Identification of Genes That Cause or Predispose to Alzheimers Disease

At the same time that studies of the Ap peptides of amyloid plaques and the tau protein of neurofibrillary tangles were proceeding, molecular geneticists combined forces with many physicians in searching for loci in the human genome that might contain defective genes underlying the well-recognized autosomal dominant cases of AD (FAD). Geneticists needed a compelling clue as to where in the enormous human genome to begin their search for a faulty gene. This clue came with the recognition that...

Cerebrospinal Fluid Tests for Alzheimer Disease

Three different biomarkers in CSF have been particularly well researched neuronal thread protein, tau, and derivatives of APP (Table 5). Although these markers are distinguishing between persons with probable AD and healthy normal individuals, it remains to be determined if they have are sensitive and specific enough to aid with the earlier detection of AD. NYMOX has developed a quantitative test for measuring levels of a specific type of neuronal thread protein (AD7c-NTP) in small samples of...

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...

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...

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....

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...

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...

Aberrant Biological Processes in the Alzheimer Brain

Aberrant biological processes associated with brain degeneration in all forms of AD include loss of up to half the brain mass, deposition of amyloid in senile plaques and blood vessels (meningeal and cerebral), and formation of neurofibrillary tangles (NFT) in certain neurons. A key molecular step underlying amyloid formation is the polymerization of the small peptide into amyloid fibrils. A key step underlying the development of the NFT is the accumulation of hyperphosphorylated tau molecules...

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...

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...

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...

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...

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...

Tests in Combination for the Earlier Detection of Alzheimers Disease

At this time, it appears that there is unlikely to be a single biomarker that can be used to directly distinguish persons with AD from those with non-AD among a group of persons with possible AD or before any clinical symptoms appear. It is suggested that different types of readily available information be used for diagnosis. When different tests are applied independently, the mis-classification rate inevitably increases. A procedure is needed to combine multiple pieces of information into a...

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...

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...

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,...

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...

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

Advanced glycation end-products trends to lower values 387 Increased blood mercury levels correlate with levels of Ap in CSF 140 Platelets Enzymes Altered antimycin A-insensitive NADH-cytochrome c reductase 424 Monoamine oxidase B activity increased in LOAD correlates 286 with emotional deterioration Increased specific activity of monoamine oxidase in demented 32 patients positive correlation with dementia severity in Parkinsonian and demented patients Increased phenolsulfotransferase activity...

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...

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...

Serial Volume Measurements

The purposes of biological markers in AD can broadly be characterized as follows 1. To diagnose the disease in individual subjects 2. To follow the course of the disease 3. To assess the response to therapeutic intervention in both individuals and in groups (i.e., drug trials) Most imaging studies in aging and dementia have been cross-sectional in nature and have addressed item 1, that is, identifying imaging criteria that will help to establish the diagnosis of AD in individual subjects....

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...

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....

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...

Other Cerebrospinal Fluid Abnormalities in Alzheimer Disease

Autopsy brain localization of immune antigens IL-6, a2-macroglobulin, C-reactive protein CD4, CD8, LA, 214, 358, IL-1, IL2-R, TNF, HLA-DR, complement proteins, S100, serum 415 amyloid A and P Cerebrospinal fluid volumes Increased in EOAD and LOAD greater increase in EOAD 374 Acute phase reaction neuroendocrine-immune markers Ferritin increased compared to Parkinson's patients and controls 195 a1-ACT closely associated with late onset AD 130 a1-ACT elevated in early and late onset AD but 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...

Functional Magnetic Resonance Imaging

A number of functional MRI techniques have recently been developed that can also measure cerebral perfusion. Several studies have been performed with dynamic susceptibility contrast MRI (DSCMRI) in patients with AD. The principle behind this technique is that passage of a concentrated bolus of a paramagnetic contrast agent distorts the local magnetic field sufficiently to cause a transient loss of MR signal on pulse sequences designed to be maximally susceptible to magnetic field...

Early Onset AD

For early-onset AD, the predictive value of genetic tests has not been formally evaluated, but it can be inferred from what is known about the genetics of the disease. Given the three known fully penetrant autosomal dominant AD genes, predictive testing is at least theoretically possible for some individuals. However, even here the scientific issues remain complex for a number of reasons. A great deal more complexity arises when the personal and social issues associated with genetic testing are...

Candidate Markers

Since the pathological process precedes the clinical manifestations of the disease, the earliest markers for the illness may not be found if the search for them begins with the first clinical symptoms. To aid diagnosis in the presymp-tomatic and preclinical stages, we need to find biological markers for the disease that are detectable well before even subtle clinical symptoms are apparent. Many of the proposed markers for the AD process will be discussed throughout this book. Although, there...

Medial Temporal Lobe MRIBased Volume Measurements at Mayo

In order to more thoroughly assess the possible utility of MR-based volume measurements of anteromedial temporal lobe neuroanatomic structures in the diagnosis of AD we undertook a study which employed a large number of control and AD patients, state-of-the-art image acquisition and image-processing techniques, and well-accepted neuroanatomic boundary criteria for the various medial temporal lobe structures that were measured (58). MR-based volume measurements of the hippocampus,...

Possible Mitochondrial DNA Markers

Mitochondrial tRNA 4336G variants Possible association with AD and Parkinson's disease Possible association with AD Somatic mitochondrial 4977 nt deletions (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,...

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

To summarize at this juncture, four genes that are unequivocally associated with the development of AD have been identified to date, and linkage analyses of other families make it clear that additional genes can be responsible (Table 1). Three of the known genes, APP on chromosome 21, PS-1 on chromosome 14, and PS-2 on chromosome 1, can be said to be causative of AD in the respective families in which mutations in these genes occur. In each of these three cases, there is now compelling evidence...

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...

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...

The Acute Phase Response and Alzheimer Disease

The acute phase response (APR) is an orchestrated physiological response of the body to tissue injury, infection, or inflammation. A prominent feature of the APR is the induction of acute phase proteins, which are involved in the restoration of homeostasis. Cytokines including interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-a) are important mediators of the APR. Different signaling pathways are activated by different cytokine-recep-tor interactions. Eventually,...

Lewy Body Variant

Lewy bodies (LB) are intracytoplasmic inclusions (74). They appear as a dense eosinophilic core surrounded by a less densely stained peripheral halo. The LB is a pathological hallmark of brains of patients suffering from Parkinson's disease (PD), within which LB are found most prominently in the substantia nigra (SN) and other subcortical nuclei. Sparsely distributed cortical LB are also found in most PD cases. The cortical LB are observed mostly in nonpyramidal neurons of layers V and VI (74)....

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...

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

As noted above, one of the greatest challenges facing the assessment of candidate early markers for AD, especially those in the presymptomatic phase of the illness, is the lack of an appropriate in vivo gold standard upon which to make a judgment. 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...

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...

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. A few studies have reported low sensitivity of functional image abnormalities in mild AD. Powers and colleagues 43 evaluated the...

Pathology of Normal Aging and Mild Dementia

A large number of investigations have indicated that SP and NFT can also occur in the brains of cognitively normal elderly 12,22,44,45 . SP and, in particular, A immunoreactive SP are commonly found in the cerebral cortex of many normal aged brains. In some of these brains, the density of A deposits has been found to be similar to that present in AD. NFT are also present in the normal aged brain. However, they are found less frequently, in much lower density and with very restricted...

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...

Sensorimotor Examination

Cjd Morbidity Rates

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...