Scientists Reverse Memory Loss in Alzheimers

All About Alzheimers

All About Alzheimers

The comprehensive new ebook All About Alzheimers puts everything into perspective. Youll gain insight and awareness into the disease. Learn how to maintain the patients emotional health. Discover tactics you can use to deal with constant life changes. Find out how counselors can help, and when they should intervene. Learn safety precautions that can protect you, your family and your loved one. All About Alzheimers will truly empower you.

Get My Free Ebook


The Great Brain Secret

This DVD shows the secret to getting back all of your brain strength and giving you the mental power and memory of a much younger person. You can learn the 60 second trick that will regrow your brain cells and get rid of all of your senior moments and give you the mental power that you have always needed. Family members have said of people that have done this program that it is like getting their grandparent back. If you find that you have trouble remembering your grandchildren's names or important dates or anniversaries, this course is for you. You will remember everything that you forgot, and have the memories that you used to not be able to form. If you already have signs of forgetfulness, you are on a dangerous path that could eventually lead to you forgetting almost everything. If you act soon, you can get your mind to all the strength that it is supposed to have!

The Great Brain Secret Overview

Rating:

4.6 stars out of 11 votes

Contents: DVD Video
Creator: Walter Bailey
Price: $37.00

Download Now

Alzheimers Disease The Scope of the Problem

Alzheimer's disease (AD) is poised to become the scourge of the next century, bringing with it enormous social and personal costs. Depending on the methods of assessment used, estimates of the prevalence of dementia due to AD in Americans 65 and older range from 6 to 10 (1-3). The prevalence of the disease doubles every 5 years after the age of 60 (4-6). For the population 85 and older, estimates of the prevalence have been as high as 30-47 (1-3). As many as 4 million Americans may suffer from a clinical dementia of the Alzheimer's type, with an annual cost of approximately 100 billion (7). Based on current rates, and in the absence of effective prevention, it is estimated that in 50 years, there will be as many as 14 million cases of clinically diagnosed Alzheimer's disease in the United States alone. While AD is a major public health problem, it also has a very private face that causes tremendous suffering to families. For the elderly, it one of the most dreaded afflictions that...

Evidence for a Role in Alzheimers Disease

Alzheimer's disease (AD) is a progressive, often insidious, dementing disease occurring in mid- to late life. Its incidence increases with age, such that at age 85+ approximately 20 of people suffer from the condition. AD causes neurone death and a reduction in brain volume. The progression of the disease (which in most cases means approximately 7 years of intellectual and personal decline until death) cannot be arrested and eventually patients become bedridden. At this stage, concomitant bedsores, feeding difficulties, and pneumonia result in death. The etiology of nonfamilial, sporadic AD is unknown. However, cases have been attributed to head injury and environmental factors, including aluminum. Involvement of aluminum in AD has been suggested because (1) of the similar symp-tomologies of AD and dialysis dementia (2) the administration of aluminum to animals produces histological changes within the brain that are, in some respects, similar to those seen in the brains of AD patients...

Interventions With Patients With Dementia

Medications are now available for Alzheimer's disease and other dementias that sometimes slow the progression of symptoms, but do not reverse the overall course of the disorder (Mendez & Cummings, 2003). Psychological interventions have focused on the early stages of the illness when people still have an awareness of their problems, and can actively participate in treatment. Early stage support groups for patients and their families have been very popular and can now be found in many communities (e.g., Yale, 1989, 1999). Examples of counseling with the person with dementia or with the person and his her caregiver have also been reported (Zarit & Zarit, 1998). Many different treatment strategies have been described, including improving communication between the person with the illness and his her spouse or other family caregiver, learning strategies for managing memory loss, exploring how to talk about the disease with family and friends, finding ways for the person with dementia...

Early Diagnosis In Alzheimers Disease Summary

There is indeed a dual challenge that faces us in our efforts to conquer Alzheimer's disease. We need to develop early, definitive, and noninvasive diagnostic tests for the disease and we need to treat early with agents aimed at stemming the pathological process of the disease. Ultimately, there is little clinical utility in the development of effective treatments without the capacity for early diagnosis, or in the development of techniques for early diagnosis of the disease without the availability of effective treatments. For Alzheimer's disease, there must be a dialectic relationship between research on diagnosis and research on treatment. We are in a critical transition period that has as yet yielded neither adequate early diagnostic strategies nor robust therapeutic interventions. Ideally, the pace of progress in therapeutics will match that of diagnostics. If the development of predictive (genetic) or diagnostic tests outpaces that of therapeutics, we will face difficult social...

An Evolving Understanding of Dementia

Within three years of the publication of Dr. Alzheimer's first case, the term Alzheimer's disease was applied to patients who developed significant difficulty in memory and other areas of cognition at an age less than sixty-five years. Individuals who developed such symptoms later in life, generally after the age of sixty-five, were said to be suffering from senility, a process

Rationale for a Genetic Approach to Alzheimers Disease

Alzheimer's disease, broadly defined, is a complex genetic disorder Multiple causative and susceptibility genes acting singly or in concert produce similar symptoms and pathologic changes in patients. In each of its forms, it manifests age-dependent penetrance, meaning that the older an individual becomes, the more likely it is that he or she will develop the disease. Disease manifestations (such as age of onset or rate of progression) may be influenced by environmental exposures (alcohol use, head injury) or other health conditions (such as cerebrovascular disease). Identification of AD genes will lead to a better understanding of the cellular processes that cause dementia.

Initiation of a Dementia Evaluation

Evaluations for dementia are initiated under different circumstances. Most often, family members bring in a loved one because they are concerned about a decline in his her cognitive or behavioral status. Patients who often lack insight due to their central nervous system (CNS) disease (or psychological defenses), are unlikely to recognize the need for such an evaluation. Other patients may accept some of the observations of decline made by their loved ones, but downplay their implications. Increasingly, patients themselves seem to be sharing concerns with their physicians about problems with forgetfulness, word-finding difficulties, or slowness in retrieving names. Some of these patients will be in the early stages of a dementing illness. Others may be particularly sensitive to the cognitive changes that are associated with normal aging or be suffering from depression (18,19). Requests for evaluation may become increasingly common as information about dementia and Alzheimer's disease...

Progressive Amnestic Dementia Probable Alzheimers Disease

The most common pattern is a progressive amnestic dementia, in which deterioration in memory functions is the salient feature. The course is insidiously progressive, with memory impairments usually being the initial source of disruption of daily activities. Informants often provide a history of progressive problems with recalling recent events, misplacing objects, repeating questions, becoming disoriented or lost, producing the wrong words, or exhibiting fluent but empty speech. Early on, there may be subtle changes in personality in the form of increased disengagement or withdrawal from activities, but grossly inappropriate behaviors are unusual (81,82). This dementia profile is the most frequent one seen in the elderly and is most often associated with the plaque and tangle pathology of Alzheimer's disease. The National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRA) (10) has codified the clinical...

Limits of Current Approaches to the Clinical Evaluation of Alzheimers Disease

If using standard clinical tools can yield such high accuracy rates for diagnosis of AD, why is there a need for other approaches This important question can be addressed in several ways. First, we are unaware of any systematic study regarding the extent to which most practitioners actually follow the guidelines reviewed in this chapter. There is likely to be a gap between the practice patterns of clinician-researchers in Alzheimer's disease centers and physicians in the community. Practitioners in research centers see a very large volume of demented patients. The impressive accuracy rates reported by such centers may not be due to the fact that the clinicians followed standard guidelines. Rather these particular clinicians may have a wealth of experience upon which they developed the kind of clinical expertise that yields excellent diagnostic results. The extension of such expertise into the community is an important goal, but one that may be very difficult to achieve. We suspect...

Pathological Hallmarks of Alzheimers Disease

In the first report on the disease which now bears his name, Alois Alzheimer (3) described two types of lesions in the brain of his patient tangled bundle of fibrils and miliary foci resulting from the deposit of a unique substance. The terms commonly used today to designate these lesions are the neurofibrillary tangle (NFT) and the senile plaque (SP), respectively. The presence, characteristic distribution, and density of these lesions are used by pathologists for the diagnosis of AD. From Early Diagnosis of Alzheimer's Disease Edited by L. F. M. Scinto & K. R. Daffner Humana Press, Inc., Totowa, NJ

Contribution of Plaques and Tangles to Dementia

Initial studies reported significant correlations between the presence and density of cortical SP and NFT and the severity of dementia in AD (21,33). A large number of more recent investigations, however, have indicated divergent relationships. More specifically, the distribution and total density of SP have been found to display little relationship with the presence, and particularly the severity, of dementia (18,34-36). Some studies, however, have reported a correlation between the density of neuritic plaques and severity of dementia (23,35). In contrast to SP, the density of NFT has been found to display a strong relationship with the presence and severity of dementia (18,37,38). A simple interpretation of the above findings would be that SP does not figure prominently in the etiology of dementia in AD. However, such a simple interpretation may be premature for several reasons. First, the presence of SP, particularly its neuritic variety, appears to be a more specific feature of AD...

Characteristics And Epidemiology Of Dementia

Most diagnostic criteria for the dementia syndrome stipulate that two or more cognitive functions must be sufficiently impaired so as to interfere with social and or occupational functioning and that there must not be clouding of consciousness. Clouding of consciousness, particularly in the context of a sudden onset of confusion, disorientation, hallucinations, disturbance in attention, or marked behavior change, is typically indicative of delirium (also termed acute confusional state). Delirium may be caused by an acute or chronic systemic illness (e.g., bacterial infection, hypoglycemia), adverse effects of medication, or serious neurological event requiring immediate medical attention. Untreated, these illnesses may result in death or irreversible impairment. The risk of developing dementia increases markedly with age in later adulthood and is the single most prevalent category of mental illness for older persons. Worldwide, between 10 and 15 of persons over the age of 65 show at...

Frontotemporal Dementias

FTD includes both Pick's disease and non-Pick's frontotemporal dementia (also called frontal lobe dementia, FLD), motor neuron disease, and progressive subcortical gliosis. Although estimates of the prevalence of FTD remain somewhat controversial, some investigators think that these disorders have been underestimated and could account for 10-19 of all demented cases. The usual age of onset is between 45 and 65 years, with equal sex incidence. A family history of the illness is present in approximately 50 of persons with FTD. FTD includes subtypes of semantic dementia, primary progressive aphasia, and progressive prosopagnosia, as described later. Pick's disease is characterized by Pick's cells (enlarged neurons with displaced nuclei) and Pick's inclusion bodies (round intraneuronal cellular inclusions) in frontal and temporal cortical areas. In Pick's disease, marked atrophy (termed knife edge'' due to the extreme thinning of the cortical gyri) is found in the frontal and anterior...

Dementia Associated With Depression

Further complicating both accurate diagnosis and treatment is the fact that various prescription and nonprescription medications (and their interactions) can cause, aggravate, or mimic depression symptoms. In addition, persons with depression show impairment on a range of neuropsychological measures of cognitive functioning, particularly on speeded tasks, vigilance tasks, and tasks with pleasant or neutral (in contrast with unpleasant) content. The magnitude of cognitive impairment tends to increase with older age, severity of depression, and history of electroconvulsive treatment (ECT). Previously, the term pseudo-dementia'' was often used to describe persons with depression and cognitive impairment, reflecting the expectation that the cognitive deficits would reverse along with effective treatment of the depression. However, this term is no longer used because several Criteria for Vascular Dementia (VAD) (1) Dementia is present, defined by (a) cognitive decline from a previously...

Treatment And Clinical Management Of Dementia

Pharmacological treatment options for the dementias presently are limited, although numerous experimental treatments are being evaluated. The one well-validated approach to symptomatic treatment of AD is based upon the documented deficit in acetylcholine neurotransmitter levels, due to the loss of cholinergic projecting neurons within the nucleus basalis of Meynert. It has been shown that this deficit can be partially compensated for by interfering with the action of that enzyme (cholinesterase), which breaks down acetylcholine after it enters the synaptic junction, allowing the constituent molecules to be taken back into the presynaptic neuron to synthesize additional acetylcholine. There are four such cholinesterase inhibitors that have been approved by the U.S. Food and Drug Administration Tacrine, Donepezil, Rivas-tigmine, and Galantamine. These drugs have all been shown to result in some temporary improvement of function in at least some AD patients. However, none of these drugs...

Alzheimers Disease AD

AD is a neuro-degenerative disease characterized by the progressive deterioration of higher cognitive functions, including memory loss. Since nicotinic receptors play a critical role in learning and memory, it is not surprising that AD patients lose the cholinergic pathways from the basal forebrain to the hippocampus and the cortex. Moreover, the brains of AD patients have a reduced number of cholinergic cells and presynaptic nAChRs. Since low levels of ACh are believed to lead to the cognitive decline observed in patients, cholinesterase inhibitors (such as tacrine, donepezil, and rivastigmine) are currently used to treat AD.

Homocysteine Cognitive Function and Dementia

As the relationship between homocysteine and vascular disease became increasingly apparent, researchers also addressed the hypothesis that hyper-homocysteinemia may affect cognitive function and the risk of dementia in older adults. This was based primarily on the recognized association between homocysteine and cerebrovascular disease, but also the observation that homocysteine and its metabolite, homocysteic acid, can induce excitotoxicity in neurons. Throughout the 1990s and into the new century, many cohort studies revealed significant inverse correlations between plasma homocysteine concentration and performance on a variety of cognitive function tests. Moreover, individuals with Alzheimer's disease were found to have higher plasma homocysteine than age- and gender-matched controls, while baseline homocysteine levels predicted the risk of incident dementia.

Anomia In Alzheimers Disease

Alzheimer's disease (AD) is the most studied of the dementia-producing diseases that can have anomia as a salient symptom. Dementia (see the article on it in this volume) may be defined as a progressive cognitive decline resulting from a number of diseases. Such a cognitive decline characteristically may include more language disturbance (as in Alzheimer's disease in all but very-late-onset instances) or less language disturbance (as in the dementia associated with perhaps one-third of the individuals with Parkinson's disease). When a language disturbance is evident, anomia is invariably a part of it. The naming problems associated with the dementias may or may not be termed anomia by different scholars however, the phenomenon is quite similar to that found in the aphasias. What underlies the problem, however, appears to be different. First, the cognitive problems underlying the dementia regularly include a variety of memory problems, so one may argue that the difficulty with...

Dementias With a Prominent Dysexecutive Syndrome

A second major dementia pattern involves patients who exhibit salient changes in personality and behavior, accompanied by compromised attention, motivation, judgment, insight, and other executive functions. This clinical entity has been given several names including frontotemporal dementia (FTD), dementia of the frontal lobe type, and comportmental dementia (30,50,86-88). In addition, there are overlapping features with the so-called subcortical dementias (89,90). This overlap is likely due to the intense connections between the frontal lobes and subcortical regions (91,92), as noted in Figure 2. frontotemporal dementia reportedly do better on tests of constructions and calculations (93). Performance in other realms may also be impaired because of a lack of motivation or mental activation. Memory is compromised mainly at the encoding or retrieval stages. With cueing, recognition memory is often relatively well preserved. There is diminished spontaneous verbal output that over time may...

The striatal dopaminergic system and Parkinsonism

In addition to the well-established degenerative changes in the dopaminergic system which are the main neuropathological features of Parkinson's disease, it is now known that aminergic and cholinergic ascending subcortical neurons, and peptidergic pathways, are also affected in this disease. Thus lesions of the locus coeruleus occur, with a loss of noradrenaline and its main synthesizing enzyme, dopamine beta-oxidase, in both cortical and subcortical regions of the brain. It would appear that the dorsal bundle from the locus coeruleus is most severely damaged, while the ascending pathways are largely unaffected. In patients at an advanced stage of the disease, cortical alpha1 and beta adrenoceptors show an increase which may be correlated with the onset of some of the symptoms of dementia in these patients. Similarly, a defect in serotonergic transmission has been reported in Parkinsonism, a change that may contribute to the depressive symptoms that often occur in the advanced stage...

Chemokine Receptors and HIVAssociated Dementia

HIV-associated dementia (HAD) is a cognitive and motor dysfunction observed after infection with HIV-1 (Kaul et al., 2001). Although about one-half of children and one-fourth of adults infected with HIV-1 eventually develop the dementia (Lipton and Gendelman, 1995 McArthur et al., 2003), there is no specific treatment for HAD. In recent years, chemokine receptors have been found to play important roles in the pathogenesis of HIV-1 infection, including HAD. In a plausible model, HIV-1 enters target cells through a direct fusion process in which HIV-1 gp120 binds to CD4, the main receptor on the target cell surface, and to one of the two chemokine receptors, usually CXCR4 or CCR5 (Berger et al., 1999 Poignard et al., 2001). Natural chemokines that bind CXCR4 and CCR5 can inhibit HIV-1 infection (Bleul et al., 1996a Oberlin et al., 1996), probably by blocking common binding sites on the chemokine receptors that are also required for gp120 interaction and or by inducing receptor...

Neuropsychological Deficits Characteristic of Dementia Associated with Alzheimers Disease

Criteria for the clinical diagnosis of probable or possible Alzheimer's disease (PrAD or PoAD, respectively) were proposed in 1984 and still constitute the standard in most research studies (24). The criteria for PrAD specify the presence of a progressive memory disorder accompanied by deficits in other cognitive domains, including aphasia, visuoperceptual constructional deficits, and abnormalities of reasoning and personality. The diagnostic criteria have been validated against neuropathological findings at autopsy (25) and have been shown to be associated with the plaques and tangles of Alzheimer's disease as specified by diagnostic criteria (26) in 85-100 of cases (9,27-28). Neuropsychological studies of patients with PrAD have provided detailed information about the nature of specific cognitive impairments. The most essential and consistent feature of PrAD is the presence of a defect of explicit learning and memory. In preclinical phases of the illness, as shown in follow-up...

TABLE 2211 Features of Delirium Dementia and Psychiatric Psychosis

Following this model, disorders of consciousness may be divided into processes that affect either arousal functions, content of consciousness functions, or combinations of both functions. Dementia may be thought of as failure of the content portions of consciousness with relatively preserved alerting functions. Predominant arousal system dysfunction describes delirium, although content of consciousness is affected as well. Coma represents one extreme with failure of both arousal and content functions. Psychiatric disorders and altered mental states may share features such as hallucinations or delusion some distinctions between the different states are summarized in Table.221-,1.1

Use of Neuropsychological Tests and Test Batteries for Detecting and Predicting Early Alzheimers Disease

A number of studies have investigated the utility of neuropsychological measures for differentiating nondemented from mildly demented patients and predicting which normal subjects will progress to a dementia state. These studies range from the use of simple screening measures or single neuropsycho-logical tests for classification and detection of disease to more sophisticated regression formulas for deriving predictions from selected tests with a high degree of sensitivity and specificity for dementia and Alzheimer's disease. The development of global screening measures such as the Mini Mental State Examination (MMSE) (74) or the Blessed Dementia Rating Scale (75) were early attempts at discriminating cognitively intact normals from those with dementia. They are still widely used in research for this purpose because of their reported utility in identifying those at high risk for developing Alzheimer's disease (76). However, there are several reports in which these measures have been...

Aberrant Biological Processes in the Alzheimer Brain

A key step underlying the development of the NFT is the accumulation of hyperphosphorylated tau molecules in neurons which bundle into paired helical filaments. Although and modified tau play a central role in Alzheimer pathology, it is becoming increasingly clear that AD results from a complex series of steps a pathogenic pathway that goes beyond the formation of amyloid and NFT. A loss of synaptic density in the AD brain has been observed consistently, although this feature is not usually assessed histopathologically because of methodological complexity (206). Synaptic disconnection and neurodegenerative sprouting in AD correlate with overexpression of particular classes of neuronal thread proteins (70-72).

Possible Order of Events in the Alzheimer Pathogenic Pathway

A clue about early steps in the pathogenic pathway has been provided by studies of brains of people with Down syndrome. (The cells of people with Down syndrome carry an extra chromosome 21, which most often is the result of meiotic nondisjunction.) Almost all persons with Down syndrome develop brain pathology resembling that in AD and frequently dementia resembling AD by age 40-50 (166,228). Trisomy 21 is known to be associated with excessive production of (which is derived from APP encoded on chromosome 21) and with an inflammatory reaction in the brain accompanied by the high expression of interleukin-1 (IL-1) and astroglial activation. These features also are characteristic of the Alzheimer brain (121,122). Genetic and biochemical studies of the Alzheimer and Down syndrome brain, the APP, a1-antichymotrypsin (ACT) and ApoE genes and proteins, and of factors initiating the polymerization of peptide into amyloid filaments, have suggested that one of the earliest steps in this pathway...

Table 179 Diagnostic criteria for vascular dementia according to WHO

Diagnostic Criteria for Vascular Dementia 1. Dementia of a specified level of severity 4. History, examination, or tests disclose severe cerebrovascular disease which may be judged to be related to the dementia Creutzfeldt-Jakob disease is a rare, rapidly progressing form of dementia. It generally presents with vague initial symptoms such as irritability and somatic sensations. Motor signs like myoclonus, Parkinsonism, and motor neuron dysfunction may also be present. Normal pressure hydrocephalus is a poorly understood cause of dementia characterized by a triad of gait disorder, urinary incontinence, and cognitive decline. Nonpharmacologic treatment is often employed for certain manifestations of dementia such as circadian rhythm disturbances, catastrophic reactions, and wandering. Alzheimer's Disease Donepezil is regarded as the first-line treatment for dementia as it is more selective, longer-acting, and has fewer side effects than tacrine. Conjugated estrogens. Estrogen shows...

Cerebrospinal Fluid Tests for Alzheimer Disease

NYMOX has developed a quantitative test for measuring levels of a specific type of neuronal thread protein (AD7c-NTP) in small samples of CSF (70-72). This protein is overexpressed in brain neurons in AD. The promotional material of NYMOX indicates that in 80-90 of autopsy-verified cases of AD, the level of this protein exceeds a designated cut-off level, while less than 5 of control values exceed this level. This test is being advertised as the first test proven to help physicians be certain in the diagnosis of Alzheimer's disease . . . now you can rule it out. Because interpathologist agreement for the diagnosis of AD by brain autopsy is about 85 , it has been suggested that the CSF test might be used as a gold standard against which other antemortem tests for AD are compared instead of brain autopsy. The 1992 publication had some important limitations. Around 70 of clinical patients with probable AD were reported to have AD7c-NTP levels > 3 ng mL in contrast to less than 5 of...

Mild Cognitive Impairment in the Elderly At Risk or Preclinical Dementia

Despite living independently in the community, many elders show some degree of abnormal cognitive decline on standardized testing. When community dwelling elders with mild cognitive impairments are studied longitudinally, some go on to develop dementia (56-59) while some do not (60-61). The presence of mild cognitive problems, by themselves, in community dwelling elders, is not necessarily predictive of a preclinical stage of Alzheimer's disease but can also be associated with the variability seen in normal aging and a variety of medical, neurological, and psychiatric illnesses (62-64). Therefore, the ability to distinguish age associated cognitive change from symptoms that herald a future dementia is critical in research on aging, particularly for those investigating early markers of Alzheimer's disease. With this in mind, several attempts have been made over the last 10 years to develop operationalized criteria for making these distinctions (65-67). Historically, memory loss has...

Other Cerebrospinal Fluid Abnormalities in Alzheimer Disease

Dementia levels correlate negatively with stage of severity of AD IL-1 increased in sporadic AD and in de novo Parkinson's patients 28 dementia complex, multiple sclerosis, systemic lupus erythymatosis, 124 CNS trauma, viral and bacterial meningitis IL-6 no change in first degree relatives and patients with AD 129 Neuropeptide changes in dementia are controversial 391 with severity of dementia Norepinephrine decreased substantially 89 Superoxide dismutase activity decreased in total dementia, DAT, 68 and non-DAT dementia groups a1-ACT, a1-antichymotrypsin DAT, dementia of the Alzheimer type EOAD, early onset Alzheimer disease GABA, 7-amino butyric acid IL, interleukin LOAD, late onset Alzheimer disease TNF, tumor necrosis factor. Abnormalities denoted with an asterisk are striking and merit further investigation.

Application of SMMChemokines to Probe Signaling Pathways Involved in HIVAssociated Dementia

To understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HIV-associated dementia (HAD), we have also applied SMM-chemokine analogues derived from natural SDF-1 a or vMIP-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. Because of the profound activities of chemokine receptors in HAD, developing selective, potent inhibitors of chemokine receptors and understanding the physiological or pathological processes of HAD are crucial in devising novel strategies for clinical interventions. normally found in brain, i.e., neurons, astrocytes, and macrophages microglia, but also express CXCR4, CCR5, and other chemokine receptor homologues (Heesen et al., 1998 Hesselgesser et al., 1997 Lavi et al., 1997 Rottman et al., 1997) that, like the human chemokine receptors, are capable of mediating HIV-1 infection via gp120 binding (Parolin et al., 1998 Plesoff et al., 1997), we demonstrated that neurotoxic...

Reported Abnormalities in Different Cells and Tissues Other Than White Blood Cells in Alzheimer Disease

Patients positive correlation with dementia severity in Parkinsonian and demented patients Increased phenolsulfotransferase activity correlation between 29 intensity of the 130 kDa and 106-110 kDa isoforms is significantly lower in AD than in controls and non-AD dementia patients significant correlation of isoform ratio with severity of disease Altered amyloid protein processing 325 DAT, dementia of the Alzheimer type GTP, guanosine triphosphate Cu Zn SOD, copper zinc containing red cell superoxide dismutase MnSOD, manganese-containing superoxide dismutase of mitochondria VAD, vascular dementia.

The Fundamental Moral Question Do People with Dementia Count

Despite the seriousness of dementia and the responsibilities it creates for caregivers, it is ethically important that the person with dementia not be judged by hypercognitive values (Post, 1995, 2000a). The self is not cognition alone, but is rather a complex entity with emotional and relational aspects that should be deemed morally significant and worthy of affirmation (Sabat). A bias against the deeply forgetful is especially pronounced in personhood theories of moral status in which persons are defined by the presence of a set of cognitive abilities (Kitwood). After discussion of the disparities in bioethical thinking about what constitutes a person, Stanley Rudman concludes, It is clear that the emphasis on rationality easily leads to diminished concern for certain human beings such as infants, and the senile, groups of people who have, under the influence of both Christian and humanistic considerations, been given special considerations (Rudman, p. 47). Often, the personhood...

Dementia Screening Tools

Because detection of age-related cognitive impairments and dementia plays a significant role in neu-ropsychological evaluation, a number of specific screening tools have been developed (Table VIII). Many of these measures are designed to quickly assess gross level of functioning in major cognitive domains and can be administered in a matter of minutes (see Blessed Dementia Scale, MMSE). The Mattis Dementia Rating Scale is a more comprehensive set of items designed to stage severity of impairment in patients with known dementia.

Tests in Combination for the Earlier Detection of Alzheimers Disease

For study 1, a group of patients diagnosed as having possible AD according to a protocol should be identified, for example, in an Alzheimer clinic. This group will consist of persons who are developing AD and others with conditions that can mask as AD. These individuals should be followed through to autopsy, which will distinguish those with definite AD from the others. Logistic regression, using biological data taken at the time of entry into the study, should be applied to all of the deceased. This will identify the biomarkers that best predict definite AD, and generate a set of coefficients that will enable calculation of the probability of definite AD, given the risk factors, among a population with possible AD.

Prevalence of Specific Dementia Types

Enlarged Brain Ventricles Dementia

More than 50 different illnesses can produce the symptoms of dementia. Available studies indicate that, on average, 5 of all causes of dementia are reversible and 11 have some specific treatment available, although not typically resulting in symptom reversal. Among the more common potentially reversible causes are those due to prescription and nonprescription drug toxicity, metabolic disorder, brain tumors, subdural hematoma (a collection of blood under the outermost meningeal covering of the brain), and depression. The more common dementia types that are presently irreversible include Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, Huntington's disease, frontotemporal dementias, vascular dementia, and traumatic brain injury. Autopsy studies have varied in their estimates of the relative proportion of all dementia cases accounted for by each of these causes or types, although all agree that Alzheimer's disease (AD) is the most common. The neuropathological...

Genetic Testing and Alzheimers Disease

DNA testing can be performed to determine whether an individual has a mutation in one of the causative genes and or whether he or she carries one or two copies of the APOEe4 susceptibility gene. Whether to test and which test to perform will depend on three conditions family history of dementia, age of onset of disease, and clinical status of the individual. If a person has dementia, the test result could be useful in determining that the cause of the dementia is a form of AD. If a person has no symptoms of dementia, an estimate of the individual's risk could be developed, using the test. In the case of such estimates, both the actual accuracy of the test and the tested individual's understanding of its accuracy are of concern. While the consensus is that presymptomatic testing for causative mutations may be performed with appropriate counseling, debate over the safety and utility of APOE testing for individuals who do not show symptoms of Alzheimer's is ongoing. In 2001, there was no...

TABLE 2217 Mnemonic for Potentially Treatable Reversible Causes of Dementia

The typical course of dementia is slow with insidious symptom onset the abrupt onset of symptoms or rapidly progressing symptoms should prompt a search for another process simulating a dementia or a comorbid problem. The physician must look for compounding factors that may be exacerbating symptoms. Some sentinel occurrence or event usually precipitates presentation to the ED. Attention should be directed to discovering any comorbid process as well as discovering any treatable causes of dementia or dementia imitators.

Dementia Associated with Sensorimotor Signs

A third major pattern in dementia is one in which cognitive decline is accompanied by sensory and motor signs. Most often, the salient mental state changes of these dementias also involve complex attention, behavior, and personality. Changes in executive functions are not universal, but depend on where the brunt of the neuropathology is located. Table 7 lists a number of disease processes that tend to have this dementia profile. The disease entity in this category with the highest prevalence is vascular dementia. Unfortunately, it is not uncommon for clinicians to automatically render the diagnosis of vascular dementia after a demented patient's MRI or CT scan returns with some evidence of strokes or small vessel disease. Many autopsy series suggest that the accuracy of clinical diagnoses of vascular dementia can be quite low (21-82 ) (103,104). A large per- Dementias Associated With Sensorimotor Signs Vascular dementia Degenerative diseases with extrapyramidal features (e.g.,...

Neurochemical changes associated with Alzheimers disease

Scan Extrapyramidal Tracts

Summary of the inter-relationships between the different pathological factors and the cellular changes seen in Alzheimer's disease. Figure 14.7. Summary of the inter-relationships between the different pathological factors and the cellular changes seen in Alzheimer's disease. Table 14.1. Changes in the neurotransmitters in the brain of an Alzheimer patient Neurotransmitter system Changes occurring in Alzheimer's disease There has been considerable interest in the involvement of the major neurotransmitters in the possible aetiology of Alzheimer's disease. Thus it is well established that the nucleus basalis of Meynert and related areas of the basal forebrain show a distinct loss of cholinergic cell bodies in patients with Alzheimer's disease. Similarly, serotonergic neurons of the midbrain raphe area and noradrenergic neurons of the locus coeruleus have been shown to be significantly diminished, particularly in early onset Alzheimer's disease. A summary of the pathological...

Alzheimers Disease Theory In

1907, the German physician neurologist Alois Alzheimer (1864-1915) first described the brain lesions associated with the degenerative brain disease, now called Alzheimer's disease, which is characterized by loss of memory and emotional psychological instability, and is accompanied by postmortem evidence of amyloid plaques and neurofibrillary tangles (insoluble nerve fibers). Some theorists speculate that the amyloid plaques (insoluble beta-amyloid proteins) are responsible for the symp Aronson, M. K. (1988). Understanding Alzheimer's disease. New York Scrib-ner's.

Delirium Dementia Amnestic and Other Cognitive Disorders

This group of syndromes is characterized by a clinically significant deficit in cognitive or memory function due to a general medical condition. There are several distinct and common causes of organic brain syndromes in which the causative factor is known for example, vascular dementia and alcohol withdrawal delirium. In these cases, the specific diagnosis is listed in DSM-IV. In other cases, the etiologic factor should be specified using the descriptor due to general medical disorder or substance for example, delirium due to hepatic encephalopathy. DEMENTIA The essential clinical feature of dementia is a pervasive disturbance of cognitive functioning in several areas including memory, abstract thinking, judgment, personality, and other higher cortical functions such as language. If clouding of consciousness is present, then the patient does not have solely a dementing illness, but has delirium or intoxication. The presence of global cognitive impairment may be detected by a bedside...

The Acute Phase Response and Alzheimer Disease

The fact that various interleukins, a1-ACT, and amyloids A and P are produced in the AD brain strongly suggests that the Alzheimer pathogenic pathway includes an APR in the CNS (or is one), since these substances are known to be an integral part of the APR in the periphery. Astrocytes, microglia, and the choroid plexus participate in the APR of the CNS. Measures of CSF cy-tokines and other factors involved in the CNS APR might be used as bio-markers of AD, although they would be expected to be relatively nonspecific indicators. Dementia, Aging, and the Stress Control System

Memory Function In Normal Aging And Dementia

Mating cell numbers in tissue samples have led to a significant revision of traditional views on age-related neural loss. This is due to the fact that most investigators had been focusing their attention on cell density, measured as the number of neurons in a fixed volume of tissue within a brain region. The counting was typically accomplished using standard histological staining procedures to visualize and count cells microscopically. If a strategy like this is employed without taking into account the fact that gliosis within a brain region may actually alter the size of a brain structure, it can lead to the possibly erroneous conclusion that the total number of neurons is decreased. Instead, studies taking into account volumetric differences between young and aged brains have led to a reevaluation of the traditional view on age-related neural loss. Modern stereological tools have been widely used to investigate neural numbers in the aged hippocampus. Earlier studies had suggested...

The clinical syndrome of dementia is characterized by

Impairment of multiple cognitive functions (e.g., memory, language, visuospatial abilities, judgment), typically due to chronic or progressive brain disease. The cognitive impairments are frequently accompanied by personality changes, including deficits in motivation and emotional control. Several different illnesses can cause the dementia syndrome, and the pattern of cognitive deficits and personality changes may differ by the type of illness as well as by the specific brain structures and systems most affected. This article will present an overview of the more common dementia syndromes, emphasizing their epidemiology, clinical presentation, and pattern of neuropsychological deficits. Neuropathological characteristics and neuro-biological research concerning causes and treatments are mentioned only briefly because these aspects are specifically reviewed in other articles (e.g., Alzheimer's Disease) within this volume.

Test of the standard models and MTT account of the pattern of semantic memory loss in amnesia and dementia

If, as MTT predicts, the advantage of high R over low R names is dependent on the hippocampal complex, then the advantage should be diminished or absent in people with damage to those structures who have poor episodic memory, such as people with amnesia or with Alzheimer's disease. People with SD, on the other hand, should retain the high R advantage even though they have neocortical degeneration accompanied by semantic memory loss. If, however, high R responses to old names are neocortically-mediated, as the standard model predicts, then performance on high R names should not be selectively impaired in amnesia, but should be impaired in AD and SD. After completing the RT tests, we had our participants rate the names they had seen as R or K. In line with our findings on the RT test, we found that people with amnesia or Alzheimer's Disease gave R ratings to far fewer of the names than did the controls in some cases, none of the names received an R rating. In contrast, the SD patients...

Dementia with Lewy Bodies DLB

In addition to occurring in brain stem structures in persons with PD, Lewy bodies are the neuropatho-logical characteristic of DLB, where they appear diffusely distributed throughout the neocortex, diencephalon, brain stem, and basal ganglia. Because of the brain structures involved, DLB is sometimes considered to be among the frontal-subcortical dementias. The core clinical features of DLB are the presence of dementia, gait-balance disorder, prominent hallucinations and delusions, sensitivity to neu-roleptic antipsychotic drugs, and fluctuating alertness. A consensus has been reached concerning the clinical criteria for diagnosing DLB (see Table II). These criteria have demonstrated high specificity, although relatively low sensitivity, against neuropathological findings. Illness progression in DLB is often rapid, with severe dementia and the motor features of PD present Criteria for Dementia with Lewy Bodies (DLB) within 1-5 years of diagnosis. It has been suggested that a diagnosis...

Dementia

Although included here under vascular disorders, dementia may also be neuro-degenerative. Pneumonia is markedly more common among those dying of advanced dementia that among those dying from cancer.32 Despite this, the prevalence of breathlessness among those dying from dementia is low (8.2 per cent compared to 27.6 per cent in cancer patients in the same study). This maybe because of the subjective nature of breathlessness as a symptom, and associated difficulties in detecting it in the presence of severe cognitive impairment.

Alzheimers Disease

Alzheimer's disease (AD) is the most common adult onset neurodegenerative disorder and accounts for up to 60 of all age-related cases of dementia in Western societies (Woodruff-Pak & Papka, 1999). The disease is characterized by a progressive decline in cognitive abilities, personality, and psychomotor functioning over a period averaging from 8 to 10 years (Filley, 1995 Morris, 1994). Memory impairment is the principal feature of AD and several distinct stages of the disease, often classified as mild, moderate, and severe, are recognized (Morris, 1994). Early manifestations of the disease include the inability to recall recent events, difficulties with word-finding, and geographic or temporal disorientation. As memory loss grows over the course of the disease, the individual's ability to carry out even simple routine activities is affected, language output and comprehension decline, and behavioral problems, such as wandering and restlessness, aggression, and suspiciousness appear....

Dementias

Dementias involve cognitive deterioration (e.g., memory decrements and deficits in attention and concentration) and confusion that progress as a function of age. The most common and most widely studied dementia is Alzheimer's disease (AD). This condition remains a focus of extensive contemporary research, and its etiology is far from clear. However, research has indicated several likely etiologic factors, including

Vascular Dementia

In the presence of cerebrovascular disease, dementia may be observed when there are multiple infarctions within both cerebral hemispheres. The clinical features that accompany multiple infarctions of relatively large cerebral blood vessels (termed multi-infarct dementia, MID) depend upon the particular brain regions Criteria for Frontotemporal Dementia (FTD) (9) Investigations, including significant impairment on neuropsychological tests of executive functioning in the absence of severe amnesia, aphasia, or visuospatial disorder normal electroencephalogram despite clinically evident dementia and brain imaging (structural and or functional) showing predominant frontal and or anterior temporal abnormality. affected. Dementia may also be the result of multiple small subcortical (termed lacunar) infarctions. As previously noted in this article, although vascular disease was earlier thought to be the second most frequent cause of dementia, more recent autopsy studies have indicated that...

Pseudodementia

This is defined as any condition which mimics dementia. The commonest psychiatric disorder which mimics dementia is depression in which the retardation can be confused with the apathy of dementia. The guiding principle is careful clinical assessment and, if in doubt, a trial of an appropriate antidepressant. Agitation and aggression are often symptoms of advanced Alzheimer's disease and high potency atypical antipsychotics such as risperidone or olanzapine may be of value in demented patients. Drugs such as chlorpromazine and thioridazine are more likely to produce hypotension, cardiac abnormalities and excessive sedation in the elderly patient, and side effects are, of course, a problem with the high potency neuroleptics in the elderly centrally acting anticholinergic agents that are used to reverse some of the symptoms of parkinsonism in such patients should be used as little as possible and in the lowest possible doses.

Early Diagnosis So What

This book addresses issues surrounding early diagnosis in Alzheimer's disease. It is predicated on the belief that early, accurate diagnosis of AD is important and will become increasingly so in the future. At first glance, this proposition may seem foolish. Given the current absence of very effective therapies to reverse, arrest, or prevent the disease process, why should clinicians and scientists be concerned that diagnosis of this illness is accurate and occurs early in its course Some might consider a book dedicated to From Early Diagnosis of Alzheimer's Disease Edited by L. F. M. Scinto & K. R. Daffner Humana Press, Inc., Totowa, NJ Alzheimer's disease is a progressive neurodegenerative disorder that leads to the death of brain cells that cannot be replaced once lost. Thus, the best hope for controlling the ravages of this disease that ultimately disrupt cognitive and behavioral functioning lies in early treatment aimed at stemming the pathological process. For treatment to...

Stages of the Illness

Figure 1 schematically illustrates a proposed time line for the development of AD pathology and its impact on functional status. It posits progressive degenerative changes and a threshold degree of neuropathological damage beyond which an individual manifests the clinical syndrome of dementia. By definition, that threshold is marked by observable decline in functional status that interferes with a person's activities of daily living. Ideally, decline is judged on the basis of changes from a particular person's premorbid status. In practice, it is often more crudely assessed by noting a disruption of common activities such as maintaining a checkbook, household responsibilities and chores, and personal hygiene. However, the more the determination of functional decline is adjusted for the patient's baseline, the less the clinical diagnosis will be affected by her socioeconomic, cultural, and educational background. For heuristic purposes, the journey between normal brain functioning and...

Distinguishing Between Diagnostic Tests and Risk Factors

Combining information about a patient's current cognitive status with her genetic inheritance may permit a more definitive set of inferences. For example, if a member of a family with an autosomal dominant form of AD secondary to a presenilin mutation exhibited cognitive impairment and early symptoms of dementia, it is extremely likely that the decline was due to underlying AD pathology. A similar argument has been made for late-onset dementias in patients with Apo s4 alleles (39,58). It has been proposed that the presence of an Apo s4 allele in an older patient with the dementia syndrome raises the probability of AD from approximately 66 to over 90 (39). However, the pattern of clinical deficits characteristic of AD would also raise the probablity of having underlying AD pathology to 85-90 (68-76). In such cases, the additional value of knowing Apo s status in improving diagnostic accuracy is less clear. A large-scale multicenter study (131) suggested that ApoE genotyping in...

Assessing the Value of Candidate Tests Administration and Cost

In addition to the predictive value of a test, its utility will be judged on practical criteria such as accessibility, ease of administration, and cost. At one extreme would be brain biopsy. Biopsy is almost never sought in elders who present with typical features of a dementia of the Alzheimer's type. Such an invasive, risky, and expensive procedure is an inappropriate tool for identifying elders in the preclinical stages of the illness. By contrast, an ideal test would not only be accurate, but also noninvasive, inexpensive, and easy to administer at a primary care provider's office. Unfortunately, we do not (yet) have such a test. Tests short of brain biopsy that demand invasive biological sampling or complex assay procedures, such as lumbar puncture or tissue culture are much less attractive option than tests without such requirements. The cost of tests is an important consideration, given the large population at-risk for developing dementia. However, at this stage, we should not...

Kirk R Daffner Introduction

Assessing the value of new diagnostic approaches to Alzheimer's disease (AD) requires an appreciation of the standard clinical diagnostic evaluation. In reality, there is no single, universally accepted clinical approach to the evaluation of demented patients. The workup is likely to vary from setting to setting. Different approaches may be found, for example, among primary care physicians, clinical neurologists in the community, and dementia researchers in academic centers. With the growth of managed care programs, more explicit standards may be established, perhaps with an increased emphasis on containing costs. Two antithetical attitudes about diagnosis of dementia are common even within the medical community, each with damaging consequences. One is that changes in cognition and behavior seen in elderly individuals are simply a reflection of the normal aging process and thus can be readily dismissed. The second is that all disruptive cognitive decline in the elderly is due to...

History Changes in Cognitive and Functional Status

Perhaps the most crucial aspect of establishing the diagnosis of dementia in a patient is obtaining a detailed history. Most often this requires a reliable informant, such as a family member or friend. The patient's dementing condition often prevents the individual from providing an accurate picture of his or her personal history. The clinician needs to inquire about the patient's pre-morbid, baseline cognitive and behavioral status, education, and highest level of personal achievements. For example, the manifestations of a decline in cog

Mental State Evaluation

A mental state examination is an essential feature of a dementia assessment. This may be the most variable aspect of the evaluation among clinicians. There is no consensus among neurologists, psychiatrists, or primary care physicians of the best mental state screening examination or testing strategy to use. Most would agree on the need to assess the following domains orientation, attention, recent memory, long-term memory, language, praxis, visual-spatial functions and executive functions (insight, judgment, planfulness). It is important for clinicians to have a means of estimating whether a patient's performance falls within age-appropriate norms. There are several standard mental state screening tools that clinicians use, including the Mini Mental State Exam (MMSE) (20) and the Blessed Dementia Scale Information-Memory-Concentration subset (BDS-IMC) (21) (Table 2A,B). Such instruments have certain clear advantages including being brief, standardized, and reasonably well-normed. In...

Neuropsychological Testing

Formal neuropsychological tests also are not part of the routine workup of patients with possible dementia. Such testing can provide a quantitative assessment of a range of cognitive domains. Establishing a patient's performance during an initial assessment allows for quantitative measurement of decline in cognitive status over time. Progressive impairments of cognitive abilities, especially if they exceed age-matched norms, are very suggestive of an underlying dementing process. Neuropsychological assessment is particularly helpful for a patient whose results on an initial evaluation and mental state screen are ambiguous, and the suspicion of an early dementing process remains. Such assessment can help establish areas of cognitive impairment before decline in functional status that accompanies clinical dementia. As noted, certain patterns of cognitive impairment have implications for which neuroanatomical networks are likely disturbed by the underlying disease process, which in turn...

First Major Decision Point Abnormal Versus Normal Status

The evaluation of dementia can proceed in a relatively orderly fashion. The first major task is to determine if a patient is exhibiting abnormal cognitive abilities and a decline in function. As noted, an appreciation of the patient's baseline mental state and achievements is crucial in making such an assessment. In addition, a clinician needs to be aware of changes associated with normal aging to determine whether a patient exceeds these bounds. On average, many cognitive functions decline in later life, including speed of mental processing and responding, digit span, visual-perceptual abilities, mental flexibility and abstractions (73-76). Acquisition of the new information also is diminished. However, once encoded, there does not tend to be a significant loss of information over time regardless of a patient's level of education (77). which the patient exhibits an inability to maintain a coherent stream of thought or behavior. The most common etiology of an acute confusional state...

Second Major Decision Point Differential Diagnosis

Once the diagnosis of dementia has been made, the clinician needs to establish the most likely underlying etiology of the condition. Traditionally, this involves trying to rule out potentially treatable or reversible etiologies of dementia that may be identified by the workup discussed earlier. Specifically, one aims to exclude encephalopathies due to metabolic problems (e.g., thyroid deficiency) or side effects from medications, CNS infections, vitamin deficiencies, or structural lesions (e.g., hydrocephalus, tumor, subdural hematoma). These conditions tend to account for small percentage of patients presenting with dementia (36-38). When these conditions have been excluded, the two largest remaining disease categories are the degenerative dementias (of which Alzheimer's disease is by far the most common) and vascular dementia.

Progressive Focal Neuropsychological Deficits

The last major dementia pattern involves progressive neuropsychological deterioration that remains relatively well circumscribed and without prominent memory problems at least in the first 2 years of the illness (30,139). These rare entities serve to remind us that degenerative processes are often relatively selective in their distribution of pathology early in their course. The clinical symptomatology associated with these dementia profiles can be interpreted as reflecting the relatively focal distribution of pathological damage to the nervous system. Primary progressive aphasia has received the most attention (139-145). Other degenerative diseases within this dementia category have been termed slowly progressive apraxia, progressive prosopagnosia, progressive semantic dementia, and posterior cortical atrophy (146-153).

Changiz Geula Introduction

The diagnosis of dementia of the Alzheimer type in living patients is a clinical judgment based upon careful neurological and neuropsychological examination combined with results from other clinical tests. Because of the existence of other dementing disorders with similar clinical presentation to that of Alzheimer's disease (AD) (some of which are of unknown pathological origin) (1,2), the clinical diagnosis of AD must be confirmed by neu-ropathological examination. Thus, at present, the most reliable (if not the only) definitive diagnosis of AD is neuropathological. For this reason, a great deal of effort has been directed, particularly in recent years, toward standardization of criteria for the pathological diagnosis of AD.

Pathological Diagnostic Criteria Ruling Out Other Pathology

Perhaps the most important task in the process of pathological diagnosis of AD is ruling out other pathology (53-55). Grossly, the AD brain should be weighed and checked for obvious lesions such as subdural hematomas, cortical infarcts, tumors, or hemorrhages. Ventricular size is variable in AD, but invariably there is general atrophy and enlargement of sulci. White matter and deep gray matter should be checked for presence of cystic or lacunar infarcts or other vascular lesions. Other causes of dementia should be ruled out. These include lobar atrophy, Pick's disease, vascular (or multiinfarct) dementia, CreutzfeldtJakob disease, diffuse Lewy body disease, and progressive supranuclear palsy. Only after the presence of other pathology has been carefully determined should an assessment of the pathological hallmarks of AD be undertaken. ficult to diagnose, such as multiinfarct dementia (58,59). Some of these additional pathologies have been shown to contribute to the dementia seen in AD...

Evaluation of Pathological Diagnostic Criteria

Given the strong correlation between the density of NFT and the presence and severity of dementia in AD, it is interesting that two of the pathological criteria described above are based so heavily on the density of SP (54). The NIA consensus criteria do factor in the presence of NFT in the diagnostic criteria. However, the number of NFT are used only in the diagnosis of young cases (younger than 50 years). In the CERAD criteria, the NFT are not used in the process of diagnosis. In the NIA-RI criteria, on the other hand, the density of NFT is used more directly in the diagnosis. One factor that complicates any diagnostic criteria is the presence of non-neuritic SP and some NFT in the brains of normal aged and mildly demented individuals. The NIA criteria do not include an explicit distinction between neuritic and nonneuritic SP in its quantification scheme except for younger cases (below 50 years). Thus, it is possible that a non-AD aged individual, possibly with mild cognitive...

Neocortical Plaque Only Variant

As many as 30 of the brains from cases with clinically diagnosed AD-type dementia display only SP in neocortical regions no neocortical NFT are present (72,73). The majority of these SPs are of the diffuse type and significantly The NIA Consensus pathological criteria explicitly recognize the neocortical SP-only presentation as AD in that its criteria for diagnosis of AD in older cases state that NFT may sometimes not be present while SP must be present in high density. The CERAD criteria, however, would categorize at least some of these cases as non-AD dementia based upon the low numbers of neocorti-cal neuritic SP. According to the NIA-RI criteria, the likelihood that AD lesions contribute to dementia in such cases is low.

Dennis J Selkoe Introduction

Progress in accurately diagnosing and effectively treating Alzheimer's disease (AD) must rest on a fundamental understanding of its pathophysiology. The application of molecular genetic, biochemical, and morphological techniques to this disorder during the last two decades has produced a large and complex body of data that is steadily being integrated into a temporal sequence of pathogenetic events. Although our understanding of the mechanism of the disease is still evolving, there is growing agreement among many investigators about the major steps in the cascade that precede the symptoms of the disease. In this chapter, we review the salient features of our current understanding of AD pathophysiology and explore how this new knowledge improves early diagnosis and illuminates the pathway to therapeutics. The neuropathology of Alzheimer's disease has provided the starting point for defining its causes and mechanism. Much of the progress in identifying factors underlying AD began with...

Clifford R Jack Jr and Ronald C Petersen

The clinical diagnosis of probable Alzheimer's disease (AD) is based on a group of signs, symptoms, and test results (1-7). No single diagnostic test has been identified, and a definitive diagnosis therefore requires biopsy or autopsy confirmation. The formal role of imaging in establishing a clinical diagnosis of probable AD is an exclusionary one that is, to exclude possible causes of dementia other than AD which may be identified through imaging. However, investigators have sought to identify positive diagnostic imaging criteria, which may aid in the clinical diagnosis of AD. A number of different imaging techniques or modalities have been employed to this end. Functional imaging modalities may reveal a characteristic regional bilateral temporal parietal lobe or posterior cingulate deficit in patients with AD. Functional deficits identified with positron emission tomography (PET) scanning include regional deficits in glucose and oxygen metabolism as well as blood flow (8-10)....

Medial Temporal Lobe MRIBased Volume Measurements at Mayo

(PHG), and amygdala were performed in 126 cognitively normal elderly controls and 94 patients with probable AD. These three medial temporal lobe neu-roanatomic structures were selected because these areas are involved early in the course of the disease, and are depicted with a high level of anatomic clarity with an appropriately performed MRI study. The clinical characteristics of the 220 study subjects are found in Table 2. The control and AD groups were well matched with respect to gender distribution and education, and fairly well matched with respect to age. AD patients as expected scored substantially lower on cognitive measures. Disease severity in AD patients was assessed by the Clinical Dementia Rating (CDR) scale very mild, CDR 0.5 mild, CDR 1 moderate, CDR 2 (59). An important distinction is made between establishing a diagnosis of AD and ranking its severity. The former was done according to NINCDS-ADRDA criteria, which emphasize a decline in cognitive performance over time...

Serial Volume Measurements

Most imaging studies in aging and dementia have been cross-sectional in nature Several groups have evaluated dementia populations using serial MRI-based volume measurements. Fox and colleagues (64,65), evaluated seven members of a family with an amyloid precursor protein 717 Val-Gly pedigree. These individuals were in their 40s and 50s. Three of these individuals deteriorated cognitively over the period of observation, and during this period their hippocampal volumes

Currently Available Genetic Tests for AD and Formal Recommendations for Their

Although marketing for diagnostic purposes has been permitted, there is no consensus on whether such use is appropriate (43,44,77-79,81-83). Available data, as detailed above, suggest that positive tests may add confidence in the differential diagnosis of dementia. However, most clinicians and investigators agree that a thorough evaluation for treatable conditions is still required, and

Sensorimotor Examination

The sensorimotor neurological examination does not contribute to making a diagnosis of dementia per se. However, the pattern of neurological abnormalities often point to likely underlying diseases that may be contributing to the dementing process. For example, a clinician should look for evidence of upper motor neuron signs (e.g., hemiparesis, asymmetric deep tendon reflexes, extensor plantar responses) that would suggest the possibility of stroke or structural lesion. Extrapyramidal signs would raise the question of Parkinson's disease, progressive supranuclear palsy, or Lewy body dementia. Abnormalities of gait may be associated with cerebrovascular disease, Parkinson's disease, and normal pressure hydrocephalus. Dysarthria would alert the clinician to possible extrapyramidal disorders, bilateral strokes, de-myelinating disease, and motor neuron disease. Sensory abnormalities (e.g., peripheral neuropathy) may be associated with B12, other vitamin deficiency states, thyroid disease,...

Correlation With Clinical Parameters

Numerous PET and SPECT studies have reported good correlations between the degree of metabolic or perfusion abnormality and dementia severity (15,16,28,29). Most of these studies utilize standard global assessment Fig. 1. Brain perfusion SPECT images. (Left) Normal control subject. (Center) Patient with Alzheimer's disease, showing reduced perfusion is most prominent in the association cortex of the parietal lobes (arrows). (Right) Quantitative group differences in perfusion are shown superimposed on the AD patient's image. Filled in areas represent those regions significantly reduced in Alzheimer's disease (n 29) compared to age-matched control (n 64 p < 0.00l). When parietal perfusion is used to discriminate all subjects (using split-half replication), the accuracy of SPECT is 92 . Fig. 1. Brain perfusion SPECT images. (Left) Normal control subject. (Center) Patient with Alzheimer's disease, showing reduced perfusion is most prominent in the association cortex of the parietal...

Functional Magnetic Resonance Imaging

Gonzalez and collaborators (75) studied 10 patients with various types of dementia, including 5 with probable AD, with both PET and DSCMRI. They found a significant correlation between the modalities both quantitatively and qualitatively. Similarly, Johnson and colleagues (76) found CBV, as measured by DSCMRI, to correlate well with perfusion by SPECT in 16 patients with AD and 10 age-matched controls. Harris and colleagues (77) performed DSCMRI in 13 patients with AD and 13 controls, and found significantly reduced ratios of temporoparietal CBV to cerebellar CBV in the AD group. Three patients with very mild dementia (mean MMSE 25.0) also had showed reductions in temporoparietal CBVs. Overall, they found that MMSE scores did not correlate well with temporoparietal CBV ratios. Fig. 3. Axial images from a 53-year old man with biopsy-proven Alzheimer's disease. (Left) Structural MRI (Tl-weighted). (Center) EPISTAR perfusion weighted MRI demonstrating bilateral posterior...

Preclinical Diagnosis

Increasing evidence from neuropsychological, neuropathological, structural, and functional imaging studies suggest that the pathophysiological disease process in AD may begin years or even decades prior to the onset of clinical dementia (90,91). It is increasingly imperative to identify individuals in this preclinical phase, as emerging pharmacological therapies, such as neuroprotective agents or amyloid precursor secretase inhibitors would likely be most effective in very early stages of the degenerative process. Even in the absence of genetic risk factors, cerebral perfusion patterns may predict cognitive decline in patients with subtle memory deficits. Johnson and associates (11) found a distinct pattern of regional hypoperfusion in 18 subjects with an initial Clinical Dementia Rating scale (92) of 0.5, who progressed over 2 years to reach criteria for probable AD (CDR of 1). Perfusion was significantly lower in the posterior cingulate, hippocampal-amygdaloid complex, and other...

Dorene M Rentz and Sandra Weintraub Introduction

Alzheimer's disease is the most common of the degenerative dementias affecting up to 47 of the population over the age of 85 (1,2). As the age distribution shifts over the next quarter century, the increasing prevalence of Alzheimer's disease poses a significant health care crisis and intensifies the need for greater research efforts toward detection, treatment, and cure. While initiatives to develop noninvasive biological tests for Alzheimer's disease are underway i.e., ApoE (3), CSF amyloid (4), tau (5), Pupil Test (6) , to date, cognitive and behavioral deficits remain the earliest, most reliable evidence of disease. Yet, by the time neuropsychological deficits are detected, it is likely that the pathological disease process has been present for many years (7-9). Now that new medicines are on the horizon to slow disease progression, a major challenge lies in identifying affected, but not yet demented, individuals in the earliest phases of illness when treatment can have a more...

Usual Age Related Cognitive Change

Intellectual decline in certain cognitive domains has been described as an inevitable consequence of normal aging but the severity of these changes varies widely among individuals (10,11). The classic aging pattern that has been observed using the Wechsler Adult Intelligence Scale suggests that the verbal IQ remains relatively stable over time while the performance IQ declines (12-14). The robustness and stability of verbally mediated cognitive processes in the face of aging is especially useful when making distinctions between normal aging and disease states. The downward trend in the performance IQ, however, is not unidimensional nor does it influence all individuals in the same manner. Furthermore, the sensitivity of the performance tests to many factors, including diminished motoric reaction time, makes them less useful for detecting and characterizing changes that might signal dementia. The most consistent finding from both cross-sectional and longitudinal studies is that delayed...

Challenges Facing Early Diagnosis

Early detection of cognitive change that heralds Alzheimer's disease poses some challenging obstacles. Early symptoms of dementia are commonly overlooked because they are relatively mild, do not call for immediate medical attention and are commonly discarded as signs of old age, fatigue, poor physical health or depression, even by primary care physicians. When a patient is initially evaluated for dementia with neuropsychological tests, it is exceedingly rare to have preexisting baseline tests for comparison. While most elderly people will have had prior measures of other health indicators (e.g., measures of blood pressure, cardiac function, pulmonary function, blood tests) as a matter of routine heath care, very few individuals will have had prior cognitive testing unless there was a specific problem in the past (including early learning disabilities or prior impairment of cognitive functions). Estimates of prior level of functioning can be derived but these can be quite imprecise...

Statistical Approaches for Data Analysis

Attention to detail in experimental design and analysis is essential. A paired case control study design and analysis is preferred when a methodological procedure is affected by environmental factors (301). For example, because the measurement of superoxide dismutase (SOD) activity in a biological sample is affected by ambient temperature, as well as the oxygen concentration in the lysates and in the assay reagents, the interassay coefficient of variation is large. To minimize such environmental effects, we assayed in parallel red cell extracts from a patient with clinical manifestations of AD and a paired control matched for subject age and gender. To determine if there were an Alzheimer effect on SOD activity, a paired analysis with corrections for gender and age effects was used to test the null hypothesis that the mean difference between pairs of patients and controls was zero (301). The application of artificial neural networks (ANNs) may be useful for separating populations on...

Evaluation of a Biomarker

Although guidelines exist for the clinical and autopsy diagnosis, both have shortcomings. In as many as 10 to 40 of cases, a clinical diagnosis of AD does not agree with autopsy findings. Part of the problem lies with the clinical diagnosis. Clinical guidelines often do not distinguish between pure AD and AD with a mixed pathology that includes vascular dementia and white matter lesions. These guidelines identify two main subgroups of patients presenile AD with an age of onset < 65 years, and senile AD with an age of onset > 65 years the second subgroup can contain a high proportion of mixed cases (402). Current clinical guidelines also often do not distinguish between AD and fron-totemporal dementia, or Lewy body disease. Furthermore, there is substantial in-terpathologist disagreement on the interpretation of autopsy findings (36). Thus studies of biomarkers must go hand in hand with improved inclusion exclusion criteria for study participants and improved guidelines for the...

Genetic and Other Approaches in Combination

The use of genetic and or environmental risk factor information in combination with sensitive tests that monitor changes in the sensory systems and brain morphology and or function is one approach that is being explored for direct and earlier AD diagnosis. In this section we explain how one genetic risk factor (the ApoE 4 allele) is being used in combination with other clinical information to increase the specificity of probable AD diagnosis. There now is evidence that persons with different ApoE genotypes react differently to certain Alzheimer drugs (95,317). One problem Fig. 2. Possible involvement of the neuroendocrine and immune systems in acute phase reaction in Alzheimer disease. CRF, corticotropin-releasing factor 5-HT, sera-tonin ACTH, adrenocorticotropin NK, natured killer. (After ref. 48.) Fig. 2. Possible involvement of the neuroendocrine and immune systems in acute phase reaction in Alzheimer disease. CRF, corticotropin-releasing factor 5-HT, sera-tonin ACTH,...

Diagnostic Classification

Several studies have attempted to calculate the diagnostic accuracy of PET or SPECT in differentiating AD from normal controls. The studies vary widely in the numbers of subjects, the severity of dementia, and the image analysis methodology. Most of the studies are plagued by lack of a gold standard, having limited numbers of autopsy-confirmed patients. Most studies, however, have reported sensitivity and specificity in the range of 80-90 . Holman and colleagues (45) performed a prospective study of SPECT scans in 132 patients referred for imaging as part of their workup for memory loss or other cognitive abnormalities. Images were evaluated qualitatively by a radiologist blinded to clinical history. The probability of Alzheimer's disease, defined by clinical diagnosis at 1 year follow-up, for patients with bilateral temporoparietal perfusion defects was 82 , but lower for patients with unilateral temporoparietal or frontal perfusion defects. Johnson and associates (6) reported 88...

Reisa A Sperling Thomas A Sandson and Keith A Johnson

The past decade has seen remarkable advances in the antemortem diagnosis of Alzheimer's disease (AD). While clinical history and examination remain the foundation of the diagnostic process, most clinicians rely on structural tomography, X-ray computed tomography (CT), or magnetic resonance imaging (MRI) to rule out other causes of cognitive impairment, such as cerebral infarction or hydrocephalus. More recently, structural image markers that are positive for the diagnosis of AD have been explored. For example, quantitative volumetric techniques permit size measurements of hippocampal substructure, and open a new avenue for the characterization of AD during life. These techniques are reviewed in Chapter 6. Functional neuroimaging has sought to identify a physiologic signature or functional neuroanatomy that corresponds to the clinical phenomenology of dementia and permits a positive identification of AD. Such a signature image feature could be the foundation for rational therapy as...

Summary and Discussion

Although considerable progress is being made in biomarker research in the Alzheimer field, particularly with regard to CSF and serum plasma markers, a review of the literature has revealed many examples of irreproducible results. Since lack of reproducibility reflects the use of differing protocols and or methodology, factors known to contribute to variability in the bio-marker field have been reviewed to aid with quality control in the Alzheimer field. These include specification of inclusion exclusion criteria for study participants, identification of biological, environmental, and technical factors, which can produce variability in test results, controlling for the effects of these variables through proper experimental design and quality control procedures, and application of appropriate statistical procedures to achieve the best possible interpretation of test data. Biomarker tests for early AD diagnosis must not only be adequately sensitive and specific, but be tolerable for the...

Assessing the Value of Candidate Tests The Problem of No Gold Standard

Consider, for example, two biological markers that are tested on a group of elderly individuals who currently are not clinically demented. If one of the markers is positive in a portion of these elders and the other is negative in all cases, how do we know which test is better. The former test either might have an unacceptably high false-positive rate, thus limiting the value of the test, or might usefully identify disease before other potential indicators turn positive. Markers of the illness that only turn positive after the onset of a clinical diagnosis of dementia ultimately will have limited value. However, they would enable the clinicians to positively confirm AD as the specific cause of dementia rather than only use a rule-out approach to the diagnosis of the illness. Currently, cross-sectional designs are most commonly used to assess the accuracy of a proposed diagnostic marker. In one form of this research strategy, test results on a group of patients with a...

Medial Temporal Lobe Atrophy

Although almost every study in which imaging measures of global or hemispheric atrophy have been employed has identified a statistically significant difference between the mean value found in AD patients and that found in control subjects, invariably substantial overlap exists between individual members of these two populations which in turn limits the clinical utility of this approach for diagnosis in individual patients (20). It is highly likely that this overlap between controls and AD patients is due in part to the manner in which normal aging is defined when selecting subjects to serve as controls. Most studies have employed as controls individuals who would fall into the category of typical aging. The result is that most elderly control populations in imaging studies include subjects with conditions that predispose toward cerebral atrophy such as hypertension, and some may be in the preclinical stages of dementia. Much better separation between AD patient and controls would be...

Clinical Versus Pathological Dimensions of AD

Rigorous study of a progressive neurological disease such as AD requires that we appreciate the distinction between its clinical and pathological dimensions. Clinically, AD most commonly manifests as an insidiously progressive decline in cognitive and functional status, with salient disruption of memory and other intellectual functions (see Chapter 2 for clinical definitions of AD). There are several different, but largely overlapping sets of criteria that specify the pattern of symptoms and signs required for a clinical diagnosis of AD (often designated as probable Alzheimer's disease or dementia of the Alzheimer's type) (62-64). Pathologically, AD is characterized by the presence of plaques and tangles (more strictly by an excessive density of plaques and tangles). As with the clinical definition of the disorder, various consensus statements offer slightly different pathological criteria (65-67). (This issue is detailed in Chapter 3.) Demented patients who fit the clinical...

Ap Deposition Appears To Be a Necessary but Not Sufficient Factor for the Genesis of AD

Genetic Factors Predisposing to Alzheimer's Disease Relationships to the P-Amyloid Phenotype Genetic Factors Predisposing to Alzheimer's Disease Relationships to the P-Amyloid Phenotype Although the rather rapid acquisition of AD-like lesions in the mice resulting from high expression of pAPP from birth cannot be considered an ideal model of AD, these transgenic mice clearly provide a highly useful and ma-nipulable experimental model of the Alzheimer process. Additional morphological and neurochemical analyses of various transgenic mice of increasing age will further establish how closely the animals' disease resembles the AD pathological process and in which ways it differs. Several mammalian models of the aging brain also have shown that fibrillar Ap is toxic to neurons (60a). DEMENTIA Fig. 2. A hypothetical sequence of the molecular pathogenesis of familial forms of Alzheimer's disease.

Possible Mitochondrial DNA Markers

(in Alzheimer brains) 12S mitochondrial rRNA polymophisms a1-ACT, a antichymotrypsin AD, Alzheimer disease ApoE, apolipoprotein E APP, amyloid precursor protein CYP2D, cytochrome P4502D variant Dx, diagnostic EOFAD, early onset familial Alzheimer disease FTDP-17, frontotemporal dementia and Parkinsonism linked to chromosome 17 Gm allotype, marker on IgG heavy chains HLA, human leukocyte antigens LOAD, late onset Alzheimer disease LOFAD, late onset familial Alzheimer disease LRP, an apolipoprotein E receptor PREDT, predictive PS-1 and PS-2, presenilin 1 and 2 rRNA, ribosomal RNA Rx, treatment SDAT, senile dementia of the Alzheimer type SP, specificity ST, sensitivity. information about diagnostic accuracy from ref. 321. Other Risk Factors for Alzheimer Disease Including Environmental Risk Factors and Genetic Environmental Interactions Positive family history of dementia Negative family history of dementia Positive family history of dementia Negative family history of dementia chemic...

Candidate Markers

Like any degenerative illness, AD does not afflict all neuroanatomical locations with equal severity. As is discussed in Chapter 3, there is a characteristic pattern of progression in the cortex that initially emphasizes limbic and posterior association regions and tends to spare primary sensorimotor areas (21,94,98,111-121). This distribution differs substantially from other degenerative processes such as frontotemporal dementia, which has a predilection for frontal and anterior temporal lobes (78,81,122-124). Many of the proposed diagnostic strategies take advantage of the relative anatomical selectivity of AD pathology, especially early in the course of the illness. The early involvement of limbic regions such as the entorhinal cortex and hippocampus is the basis for using morphometric MRI analysis of mesial temporal structures to distinguish patients with AD from normal controls, as discussed in Chapter 6. The early destruction of these regions essential to neuropsychological...

Diagnostic Criteria

The defining criteria for dementia vary (9,10,16,17). Our working definition is as follows Dementia is a progressive, but not necessarily irreversible, decline in cognitive or behavioral functioning that interferes with daily living activities that are appropriate for one's age and background and is not simply due to a delirium, confusional state, or related alteration in sensorium. Both DSM-IV and NINCDS-ADRDA diagnostic criteria for dementia require a decline in memory and other cognitive processes such as language, visual-spatial abilities, or executive functions. DSM-IV criteria explicitly states that such cognitive deficits must cause significant impairment in social or occupational functioning (e.g., going to school, working, shopping, dressing, bathing, handling finances, and other activities of daily living) and must represent a decline from a previous level of functioning (9). This criterion is not explicitly included in the NINCDS-ADRDA formula (Table 1). In both Fig. 1....

Past Medical History

Past medical history and ongoing medical conditions also may provide clues about processes contributing to a decline in cognitive functioning. Specifically, the clinician wants to inquire about a history of cerebrovascular disease, systemic illness, and risk factors for infections. Also pertinent are current and past medication use, a history of alcohol or substance abuse, major head trauma, depression or other psychiatric illness, poor nutritional status, and potential exposure to toxins. Finally, one wants to identify if there is a family history of dementing illness or other diseases that can affect the central nervous system. If so, what was the age of onset of the dementia in the family member, the clinical characteristics, and was there an autopsy that confirmed the suspected underlying pathology

Laboratory Studies

Laboratory studies help to rule out potentially reversible causes of dementia. Initially, the literature suggested that reversible dementias occurred in 10-15 of cases however, recent reports have pointed to a lower frequency (35-38). The practice parameters of the American Academy of Neurology (14) recommend that a workup include the following complete blood count, electrolytes, calcium, glucose, BUN, creatinine, liver function tests, thyroid function tests, B12, and syphilis serology. Many would also include a sedimentation rate, urinalysis, and chest radiograph. A patient's history should help guide other tests that may need to be ordered. For example, a patient with a long history of smoking should have a chest radiograph if none has been done recently. Someone with a history of high-risk sexual behaviors or exposure to intravenous drugs should have HIV testing. Patients who may have been exposed to industrial toxins at work should be considered for 24-hour urine collection for...

Neuroimaging

Traditionally, neuroimaging computed tomography (CT) scan or magnetic resonance imaging (MRI) has been used to rule out potential structural abnormalities that may be causing or contributing to a decline in cognitive functioning. Specifically, the clinician is looking for evidence of tumor, subdural hematoma, hydrocephalus, large and small vessel strokes, and white matter disease. The MRI is much more sensitive than CT in detecting abnormalities in white matter (44), although the clinical significance of such white matter changes is often unclear (45). Atrophy is common in degenerative dementias such as Alzheimer's disease. However, such a finding is not diagnostic and cannot clearly distinguish demented patients from those undergoing normal aging (46). Structural lesions, such as tumor, hydrocephalus, or subdural hematomas, are reported to be relatively uncommon in several recent series of patients being evaluated at out-patient dementia clinics (36,37,47). By contrast, Bradshaw and...

Cerebral Biopsy

Currently, brain biopsy in patients with dementia is pursued very infrequently. In experienced centers, mortality is probably under 1 and postoperative morbidity is relatively low (70-72). However, most clinicians would not recommend such an invasive procedure unless the results would lead to a change in the therapy or management of the individual patient. Thus, biopsy is considered in cases in which there is a concern about possible atypical infectious, inflammatory, vasculitic, or demyelinating processes. Unfortunately, 20-25 of cerebral biopsies for dementia do not yield a specific diagnosis (70).

Summary

The chapter reviewed diagnostic criteria, guidelines, and practice parameters offered by major clinical and research bodies. In studies that have employed such guidelines, the accuracy rates for the diagnosis of probable Alzheimer's disease has ranged from 64 to 100 , as determined at autopsy using a variety of standard neuropathological criteria (1,12,30,154-159). Most of the studies achieved a positive predictive value in the mid to high 80s. Such results are very encouraging and are as good as or better than those yielded by many of the experimental diagnostic strategies being investigated. In fact, most of the experimental diagnostic assays have used clinical research criteria as a provisional gold standard to diagnose their patients with AD, presumably until a large enough series of their patients has been brought to autopsy.

NIARI Criteria

The NIA-RI criteria represent a reassessment of the original NIA Consensus criteria. The pathological diagnosis of AD is based on the presence of both plaques and tangles. Areas to be sampled include four neocortical regions (superior temporal gyrus, inferior parietal lobule, midfrontal cortex, and occipital cortex), hippocampal formation at the level of the lateral geniculate nucleus, hippocampal formation, and the entorhinal cortex at the level of the uncus, the substantia nigra, and the locus ceruleus. The NIA-RI diagnostic scheme is based on the fact that dementia in the elderly may arise from more than one disorder, several of which may coexist in the same individual. Based on semiquantitative measures of the density and distribution of both neuritic SP and NFT, the NIA-RI criteria provides the likelihood (high, intermediate, or low) that the observed clinical dementia is due to AD lesions. The identification of coexisting pathology is emphasized. It is also recommended that the...

Tangle Only Variant

In some cohorts, approximately 5-10 of clinically diagnosed AD-type dementia cases show NFT only, and then only in limbic paralimbic regions and some subcortical areas (69-71). Some neocortical regions, such as the inferior temporal cortex, may contain a few NFT in some cases. However, NFT are generally absent from the neocortex. Very rare A -positive diffuse SP are seen in some cases. No neuritic SP is present. Most of these cases are of late onset. It has been proposed that this type of clinicopathological presentation be recognized as an NFT-only or NFT-predominant variant of AD (69). Others have used the term atypical AD to refer to such cases (55). The CERAD and NIA Consensus diagnostic criteria would diagnose such cases as non-AD type of dementia since they rely primarily on the presence and density of SP to make a diagnosis. The NIA-RI criteria would postulate that there is a low (or perhaps moderate) likelihood that AD pathology contributes to dementia in such cases.

Early Onset AD

In any case, when considering genetic testing for the early diagnosis of early-onset AD, the marginal information offered by even fully informative genetic testing is unclear, and depends to a great extent on the status of the family and the individual. For clearly symptomatic individuals in early-onset families with autosomal dominant inheritance, the probability of AD is already very high the individual is known to have a 50 chance of carrying a pathogenic mutation, and no other cause of memory impairment is likely at this age. Thus, genetic testing may not contribute greatly to diagnostic confidence. For questionably affected individuals in similar families, individuals with subtle symptoms such as mild memory loss, seeking an early diagnosis of AD, the probability that these symptoms represent AD remains fairly high, but undue vigilance about their risk may lead them to over-interpret their symptoms. Thus, the information offered by fully informative genetic testing might provide...