How To Treat Alzheimer Naturally

Super Memory Formula

After the harsh reality that the doctor had to face his son ending his life, he suffered a major irreversible memory loss disease. This caused him to fall into depression and depend on the drugs from the pharma which was devasting for his mental and physical health and on so many other levels. After countless hours of research and experimentation, he realized that the root of all problems of memory loss was an enzyme that eats away the memory cells when the person gets older. This makes the person forget their loved ones, family and friends as if they have never met them. In some cases, they even forget about their past experiences, if they had children, how they came to the place they are in right now and who they are in the first place. This was exactly what the doctor had in his future if he did not make a decision. But he did and met with great people who helped him find the cure. This was a groundbreaking study that no one wanted to believe or endorse because it would go against the large pharma industry. However, the information is in there to protect yourself and your loved ones from such a devastating experience. You only need to follow the link and you will be guided to get the information downloaded to your device and follow the all-natural ways to get rid of memory loss. Read more here...

Super Memory Formula Summary

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Author: Dr. Michael Duckett
Official Website: supermemoryformula.com
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My Super Memory Formula Review

Highly Recommended

I usually find books written on this category hard to understand and full of jargon. But the author was capable of presenting advanced techniques in an extremely easy to understand language.

All the modules inside this e-book are very detailed and explanatory, there is nothing as comprehensive as this guide.

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...

Alzheimers Disease DRG 012

Alzheimer's disease (AD) is a degenerative disorder of the brain that is manifested by dementia and progressive physiological impairment. It is the most common cause of dementia in the elderly but is not a normal part of aging. More than 4 million Americans suffer from AD. Dementia involves progressive decline in two or more of the following areas of cognition memory, language, calculation, visual-spatial perception, judgment, abstraction, and behavior. Dementia of the Alzheimer's type (DAT) accounts for approximately half of all dementias. The average time from onset of symptoms to death is 8 to 10 years. The pathophysiological changes that occur in DAT include the following

Alcoholrelated Dementia

The existence of alcohol-related dementia is complicated by the various syndromes described in individuals who abuse alcohol, as well as other possible comorbidities contributing to cognitive dysfunction in these individuals (vitamin B12 deficiency, subdural hematomas and head injuries, cerebrovascular disease, etc.). Knowledge about whether alcohol abuse may be a risk factor for other dementias is also sparse. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), classification relies on alcohol use to identify alcohol-related dementia, a process that may be subjective or based on limited information. Oslin et al. propose diagnostic criteria following the model used in the National Institute of Neurological and Communicative Diseases and Stroke Alzheimer's Disease and Related Disorders Association (NINCDS ADRDA) criteria for Alzheimer's disease (AD). It also uses cutoffs for heavy drinking of 28 drinks per week for women and 35 for men. As the authors...

Frontotemporal Dementia

Frontotemporal dementia (FTD) is a term encompassing a number of disorders now grouped together on the basis both of clinical expression and pathology. Some of the disorders now included under FTD are Pick's disease, progressive nonfluent aphasia, and semantic dementia. About 15 of FTD cases are familial, associated with mutations in the microtubule-associated protein, tau, whose

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...

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...

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...

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...

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).

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.

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.

Vascular Dementia

Vascular dementia (VAD) may account for up to 20 of patients with dementia. VAD is a clinically heterogeneous disorder, but in general multiple infarcts in both cortical and subcortical structures and ischemic injury to white matter are thought to be the primary causes of cognitive impairment in VAD 237 . Reactive gliosis around infracted regions was noted by Alzheimer in his 1895 description of the pathology of VAD 238 . Glial activation, also noted in subsequent descriptions of VAD pathology 239 , suggests that an inflammatory process could be involved in this disorder.

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...

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

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.,...

Studies In Man Cognition And Dementia

Studies into the effects of diabetes on cognitive functioning in man can be broadly divided in two categories case-control studies, which are mostly cross-sectional, and population-based surveys, which are often longitudinal. The case-control studies usually involved selected populations of patients and matched nondiabetic controls, using performance on a battery of neuropsychological tests as an outcome measure. Population-based surveys mostly involved elderly subjects, and used either relatively crude cognitive screening tests or a clinical diagnosis of dementia as a primary outcome measure. Although, the risk of cognitive impairment in type 2 diabetes is well established, the underlying mechanisms remain largely unidentified. Type 2 diabetes typically develops in the context of a cluster of vascular and metabolic risk factors (including hypertension, dyslipidemia, and obesity), referred to as the metabolic syndrome. The metabolic syndrome itself, with or without hyperglycemia, is...

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 normal...

Alzheimers Disease Ad

The first description of AD was given by Alois Alzheimer in 1907. His words are worth quoting The generalised dementia progressed. After 4 years of the disease death occurred. At the end the patient was completely stuporous she lay in her bed with her legs drawn up under her, and in spite of all precautions she acquired decubitus ulcers. Alzheimer's disease is without doubt one of the most terrible afflictions of late middle age to old age. It has often (on the analogy of heart failure) been termed 'brain failure'. Others have referred to it as amentia - death of the mind. At present there is nothing that can be done. The disease must run its course. It is debatable whether the patient or his her carers suffer most for both it is a near intolerable condition. In the West the demographic trends point to an increasingly elderly population. In 1950 there were about 214 million people older than 60 world-wide in 2025 there will be 1000 million. Alzheimer's disease shows a penetrance of...

Dementia With Lewy Bodies

Combining both features of a primary degenerative dementia and an akinetic-rigid, parkinsonian syndrome with prominent behavioral features, dementia with Lewy bodies (DLB) illustrates some of the shortcomings of current nosological schemata. Lewy bodies are the pathological hallmark of Parkinson's disease, where they are primarily restricted to substantia nigra and pigmented brainstem nuclei. However, the presence of Lewy bodies in the cerebral cortex coupled with behavioral symptoms, such as visual hallucinations, led to the recognition of DLB as a distinct syndrome. Complicating this assessment is the presence of AD pathology in about 50 of autopsies of clinically diagnosed cases of DLB, leading to the concept of a Lewy body variant of AD. A number of diagnostic criteria have been proposed and are summarized in Table 46. A number of studies, utilizing varying proportions of DLB cases have reported validity, and reliability of the clinical criteria of DLB, often in relation to...

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.

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...

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...

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...

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...

Dementia

Dementia is very common, and is the most disabling psychiatric disorder in the adult population. The incidence increases exponentially with age, from 0.5 at age 40 years up to 20 of the population aged 80 years and over. Over 80 of patients with dementia suffer from a small number of conditions, associated with characteristic types of pathology and different etiologies. of dementia cases Alzheimer's disease AIDS dementia (prion disease) Presenile dementia - Alzheimer's disease Senile dementia Multi-infarct dementia A series of relatively large infarcts damaging a sufficient volume of brain results in dementia. Neuro-pathological calculations indicate that infarct volumes that total over 50 mL are often associated with dementia, and that a total infarct volume over 100 mL is always associated with dementia. Vascular dementia may coexist with Alzheimer's disease in 20 of cases, and smaller volumes of infarct could therefore contribute significantly to the dementia symptoms Subdural...

Alzheimers Disease

AD is the most common form of dementia, accounting for an estimated 65-75 of cases of dementia, especially in aged individuals. Dementia itself is a symptom, not a diagnosis. Dementia is defined as acquired loss of cognitive functioning, and occurs in clear consciousness. This distinguishes it from mental retardation developmental delay and cases where consciousness is fluctuating or impaired, such as delirium or coma. Classification of Alcohol-Related Dementia Dementia Dementia is defined as a significant deterioration of cognitive function sufficient to interfere in social or occupational functioning. As defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, this requires a deterioration in memory and at least one other area of intellectual functioning. Moreover, the cognitive changes are not attributable to the presence of delirium or substance-induced intoxication or withdrawal. Definite Alcohol-Related Dementia At the current time, there are no...

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 have...

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).

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...

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.

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

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 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...

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

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...

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 lobes...

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 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 clinical and autopsy diagnosis of AD (164,232). 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,...

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...

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.

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...

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...

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...

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...

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...

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,...

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...

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...

CSF Evaluation

Lumbar puncture with cerebrospinal fluid (CSF) analysis is no longer part of the routine evaluation of dementia. This procedure is appropriate if there are concerns about any of the following CNS infection (e.g., fever, headache), carcinomatous meningitis, reactive syphilis serology, subacute onset, or other atypical presentations of dementia, or if dementia occurs under the age of 50 (14,63,64). In addition, lumbar puncture is indicated when there is evidence that a patient may be suffering from an inflammatory or vasculitic process or when the patient is immunosuppressed. A recent report suggested that the diagnosis of Creutzfeldt-Jakob disease could be confirmed with reasonably high sensitivity and specificity in demented patients without a history of recent infarction or encephalitis who were found to have the protein 14-33 in their CSF (65, 65a, 65b, 65c). The potential usefulness of CSF levels of tau protein, -amyloid, or a1-antichymotrypsin for the diagnosis of Alzheimer's...

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.

Lewy Body Variant

The prescreening for other pathological causes of dementia suggested by the diagnostic criteria discussed above would most likely result in the exclusion of the cases under discussion as typical AD cases. According to the NIA consensus criteria, the most comfortable classification of these cases would be as coexistent DLBD and AD, because of the presence of LBs and high cortical SP counts. The CERAD criteria, however, would not consider such cases as AD owing to the small number of neocortical neuritic plaques. The NIA-RI criteria would postulate that AD lesions have a low to intermediate likelihood to contribute to dementia in such cases, while perhaps LBs are more likely to do so. It is important to note that the three possible variants of AD discussed above share one neuropathological feature in common with typical AD all are characterized by a relatively high density of NFT in limbic paralimbic regions. It remains to be determined if the presence of this one feature is sufficient...

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...

Regional Patterns

Since the earliest studies of functional imaging in Alzheimer's disease (14-18), it has been observed that the regions of greatest reduction in functional activity are found in association cortices, primarily in the temporal and parietal lobes. This regional pattern or functional signature (Fig. 1) has been replicated by numerous PET, SPECT, and recent fMRI studies (9,19-21). Premotor and prefrontal cortex abnormalities have also been reported in a number of studies (22,23), but others have observed relative sparing of frontal cortex (15). These apparent discrepancies may reflect variations in clinical presentation or disease severity, as most studies have reported temporoparietal abnormalities earlier in the course of dementia, with frontal abnormalities appearing later in the disease. Primary sensory and somatomotor cortices are usually relatively spared, as are deep gray matter structures and cerebellum. It remains somewhat uncertain why the temporoparietal association cortices...

Atrophy Correction

Typical functional maps of the normal brain at rest demonstrate fairly uniform activity in gray matter. When the images indicate an area of abnormal function, a variety of underlying causes should be considered. Diminished metabolism or blood flow is often interpreted as a pure reduction in functional activity, but may actually be due to alterations in underlying structure, such as atrophy or infarction. These defects likely reflect tissue loss rather than tissue dysfunction. One of the primary difficulties in the interpretation of SPECT or PET images in patients with dementia (Fig. 2) is the artifactual underestimate of function due to cerebral atrophy (38). Most functional image analysis yields activity in counts per unit volume of space, not in counts unit volume of brain, a potentially important dimension that more fairly represents functional activity. In diseases associated with aging and neurodegeneration, reduced brain volume is the rule, and any attempt to quantitate a purely...

Activation Studies

Sponse to higher frequency stimulation. Becker and associates (73) used PET to study verbal memory in patients with Alzheimer's disease and age-matched controls. Patients were asked to repeat or recall word lists of varying lengths during PET acquisition. Paradoxically, the AD patients showed a larger area of activation than controls in regions involved in verbal memory and also showed activation in some cortical areas that did not activate in controls. The authors speculate that this may represent a functional reallocation of brain resources to compensate for dysfunction.

Genetic Effects

Several recent reports have suggested that the presence of apolipoprotein E e4 allele may alter the pattern of cerebral metabolism in persons without evidence of clinical dementia. Small and coworkers (85) found evidence of parietal hypometabolism and increased parietal asymmetry in nondemented relatives of patients with AD who carried one or two ApoE e4 alleles. Reiman and coworkers (7) reported reduced glucose metabolism in posterior cingu-late, parietal, temporal, and prefrontal regions in cognitively normal individuals with a family history of AD who were homozygous for the ApoE e4 allele.

Clinical Utility

In this age of shrinking resources for diagnostic workup, the obvious question arises as to the clinical utility of functional imaging in the assessment of dementia. We have found these techniques particularly useful in evaluating patients whose clinical presentation is unusual. Specifically, functional imaging may be useful in patients with prominent behavioral symptoms early in the course of their dementia, when the differential is frontotemporal dementia versus AD. It may also have utility in differentiating the cognitive symptoms associated with mood disorders, such as the pseudodementia of depression from abulia associated with early AD. We have also found functional imaging to be helpful diagnostically, in patients who present with a dementing illness at a younger age than typical AD but who demonstrate typical temporoparietal abnormalities. Conversely, the functional imaging can be reassuring in older patients with subjective complaints of memory impairment but who show a...

Overview

Many genetic and biological abnormalities are associated with AD. The challege is to choose the markers which alone or in combination best predict the development of AD, or which best indicate the presence of AD at the earliest possible stage. The authors' conception of pathogenesis of AD is given in Figure 1. Figure 2 depicts the bidirectional interactions thought to occur between the neuroendocrine and immune systems during the acute phase response. Tables 2-10 summarize peripheral biological markers that have been reported to be associated with AD since 1993. Sensitivities and specificities have been provided in the present chapter only for markers that have been well-researched and confirmed. Studies carried out before 1993 are summarized in Ref. 294. The reader also is referred to other reviews of peripheral markers of Alzheimer disease that have appeared recently (15,18,25,26,76, In this section we describe some peripheral biomarkers presently under investigation, and discuss...

Urinary Markers

Researchers have begun to explore the possibility that urine analysis can be used in testing for AD (Table 8). Increased levels of truncated nerve growth factor receptor previously were described in the urine of mildly demented patients with Alzheimer disease, a marker also present in the urine of patients with diabetic neuropathy (220). Urinary acid-stable proteinase inhibitors (kallikrein and trypsin inhibitors) also have been examined and their levels compared in the urine of healthy and Alzheimer subjects (370). The levels of antikallikrein activity were similar in both groups. By contrast, urinary levels of trypsin inhibitors were significantly increased in both males and females with AD. These data raise the possibility that an imbalance in acid-stable proteolytic enzyme inhibitors may be involved in the pathogenesis of AD and that levels of these inhibitors in urine might be further explored as markers of the disease. Normal urine has been shown to contain low levels of soluble...

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).

The Pupil Assay

There is a deficiency of the neurotransmitter acetylcholine in the brain of persons with AD and also in older persons with Down syndrome (who are at greatly increased risk of developing AD-like brain changes and also clinical dementia resembling AD). Based on additional observations that the neuronal controls of the heart and iris of persons with DS are hypersensitive to a class of drug that inhibited acetylcholine-mediated neurotransmission as evidenced by an abnormally increased heart rate and a hypersensitive pupillary response to atropine (or its synthetic analog, tropicamide), Scinto and associates (339), hypothesized that persons with AD might respond similarly. As testing the heart response is potentially dangerous, the decision was made to focus on the pupillary response. As anticipated, the pupillary response to a very low concentration of tropicamide instilled in the eye indeed was found to be hypersensitive in persons with AD. Furthermore, one false positive case developed...

Genetic Disorders and Social Issues

Many advances in genetics have had their greatest impact on our understanding of human health and disease. One of the most important areas of research is in the understanding of complex diseases, such as cancer and Alzheimer's disease, in which genes and environment interact to produce or prevent disease. Genetics devotes more than two dozen entries to both singlegene and complex genetic disorders, offering the latest understanding of

Clinical Description

Alzheimer's disease is characterized by gradual loss of memory, decline in other cognitive functions, and decrease in functional capacity. Other common symptoms include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Some patients The clinical diagnosis of AD is based on criteria defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R, American Psychiatric Association 1987) and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association Work Group (NINCDS-ADRDA). 7 The NINCDS-ADRDA criteria provide guidelines for a clinical diagnosis of probable and possible AD. A diagnosis of definite AD can be confirmed by neuropathological examination of the brain tissue either from biopsy or autopsy material. The criteria of the Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) 8 have been...

Neurologic Manifestations of HIV

Neurological complications of HIV infection are common, with more than 50 HIV patients ultimately developing some clinical manifestations. The spectrum of the disease is broad. Classical neurologic complications of HIV infection recognized in the 1980s include (1) aseptic meningitis, (2) HIV-associated dementia (HAD), (3) vacuolar myelopathy, and (4) distal symmetric sensory polyneuropathy. More recently, neurologic manifestations are most commonly associated with the therapeutic agents used in HAART. The most dramatic neurologic manifestations occur in HIV patients not on HAART. These include manifestations secondary to opportunistic diseases like progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, cryptococcal meningitis, tuberculosis, and malignancies like CNS lymphomas. HIV-associated dementia HIV-associated dementia (HAD) is the most common neurological manifestation of chronic HIV infection and developed in 20 60 HIV patients before effective antiretroviral...

Autistic Spectrum Disorders

Probable Alzheimer's Disease According to NINCDS-ADRDA Criteria I. Criteria for the clinical diagnosis of probable Alzheimer's disease a. Dementia established by clinical examination and documented by the mini-mental test, Blessed Dementia Scale, or some similar examination, and confirmed by neuropsychological tests. II. The diagnosis of probable Alzheimer's disease is supported by the following III. Other clinical features consistent with the diagnosis of probable Alzheimer's disease, after exclusion of causes of dementia other than Alzheimer's disease, include the following IV. Features that make the diagnosis of probable Alzheimer's disease uncertain or unlikely include the following Adapted from McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984 34 939-944. The roots of this...

Delirium And Intoxications

Criteria for probable sporadic CJD The clinical diagnosis of CJD is currently based on the combination of progressive dementia, myoclonus, and multifocal neurological dysfunction, associated with a characteristic periodic electroencephalogram (EEG). However, new variant CJD, most growth hormone-related iatrogenic cases, and up to 40 of sporadic cases are not noted to have the characteristic EEG appearance. This hampers clinical diagnosis, and hence surveillance, and illustrates the need for additional diagnostic tests. Proposed criteria for probable sporadic CJD a. Progressive dementia. and of the effects of intoxication (e.g., alcohol or phencyclidine, etc.). The cardinal finding in delirium is altered mental status, which helps distinguish it from dementia, generally conceived of as occurring in clear consciousness. Not all individuals with delirium are agitated or hyperexcitable. In that regard, there is broad overlap with conditions capable of causing stupor or coma. The...

Mild Cognitive Impairment

Mild cognitive impairment (MCI) describes a condition that lies intermediately between normal cognition and dementia, defined broadly as acquired loss of cognitive abilities. The major operational Validity and Reliability of Consensus Criteria for Dementia With Lewy Bodies Validity and Reliability of Consensus Criteria for Dementia With Lewy Bodies

First Description of AD

In 1907, Alois Alzheimer, a German physician from Bavaria, published the case of one of his patients. The patient, Mrs. Auguste D., at the age of fifty-one years developed an unfounded jealousy regarding her husband. This behavioral change was followed closely by a subtle and slow decline in other cognitive abilities, including memory, orientation to time and to physical location, language, and the ability to perform learned behaviors. All of her difficulties gradually progressed in severity. Within three years, the patient did not recognize her family or herself, could not maintain her self-care, Eugenie Bonenfant, left, is a resident in Rhode Island's first assisted living community designed exclusively for people with Alzheimer's disease. The unit supervisor, Margaret Knight, visits, and she is surrounded by her own, familiar furniture. and was institutionalized. She died a short four and a half years after her illness began. Her brain was removed at autopsy. Using a novel (at the...

Primary Progressive Aphasia

As originally formulated by Mesulam, primary progressive aphasia is recognized by the presence of aphasia dissociated from the general cognitive decline in other cognitive spheres characterizing the dementing illnesses. The original description emphasized the long clinical course, without progression to a more generalized dementia. Subsequent to that, cases progressing to dementia with wide variety of pathological entities have been described in case reports.

Role of Oxidative and Bioenergetic Stress in MDMA Neurotoxicity

In addition to a role of oxidative stress in MDMA-induced neurotoxicity, alterations in energy metabolism also may contribute to the process of neuro-toxicty induced by psychostimulant drugs. Methamphetamine reduces brain concentrations of ATP (78) and increases the extracellular concentration of lactate (79). In addition, the administration of energy substrates attenuates dopamine neurotoxicity elicited by methamphetamine (79,80). These findings suggest that psychostimulants may acutely impair mitochondrial function. Indeed, methamphetamine and MDMA acutely inhibit the activity of the mitochondrial enzyme cytochrome oxidase (72). Furthermore, the combined administration of methamphetamine and malonate, a complex II inhibitor of mitochondrial function, synergize to deplete striatal dopamine concentrations (81,82). The intrastriatal administration of malonate and MDMA, neither of which alone depletes tissue 5-HT concentrations, together produces significant reductions in striatal 5-HT...

In Inattentive Or Aphasic Adults

Patients who cannot understand or cooperate pose a special challenge to any sensory testing, which usually depends on some self-report of perceptual experience. Self-report requires that the patient comprehend instructions and communicate back hence, dementia, confusional states, and aphasia are limiting factors in testing sensation.

Addictive Drugs and Learning Processes

Striatal dopamine is also elevated by drugs of abuse. Indeed, although such drugs have a wide variety of effects in numerous parts of the brain, the shared ability to enhance striatal dopamine release remains the best candidate for a key common action (see references in ref. 1). The mechanisms by which drugs produce altered striatal dopamine release are varied for example, nicotine likely achieves this both through actions on midbrain dopamine neurons (74) and through local modulation of dopamine release in striatum (75). By altering release of dopamine throughout the striatum, drugs of abuse can alter both acute information-processing and long-lasting plasticity across a wide range of cortex-basal ganglia circuits. If striatal dopamine can act as a reinforcement learning signal, then it makes sense that self-administration of drugs that elevate dopamine is reinforced. In fact, multiple kinds of learning contribute to any given drug's reinforcing properties (76,77). Besides affecting...

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