onset of neurodegenerative conditions, principally Alzheimer's...

Association Studies From Genotype to Phenotype

The strength and attraction of association lies in its simplicity and statistical power. As association studies represent a direct test of each al-lele, they offer the greatest sensitivity to detect the relationship between a variant and disease.20 This statistical power will likely be necessary as available data suggest that common, multifacto-rial diseases may well be largely attributable to the contribution of many variants of individually modest effect. Examples of associations include variation in APOE (encoding apolipoprotein E) with Alzheimer's disease,71 F5 (encoding factor V) with deep venous thrombosis,72 and PPARG encoding peroxisome proliferator-activated receptor j (PPARj) with Type 2 diabetes.17 In each of these cases, it was possible to demonstrate association using only hundreds or thousands of patients, whereas many more would have been needed in a linkage study. For the most extreme example, the common Pro12Ala variant in PPARj, a p value of 10-3 was obtained in at...

Parkinsons Disease Diagnosis Accuracy

Prevalence studies of parkinsonism suggest a diagnostic accuracy of 80 after examination and application of clinical diagnostic criteria (49-51). Long-term clinico-pathologic studies evaluating the diagnostic accuracy of PD demonstrate that the diagnoses most commonly mistaken for PD are progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (52,53). However, early in the course of PD, the most common misdiagnoses include essential tremor, vascular parkinsonism, drug-induced parkinsonism, and Alzheimer's disease (54,55). It has been estimated that the diagnosis is incorrect in as many as 35 of those initially diagnosed as PD by generalists (56). In addition, symptoms of parkinsonism are relatively common in elderly subjects, making the diagnosis most challenging in this population. Subtle extrapyramidal signs on neurological evaluation are common in the elderly with recorded prevalences of 32 (57) and 35 (58). Prevalence estimates for clinically evident parkinsonism in...

Locus and allelic heterogeneity the good and the bad

The strategies for hunting genetic risk factors in common disease are mainly predicated on the common disease common variant hypothesis. Although we and others have challenged some of the assumptions inherent in this hypothesis (e.g. Wright and Hastie, 2001), there is no doubt that it applies in a number of cases. The most notable example is the increased risk of early-onset Alzheimer's disease for carriers of the apolipopro-tein E e4 allele and, conversely, the protective effect of the e2 allele (Roses, 1996). One daunting theme emerging from single gene disorders which may have considerable and alarming implications for common disease is the (perhaps) surprising level of locus and allelic heterogeneity. Furthermore, such heterogeneity has been recorded in numerous late-onset Mendelian disorders, some of which are subsets of more common, polygenic diseases. In regard to locus heterogeneity, mutations in at least three different genes may lead to early-onset familial Alzheimer's...

Tau Phosphorylation By Gsk3

Phosphorylation of Tau has been proposed as an important nongenetic factor involved in tauopathies as AD. In addition to the residues present in the microtubule binding domain (MBD), Tau molecules present in PHFs are hyper-phosphorylated at sites flanking the MBD. More than 30 sites could be modified by phosphorylation in Tau protein. These sites have been divided in nonpro-line kinase directed sites and proline kinase directed sites 54 with mainly the second class being preferentially modified by GSK-3. Many GSK-3 substrates require a priming phosphorylation by a priming kinase on a Ser or Thr residue with four amino acids at the C-terminal to the phosphorylatable Ser or Thr residue. The crystal structure of human GSK-3P has provided a model for the binding of prephosphorylated substrates to the kinase (PDB ID are 1I09 33 and 1H8F 34 ). Thus, primed Ser Thr are recognized by a positively charged binding pocket that facilates the binding of primed substrates. Nevertheless, the GSK-3...

The study of monogenic subsets give mechanistic insights into common disease leading to novel therapeutic approaches

Alzheimer's disease (AD) is a neurodegenerative condition always associated with pathological structures in the brain called amyloid plaques. One of the main constituents of these plaques is the 42 amino acid peptide called amyloid-b (Ab) which is produced by cleavage from a neuronal transmembrane protein, the amyloid precursor protein (APP). There are a number of rare Mendelian subsets of AD, all characterized by early-onset, highly penetrant disease. Individuals affected with the monogenic forms of AD also exhibit plaques, as in the common form of AD. Prior to the genetic breakthroughs described below, there was much debate about whether the Ab protein and the plaques were a cause or consequence of the disease. Now it seems there is little doubt that the production of excess Ab and the resultant plaque formation cause disease by an, as yet, unknown mechanism (Roses, 1996). The three genes mutated in monogenic AD encode APP itself, and the presenilins 1 and 2. The APP mutations are...

Monogenic genes as genetic risk factors in common disease

Janus, C., Pearson, J., McLaurin, J. et al. (2000). A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature, 408, 979-82. Lettice, L.A., Heaney, S.J., Purdie, L.A. et al. (2003). A long-range SHH enhancer regulates expression in the developing limb and fin and is associated with preaxial Polydactyly. Hum Mol Genet, 12, 1725-35. Liu, H.-X, Cartegni, L., Zhang, M.Q. and Krainer, A. R. (2001). A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nat Genet, 27, 55-8. Myers, R.H., Schaefer, E.J., Wilson, P.W. et al. (1996). Apolipoprotein E e4 association with dementia in a population-based study the Framingham Study. Neurology, 46, 673-7. McKusick, V.A. (1998). Mendelian inheritance in man. A catalog of human genes and genetic disorders, 12th edn. Baltimore, MD Johns Hopkins University Press. Pharoah, P.D., Antoniou, A., Bobrow, M. et al. (2002). Polygenic susceptibility to breast cancer...

Familial Parkinsonism

Less common than ARJP are autosomal dominant forms of early onset PD. The best characterized is the Contursi kindred, a familial PD due to a mutation in the a-synuclein gene (62). The pathology of the Contursi kindred is typical Lewy body PD however, given the young age of onset, by the time the individual dies, Lewy body pathology is typically widespread in the brain. Lewy neurites are also prominent in many cortical areas. Some young onset autosomal dominant PD kindreds, such as the Iowa kindred, have atypical clinical presentations and include family members with dementia and psychosis. The Iowa kindred has a multiplication of the a-synuclein gene (63). Families with duplications have a milder phenotype than those with a triplication of the a-synuclein gene, suggesting a role for overexpression of a-synuclein in the pathogenesis of even sporadic PD (64). The pathology in cases with gene triplication is associated with severe Lewy body-related pathology in the cortex, hippocampus,...

Prolong Life Or Forgo Lifesustaining Treatments

To focus our attention in this chapter on the elderly and their families is especially important since death occurs more at older ages and older people are at greater risk of terminal illnesses and dementing diseases than are younger people. As a result, elderly persons are more likely to become candidates for life-sustaining treatments as well as to face decisions to refuse such treatments. Consequently, decisions to withhold or withdraw life-sustaining treatments directly affect older people more frequently than younger people. Such decisions and other care decisions are likely to come at a time when cognitive impairment is present due either to a terminal illness, unconsciousness, or dementia. When one or more of these impairments occur, consent to or refusal of treatment must be made by someone other than the patient. Prior to the extensive use of life-sustaining technologies, families were typically called upon to make such decisions, or, alternatively, very few end-of-life...

Joint effects of genes and environment

More commonly, we see a quantitative gradient in the environmental potentiation of effect across allelic subgroups of genotype. For example, the risk of developing Alzheimer's disease is raised by a factor of eight in individuals with an atherosclerosis score in the top quartile but only if they carry at least one copy of the e4 allele of the ApoE gene (Hofman et al., 1997). The risk in individuals with an atherosclerosis score in the top quartile and with non-e4 alleles on both chromosomes is still increased, but only by a factor of three, relative to individuals in the lowest quartile of the atherosclerosis score (Figure 11.2).

Major Mendelian genes versus minor polygenes as predisposers

Figure 11.2 Joint risk of developing Alzheimer's disease as a function of apolipoprotein-E genotype and atherosclerosis score (from Hofman et at, 1997). Figure 11.2 Joint risk of developing Alzheimer's disease as a function of apolipoprotein-E genotype and atherosclerosis score (from Hofman et at, 1997).

Prion proteins and prion diseases

Apart from prion diseases the conversion of proteins into an insoluble form (amyloid) occurs also in other diseases like Morbus Alzheimer. Like in prion disease conversion of part of the protein into -sheets seems to be the root of the problem. Recent evidence may indicate that the strands in these sheets are relatively short and have little twist 83 . As a result, amino acids in amyloid -sheets have a much narrower range of and & values than normal 3-sheets, making them occupy a small region in the RAMAOHANDRAN-plot near the diagonal. However, although this hypothesis is attractive, experimental evidence for it is currently limited.

Clinical features

Fever, weight loss, diarrhoea, skin changes, CNS manifestations. Haematological abnormalities include thrombocy-topaenia, leucopaenia, neutropaenia, hypergammaglob-ulinaemia and anaemia. Infections may start to occur with organisms such as herpes simplex or zoster, Pneumococcus and Salmonella. When the CD4 count falls below 0.2 X 109 l, the patient becomes susceptible to a wide spectrum of opportunistic infections (Streptococcus pneumoniae, Haemophilus influenzae, Pneumocystis carinii, toxoplasmosis, Mycobacterium tuberculosis, atypical mycobacteria, histoplasmosis, Cryptococcus, cryptosporidiosis, fungal infections, Jamestown Canyon (JC) virus infection and CMV infections), malignancies (Kaposi's sarcoma and non-Hodgkin's lymphoma) and CNS disease such as dementia may develop. This stage of infection is classified by the Centre for Disease Control (CDC) as fully developed acquired immunodeficiency syndrome (AIDS). Many staging systems for HIV have been proposed and exist. Mostly...

Comparability To Human Agerelated Cognitive Decline

There is substantial evidence that specific factors that adversely impact cognition in rat models also correlate with age-related cognitive impairment in primates, including humans. For example, assessment of the degree of atrophy of the medial temporal lobe in humans is an effective predictor for the development of dementia in patients with mild cognitive impairment (Korf et al., 2004), and medial temporal lobe atrophy in stroke patients predicts poor cognitive performance (Jokinen et al., 2004). Likewise, lesions of medial temporal lobe structures induce memory impairments in rodents (reviewed by Jarrard, 1993). Moreover, age-related changes such as alterations in the glucocorticoid system and increases in oxidative stress are found among aged rat and human populations (Bizon et al., 2001 Nicolle et al., 2001 de Quervain et al., 1998 Roozendaal, 2002 de Quervain et al., 2003 Lupien et al., 2005). Finally, as discussed in more detail below, the absence of frank neural loss among aged...

The Longevans Hooded

As can be observed in the circuit diagram shown in Figure 32.1, information flow in the system is multidirectional. Memory processing involves the hippocampal formation and entorhinal cortex, and information flows bi-directionally between these structures. Both of these brain regions receive direct projections from other brain areas, including the neocortical regions and subcortical structures. Communication with the hippocampus to other cortical regions is through the entorhinal cortex that receives input from and sends output to the para-hippocampal gyrus (which includes the perirhinal and postrhinal cortices). Cellular regions of the hippocampus can be observed in the lower diagram (Figure 32.1), which highlights circuitry in a coronal section of rat hippocampus. The entorhinal cortex provides input to the dentate gyrus granule cells via the perforant path. The subgranular zone is a site of new neuron generation throughout the lifespan, a phenomenon that is the focus of...

Model For The Ageimpaired Medial Temporal System

Using the derived spatial Learning Index Score, one is then able to correlate a variety of neurobiological and neuroanatomical data with spatial learning performance among aged rats. Figure 32.4 shows data obtained using the behavioral model described above. In this study, the total number of neurons in the hippocampal region was assessed in behaviorally characterized rats using quantitative unbiased stereology, as many theories of age-related memory loss at the time regarded cell loss as the endpoint for age effects on cognition. However, as shown

Nonpsychotic Disorders

Because alcohol is rich in carbohydrates but low in proteins and vitamins, long-term users can develop cirrhosis of the liver due to protein deficiency or Korsakoff's syndrome due to vitamin B deficiency. The symptoms of Korsakoff's syndrome, a chronic brain disorder occurring most often in chronic alcoholics in their fifties and sixties, include disorientation, impulsiveness, memory loss, confabulation,1 and inflammation of the peripheral nerves of the body.

Risks of coercion in counseling

Same time, we have to recognize that the ability to identify the genetic coding indicative of the presence of a particular disease or disability, such as Huntington's Chorea or Alzheimer's, does not extend to the ability to estimate the likely severity of the condition, should it develop, or the age of onset (Larson, 2002, p. 929). This means that counseling patients on the question of whether or not an identifiable genetic characteristic constitutes a serious risk, or a sufficiently serious condition to warrant embryonic de-selection, for example, is currently unanswerable, and therefore ethically problematic. In addition, many of the conditions for which we are able to identify the genetic hallmarks can vary significantly in their effect on the quality of life of the individual in question. The fact that the genetic factors for a condition can be identified through genotyping does not yet indicate, with a sufficient degree of certainty, whether, or to what extent, the condition will...

Micronutrients Alleviating Nutritional Disorders By Nutraceuticals

Also, now it is known that vitamins, minerals, and other dietary components consumed at varying levels, higher than RDAs, are significant contributors to the reduction of risks of chronic diseases such as cancers, cardiovascular diseases, and degenerative diseases associated with aging (Alzheimer's, premature aging). Their role in maintaining human genomic stability is likely to be critical to alleviating the classical nutritional deficiency diseases which include scurvy (vitamin C), anemia (folic acid, iron), and pellagra (niacin) (Tables 5.1, 5.2) (4-7,17,20,21).

Cognitive Function and Aging in the

Others exhibit a mild decline frequently observed in normal human aging. In certain cases, some dogs exhibit severe impairment corresponding to features of dementia observed in humans. Our studies have also revealed that learning and memory impairments can occur independently of one another and that executive dysfunction may be the earliest hallmark of cognitive decline in aging dogs.

Impaired Learning In The Aged

Procedural learning The procedural learning task, designed to assess skill acquisition in the dog, consists of two learning phases reward-approach and object-approach learning (Milgram et al., 1994). Procedural learning is well preserved in normal human aging (Vakil and Agmon-Ashkenazi, 1997) and Alzheimer's disease (Almkvist, 1996). In dogs, however, procedural learning depends on previous rearing experience. Aged dogs raised as pets, having diverse and varied life experiences, perform as well as or better than young dogs. Conversely, old kennel-reared dogs with limited experiences in the environment are slower than