Spotlight

Spotlight:  Diagnosis of Alzheimer's Disease

Barry Reisberg, Alistair Burns, Henry Brodaty, Robin Eastwood, Martin Rossor, Norman Sartorius, and Bengt Winblad

Report of an IPA Special Meeting Work Group* Under the Cosponsorship of Alzheimer’s Disease International, the European Federation of Neurological Societies, the World Health Organization, and the World Psychiatric Association

Alzheimer’s disease (AD) is an illness that at this time is estimated to afflict 15 million people around the world (Khachaturian, 1997). This illness has recognized clinical and pathologic manifestations. Although the etiology is unknown, there are known risk factors such as age, Down’s syndrome, and genetic predisposition. The manifestations of the illness evolve continuously as the disease progresses. These include prominently neuropsychological features, neuropsychiatric manifestations, and disturbances in daily living. Traditionally, the neuropathology of the disease has been described as senile plaques and neurofibrillary tangles that are present in the brain and visible upon pathologic examination. The senile plaques are now known to contain the ß-amyloid protein as the major pathologic constituent and are presently more commonly referred to as amyloid plaques. The neurofibrillary changes have also been prominently linked to a particular pathogenetically relevant proteinaceous constituent known as the tau protein.

There have been a number of consensus statements regarding the clinical and pathological diagnosis of AD over the last 15 years (American Psychiatric Association, 1980, 1987, 1994; Khachaturian, 1985; McKhann et al., 1984; Mirra et al., 1991; World Health Organization, 1992). A meeting was held in Geneva in November 1996, which brought together 59 scientists and clinicians from around the world.1< Current progress, issues, and controversies with respect to the diagnosis of AD were addressed.

There was agreement that AD is a clinicopathologic syndrome. Traditionally, the diagnosis of AD has been said to be a process of exclusion. In this way, AD differed from most other medical diagnoses in that doctors were to arrive at this diagnosis only after an exhaustive work-up. However, research during recent decades has indicated that AD has clear clinical manifestations at all points in the manifest progression of the disease. Additionally, AD has physical manifestations that may be evident using neuroimaging and other methods and AD has evident brain changes upon postmortem examination. These features permit clinicians to diagnose this commonly occurring condition.

Diagnostic progress in the areas of differential diagnosis, mental status, functional and global evaluation, neuroimaging, electrophysiology, neuropathology, and peripheral markers was reviewed. A summary of this review follows.

Differential Diagnosis

Differential diagnosis rests upon a knowledge of the salient characteristics of AD and a recognition of conditions that can mimic the presentation of this disease and/or add to morbidity in patients with AD. A complete list of conditions that can produce dementia apart from AD encompasses metabolic disorders, endocrine disorders, nutritional disorders, toxic conditions, infectious processes, neoplastic disorders, normal-pressure hydrocephalus, cerebrovascular events, genetic disorders, and other conditions of known and unknown etiology (e.g., prion diseases, Pick’s disease, frontal lobe dementias, Lewy body dementia, and parkinsonian dementia).

Prior to arriving at a diagnosis of AD, clinicians will wish to conduct a diagnostic work-up that indicates the possibility that these other conditions may either be causative of, or contributory to, observed symptomatology. This will consist of a full history (preferably with a knowledgeable informant). The history should include the nature of the patient’s symptoms, particularly with regard to mode and time of onset, progression, and associated interference with work and social activities. Queries should also include a complete review of patients’ medical and surgical history, psychiatric history, family history, and concomitant medications. A physical examination can identify major medical conditions that may be of relevance, e.g., stroke, cancer, nutritional disorder, and thyroid disorder.

Laboratory procedures that are useful in the diagnostic work-up and that are widely accessible include blood studies, e.g., serum urea and electrolytes, glucose, liver function tests, complete blood count, thyroid function tests, serum vitamin B12<, and serum folic acid. In many settings, physicians will want to obtain syphilis serology. Also, in some settings, blood tests might include a serum Lyme disease titer, HIV testing, or other special procedures.<

One prominent cause of dementia that should be considered, and that also commonly occurs in association with AD, is cerebrovascular disease. In recognizing the role of this condition and other central nervous system disorders that can coexist with AD, a neurologic examination and neuroimaging are useful. Important conditions to be considered in the differential diagnosis of dementia are depression and delirium (confusional state). Delirium can be produced by many medical conditions, such as electrolyte disturbance, metabolic disorders, and postoperative states. Both delirium and depression are predisposed to by the coexistence of AD and both can present as harbingers of subsequently manifest AD.

In diagnosing AD, physicians need to be aware of salient features of normal brain aging and the boundaries between normal brain aging and AD. Subjective complaints of cognitive and functional impairment, e.g., complaints of not recalling names as well as formerly, complaints of declining concentration, and complaints of not recalling where one has placed things as well as formerly, are very common in normal aging people. These complaints are frequently troubling to many aged people, particularly because they view these complaints as harbingers of AD or other serious medical illnesses. Subjective complaints of memory loss may be more an indication of depression in an older person. These subjective complaints are common reasons for which many elderly people take both over-the-counter and prescription medications. Studies have indicated the generally benign nature of these subjective complaints, over intervals of many years, in otherwise healthy elderly people.

The earliest manifest clinical symptoms of AD are very subtle and blend with symptoms produced by various conditions that can create subtle deficits that may not be identifiable from the medical work-up. This incipient and uncertain stage has been given a number of different labels such as mild cognitive impairment, which is the most widely used term at present for this disorder. Patients with these subtle symptoms may present with objective clinical evidence of memory impairment or other cognitive problems, they may present with functional difficulties such as difficulties at work, or with emotional problems such as anxiety. Prognostic studies have indicated that many of these people present with diagnosable AD upon subsequent follow-up over 3 or more years; however, not all persons who present with mild cognitive impairment progress to subsequently manifest dementia.

Mental Status, Neuropsychological, and Neuropsychiatric Assessment

Mental status and/or neuropsychological assessment is presently used nearly universally to establish the presence of dementia. Because these assessments are sometimes misused and/or misunderstood, it is important to emphasize that a low score on any (or all) of these measures conveys no information on the etiology of a dementing disorder. In conjunction with a premorbid history, however, including an educational, occupational, social, cultural, and medical history, comprehensive mental status and/or neuropsychologic assessments can establish the presence of dementia, i.e., a generalized decline in intellectual and cognitive capacities from premorbid levels. Repeated assessments can convey further information regarding the etiology of a dementing disorder. Over a period of a few to several months, AD tends to be quite stable in the absence of physical or other medical insults. In contrast, delirium, dementia associated with medical disorders, the dementia syndrome of depression, and other dementias are frequently less stable. Also, AD tends to deteriorate over time and these assessments can be useful in documenting this deterioration, with the important caveat that stability over intervals of years is also seen in AD (sometimes referred to as plateauing). Slight improvement in these assessments over intervals of months or even years is also compatible with AD. The likelihood and magnitude of improvements on reassessments seen in AD vary with the severity of AD, practice effects, psychological variables in the test situation and in the disease, inherent, measure-related variability (test/retest reliability), and other factors.

Mental status assessment has a long tradition in the evaluation of dementia (e.g., Jacobs et al., 1977; Kahn et al., 1960; Pfeiffer, 1975). The Mini-Mental Status Examination (MMSE) is the most widely used mental status test and includes assessments of orientation, memory, attention and calculation, language, ability to follow commands, reading comprehension, ability to write a sentence, and ability to copy a drawing (Folstein et al., 1975). Folstein has suggested a cutoff score of 23 or less for the presence of dementia on this measure in persons with at least 8 years of education. However, normal educated elderly persons commonly score 29 or 30 on this 30-point screening measure. It should be noted that education, occupation, and cultural and background factors can strongly influence MMSE scores (Frisoni et al., 1993; Murden et al., 1991; Tangalos et al., 1996; Tombaugh & McIntyre, 1992; Uhlmann & Larson, 1991; Weiss et al., 1995). For example, mean scores of aged nonreaders in a U.S. public assistance housing project were found in one study to be 1 point below Folstein’s proposed dementia cutoff score of 23 (Weiss et al., 1995) and, similarly, after age, education, and other factors were controlled for, farmers were found to score an average of more than 2 points lower on the MMSE than white-collar workers (Frisoni et al., 1993).

The MMSE permits considerable flexibility in administration, and the mode of administration and the versions utilized have also been shown to strongly influence scores (Ganguli et al., 1990; Molloy et al., 1991). Within the conventional dementia range, in well-educated subjects, mean changes in MMSE scores of approximately 2 to 5 points per year have been found in AD subjects. However, the correlation of MMSE change scores with the temporal progress of AD has been found to be only approximately .3, indicating wide variability even in selected populations (Becker et al., 1988; Burns et al., 1991a; Morris et al., 1993; Mortimer et al., 1992; Reisberg et al., 1996; Salmon et al., 1990; Teri et al., 1990; Yesavage et al., 1988).

Because of the wide variability in MMSE scores depending upon the mode of administration, a standardized MMSE has been suggested (Molloy et al., 1991). However, in any version, additional well-known limitations of the MMSE, apart from those already noted, include (a) floor effects, which preclude the ability to track the latter portion of AD entirely with this measure (rendering diagnostic assessment of course impossible in patients with severe AD); (b) ceiling effects, which limit dementia detection in well-educated populations; and (c) variable sensitivity over the optimal range of this widely utilized screening measure. Neuropsychological measures can overcome some of these assessment problems. For example, the Alzheimer’s Disease Assessment Scale (ADAS) (Rosen et al., 1984) is widely used in many pharmacologic trials, partly because it is believed to have improved sensitivity over a particular range of dementia. Similarly, the Severe Impairment Battery (Saxton et al., 1990) and the Modified Ordinal Scales of Psychological Development (M-OSPD) (Auer et al., 1994) assess dementia severity in ranges where the MMSE scores are low or at bottom. Many neuropsychologic tests have been shown to be useful in identifying dementia, possibly due to AD, at ranges in which mental status scores are generally normal. Another neuropsychologic test battery that appears to be quite useful for dementia diagnosis and quite sensitive to change with dementia evolution is the SKT (Erzigkeit, 1989).

Emotional changes and neuropsychiatric manifestations have long been recognized as characteristic and probably integral features in the clinical presentation of AD (Alzheimer, 1907; American Psychiatric Association, 1980, 1987, 1994; Esquirol, 1838). Various studies over recent years have characterized these emotional changes in some detail (Burns et al., 1990a, 1990b, 1990c, 1990d, and 1990e; Cohen-Mansfield et al., 1992; Cummings, 1985; Cummings et al., 1987; Drevets & Rubin, 1989; Lerner et al., 1994; Levy et al., 1996; Oppenheim, 1994; Reisberg et al., 1987, 1989; Rockwell et al., 1994; Rosen & Zubenko, 1991; Rubin et al., 1987; Rubin & Kinscherf, 1989; Teri et al., 1988; Weiner et al., 1997; Wragg & Jeste, 1989), and instruments are presently available that can assist the clinician in the identification of the characteristic emotional and neuropsychiatric manifestations of AD. These include the Behavioral Pathology in Alzheimer’s Disease scale (BEHAVE-AD), the Neuropsychiatric Inventory (NPI), the Cohen-Mansfield Agitation Inventory (CMAI), the Consortium to Establish a Registry for Alz-heimer’s Disease (CERAD) Behavior Rating Scale for Dementia, the Columbia University Scale for Psychopathology in Alzheimer’s disease (CUSPAD), and the Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia (MOUSEPAD) (Allen et al., 1996; Cohen-Mansfield et al., 1989; Cummings et al., 1994; Devanand et al., 1992; Reisberg et al., 1987; Tariot et al., 1995).

Global and Functional Assessment

Global assessments can outline the characteristic cognitive, functional, and behavioral course of AD. These outlines can be very useful in affording clinicians a rapid and comprehensive overview of AD. Features that may be occurring out of sequence and/or prematurely can be readily identified, encouraging clinicians to search for physiologic and/or social etiologies for these features. Similarly, dementing disorders that present differently from AD can readily be identified. Incipient stages of AD can be described using global measures and these measures can also potentially extend descriptions of the disease to the final stages of the disease process.

Two independently developed global staging procedures have come into wide usage, the Global Deterioration Scale (GDS) and the Clinical Dementia Rating (CDR) (Hughes et al., 1982; Reisberg et al., 1982). These procedures divide normal brain aging and progressive AD into seven stages, in the case of the GDS, or five stages, in the case of the CDR. Interestingly, these staging procedures have been shown to be at least as reliable in the categorization of AD severity as the best mental status or psychometric measures (Burke et al., 1988; Dura et al., 1990; Foster et al., 1988; Gottlieb et al., 1988; Hartmaier et al., 1994; McCulla et al., 1989; Morris et al., 1997). More importantly, staging procedures may be superior to mental status and neuropsychological assessments in the long-term, longitudinal tracking of the course of AD. For example, in a five-year prospective study of patients fulfilling criteria for probable AD (McKhann et al., 1984), GDS change scores accounted for more than twice the temporal variance in AD course of the MMSE (Reisberg et al., 1996). Another study has found that the CDR was more sensitive and reliable than psychometric measures for tracking dementia progression relevant for clinical trials (Berg et al., 1992).

There is also considerable evidence for the utility of global staging procedures in the identification of generally benign, normal aged subjective forgetfulness, and boundary states that may be associated with incipient AD (Berg et al., 1993; Flicker et al., 1991, 1993a, 1993b; Morris et al., 1991, 1996).

In the case of both the GDS and the CDR, semistructured procedures are available for further guiding staging assignments. In the GDS staging system, these measures include the Brief Cognitive Rating Scale, which consists of measures derived from, and designed to be optimally concordant with, the GDS (Reisberg et al., 1993, 1994). In the case of the CDR, a "sum of boxes" semistructured staging procedure has been developed (Berg et al., 1988; Morris, 1993).

Functional assessments are useful in the identification of the existence of a dementing condition. Additionally, certain functional measures of dementia may be very useful in tracking the course of AD and even in the diagnosis, differential diagnosis, and assessment of morbidity in AD. AD is recognized as proceeding from: (a) a loss of executive functions, such as the ability to fully execute the responsibilities associated with a professional job; to (b) a loss in ability to carry out complex activities of daily life, such as the ability to market, to manage personal finances, and to prepare complex meals; to (c) a loss in ability to perform basic activities of daily life, such as dressing, bathing, and toileting; to (d) a loss in ability to perform basic bodily functions such as speaking and walking.

A variety of assessments are available for documenting these functional deficits. These include the Disability Assessment for Dementia (DAD), the Interview for Deterioration in Daily Living Activities in Dementia (IDDD), the Cleveland Scale for Activities of Daily Living, the Instrumental Activities of Daily Living (IADL) Scale, the Physical Self-Maintenance Scale (PSMS), and the Functional Assessment Staging (FAST) procedure (Gélinas et al., 1995; Lawton & Brody, 1969; Patterson et al., 1992; Sclan & Reisberg, 1992; Teunisse et al., 1991).

In conjunction with a premorbid history, each of these procedures can be useful in documenting the presence of functional deterioration, which may be due to dementia or an incipient dementing disorder. However, just as a variety of conditions apart from dementia can impact upon cognition and influence mental status and neuropsychological assessment, many nondementing disorders can produce functional deterioration. For example, the decreased ability to function in a job, to prepare meals, to dress, to bathe, and/or to toilet can be produced by mental disorders, including depression or delirium; physical disorders, including arthritis; neurologic disorders, including a stroke; endocrine disorders, including hypothyroidism; nutritional disorders, including vitamin B12< deficiency; traumatic disorders, including head trauma or a hip fracture; genetic disorders, including Huntington’s chorea; infectious disorders, including parasitic, bacterial, or viral central nervous system disorders; neoplastic disorders; toxins, including heavy metal poisoning; medications; or other conditions. Furthermore, other dementias apart from AD also produce functional disturbances. Consequently, although useful in confirming the presence of dementia, functional deficits must be used diagnostically in conjunction with other differential diagnostic procedures.

However, functional assessments can play a unique and very valuable role in AD diagnosis. A characteristic pattern of progressive functional losses in AD has been described in 16 successive levels (Reisberg, 1986; Sclan & Reisberg, 1992). Clinicians can use a knowledge of these levels to: (a) identify a pattern of functional deterioration consistent with AD; (b) identify excess functional disabilities that may be adding to the morbidity of the AD patient and that may be remediable; (c) track the course of AD in considerable detail, including the latter half of AD in which mental status and conventional psychometric assessments are at bottom. A recent prospective study in patients with probable AD (McKhann et al., 1984) has indicated that over a 5-year period, these functional measures were able to explain twice the variance in the time course of AD as that accounted for by changes in MMSE scores (Reisberg et al., 1996). Furthermore, these functional change measures have demonstrated some of the most robust relationships to postmortem neuropatho- logic changes yet to be uncovered in AD (Bobinski et al., 1995, 1997).

Global and functional assessments can be, and commonly are, used together in the diagnosis and assessment of AD, and in tracking the course of the disease. For example, both of the currently widely used global assessments, the CDR and the GDS, incorporate functional assessments of deterioration. Furthermore, the FAST can be used as part of the GDS staging system (Reisberg et al., 1993). In assessing the temporal course of AD, the FAST and GDS in conjunction have been found to be superior to usage of either of these measures alone. Together, these measures can explain nearly three times the temporal variance in AD course accounted for by changes in MMSE scores (Reisberg et al., 1996). Consequently, just as one can inform clinicians of guidelines with regard to annual rate of change scores in the MMSE or psychometric measures, one can, with somewhat greater accuracy, provide clinicians with published mean change durations on global and functional assessments such as the GDS and FAST, which can be used to assist clinicians in diagnosing and tracking the course of AD (Reisberg et al., 1994).

Neuroimaging and Electrophysiology

Brain imaging is traditionally divided into two main types: structural imaging (computed tomography [CT] and magnetic resonance imaging [MRI]), which reflects the anatomy of the brain; and functional imaging (single-photon emission tomography [SPECT] and positron emission tomography [PET]), which assesses cerebral function in relative or absolute terms. This division is useful in attempting to understand the two types of brain imaging. However, increasingly, there is an integration of the two methods exemplified by functional MRI.

CT revolutionized the ability of clinicians to exclude intracranial lesions that could mimic the dementia syndrome and, in many places, remains the imaging technique of choice to visualize cerebral structures (Burns, 1990). In structural neuroimaging techniques such as CT, the appearance of AD is characterized by increased ventricular size and the presence of cortical atrophy (Burns et al., 1991b; de Leon et al., 1980; Forstl et al., 1995). The capacity of the brain CT imaging technique to differentiate between normal aged subjects and patients with primary dementia has been established (DeCarli et al., 1990) and clearly, the more sophisticated the analysis, the better the sensitivity and specificity (Burns & Pearlson, 1994). CT views of the medial temporal lobe have permitted particularly high levels of diagnostic ability in differentiating patients with AD from normal controls and may represent an early marker for the disease (de Leon et al., 1989; Jobst et al., 1992a). This accuracy increases when a functional imaging technique such as SPECT is combined with CT (Jobst et al., 1992b).

MRI, with better anatomical resolution than CT, has shown that atrophy of the hippocampus is a hallmark of AD and can be seen in very early cases (Convit et al., 1997). Longitudinal studies have shown that dilatation of the peri-hippocampal fissure can predict the diagnosis of AD with over 90% accuracy (de Leon et al., 1993). In a more extensive study, visual ratings of hippocampal atrophy showed 70% of people with mild cognitive impairment were affected, rising to 96% in those with moderate or severe dementia compared to 29% in normal controls (de Leon et al., 1997). Visual ratings of MRI scans of the entorhinal cortex have been shown to be particularly useful in one study in discriminating AD from normal aging (Erkinjuntti et al., 1993). Alternative measures of atrophy have been proposed including the interuncal distance (Dahlbeck et al., 1991) and quantitation using registration of serially acquired volumetric data (Fox et al., 1996). The ability of MRI to differentiate between depression and AD has been demonstrated with 90% of cases correctly classified (O’Brien et al., 1994). Subcortical white-matter lesions (leukoariosis) are related to age whereas lesions around the ventricular system appear to be associated with cognitive decline and are found in AD (Matsubayashi et al., 1992; McDonald et al., 1991). The prevalence of leukoariosis varies from 20% to over 60% and specific relationships have been found between the severity of the white-matter change and the degree of cognitive impairment, particularly deficits of attention and comprehension (Kertesz et al., 1990).

SPECT involves the administration of compounds that are distributed in the brain according to cerebral blood flow; in this way, a relative measure of cerebral activity can be assessed in different brain regions. Most commonly, SPECT investigations measure blood flow per se; however, muscarinic and dopamine receptors can also be imaged (Fontaine & Nordberg, 1996). In AD, temporoparietal hypoperfusion is usually seen, with frontal lobe blood flow sometimes being diminished as well (Burns et al., 1989a; Gemmell et al., 1989). When present in sufficient magnitude, the decrease in frontal lobe blood flow is diagnostic of dementia of frontal lobe type (Neary et al., 1988). Correlations have been found between areas of regional hypoperfusion and cognitive impairment, and specific associations have been described between amnesia and hypoperfusion in the temporal region, between apraxia and posterior parietal hypoperfusion, and between aphasia and hypoperfusion throughout the left hemisphere (Burns et al., 1989b). Other associations have included the level of previous occupation with parietal perfusion (Stern et al., 1995). SPECT is increasingly used to assess the response to drug treatment with and without brain activation (e.g., Geaney et al., 1990; Hunter et al., 1989).

PET provides a direct measure of cerebral metabolic activity. Most commonly in AD studies, PET is used to assess the absolute magnitude and/or regional patterns of cerebral glucose metabolism. Patterns of impairment in AD include temporoparietal and frontal hypometabolism with relative sparing of the visual and sensorimotor cortex (Burns et al., 1989a; de Leon et al., 1983; Rapoport, 1991). The changes are often asymmetric (Ichimiya et al., 1994) and this asymmetry relates to age of onset of disease. Frackowiak and colleagues (1981) were the first to use the isotope O15< in dementia, showing that in AD there was diminished oxygen consumption in the fronto- temporal-parietal lobes with the frontal lobes being more affected in severe disease. The role of PET in early diagnosis has been underscored recently with the findings of abnormalities in patients at risk of AD who possess the e4 allele of apolipoprotein (Small et al., 1995) and of abnormalities in individuals at risk from amyloid precursor protein (APP) and presenilin mutations (Kennedy et al., 1995).

Clearly, imaging techniques have an important role to play in the diagnosis and assessment of patients with dementia and in the specific diagnosis of AD. Techniques such as functional MRI hold promise for the future, and imaging will be used increasingly in innovative ways to aid in early diagnosis and in differential diagnosis.

The electroencephalogram (EEG) in patients with severe dementia generally reveals significant abnormalities in terms of regular slow wave activity. Those with less advanced disease have less consistent changes that may sometimes appear to be less well correlated with the degree of dementia. Cummings and Benson (1983) have summarized the clinical situation in stating that a normal EEG in the presence of severe dementia is likely to be indicative of AD, whereas an abnormal tracing with minimal clinical changes is associated with delirium. Generally, as AD progresses, there is progressive slowing of the EEG tracing with decreased alpha and beta activity and increased, somewhat symmetrical, delta and theta waves. EEG abnormalities have been found to be significantly more common in patients with AD compared to normal controls (Soininen et al., 1982), and important features include dominant occipital alpha wave activity (Prinz & Vitiello, 1989), increases of theta power (Coben et al., 1983; Prichep et al., 1994), and decreased EEG coherence (Besthorn et al., 1994).

As is the case with most assessment modalities, the rigor and sophistication of the techniques employed can determine the usefulness of the modality. In the case of EEG, computerized quantitative EEG can result in vastly increased information in comparison with traditional EEG tracing procedures. Using these computerized procedures, Prichep and colleagues (1994) have noted that in examining patient group data, there are clearly evident increments in theta activity in a mild memory impairment subject group, consisting of persons with subtly manifest deficits who frequently have incipient AD, in comparison with a control elderly subject group with subjective complaints of cognitive impairment only. Prichep and associates also found that each subsequent stage of AD, from mild to moderately severe, was accompanied by increased theta activity and subsequently also increased theta and delta slow wave activity. Overall, the Pearson correlation between increased slow wave activity and progression of global impairment stage was .5. Although very robust, the magnitude of this relationship between EEG slowing and the progression of AD remains somewhat less than with other modalities. Nevertheless, Prichep and colleagues and others believe that computer-analyzed quantitative EEG techniques can be of utility both in the early diagnosis of incipient AD and in the subsequent tracking of the course of the disease. Their belief in the utility of these procedures in early diagnosis is supported by observations that even normal elderly persons with only subjective complaints of cognitive loss appear to have increased theta activity in comparison with normal elderly persons, the same age, who are free of subjective complaints of cognitive impairment.

In dementias other than AD, the EEG findings vary: in cerebrovascular dementia, 75% have been found to have focal abnormalities (lateralized slow, sharp, or spike waves); whereas in dementia of frontal lobe type, the EEG is characteristically normal, and in Huntington’s disease, there is low-amplitude background activity (see Forstl & Hentscel, 1997, for a summary).

Neuropathologic Assessment

AD-related neuropathologic changes have traditionally been relied upon for a diagnosis of definite AD (McKhann et al., 1984) and appealed to as a diagnostic "gold standard." However, in practice, the situation is much more complex because the "assay procedures" are variable and subject to considerable debate and, even when there is agreement on the assay standard, the circumstances under which it was obtained (i.e., the clinical history) is of relevance in interpreting the findings.

Microscopically evident brain changes upon postmortem examination, most notably neurofibrillary tangles and senile (amyloid) plaques, have long been recognized as occurring in AD and have even been integral components of traditional definitions of AD (Alzheimer, 1907; Redlich, 1898; Simchowicz, 1910). Electron microscopic and other studies revealed that the neurofibrillary tangles are composed of paired helical filaments (Kidd, 1963) and that the amyloid plaques occur in various morphologic forms. The diagnostic and prognostic meaning of this diverse morphology of the amyloid plaques remains controversial; however, the most important form is the neuritic plaque, which is composed of a central core of homogeneous material, primarily ß-amyloid, and a reactive outer zone with fibrillary and cellular material. Modern molecular techniques have revealed that the most important constituent of the paired helical filaments of the neurofibrillary tangles is the tau protein (Kondo et al., 1988; Wischik et al., 1988a, 1988b), although other important constituents including ubiquitin, a very widely distributed protein, have also been identified (Mori et al., 1987; Perry et al., 1987). The ß-amyloid, which forms the core of the senile plaque, is known to be composed of a 42-43 amino acid peptide, the ß-amyloid peptide. The ß-amyloid peptide is derived from a longer molecule, the amyloid precursor protein.

Although there is increasing knowledge regarding the precise molecular nature and the genetic and molecular etiopathogenesis of AD-related cerebral pathology, two fundamental findings that have been recognized for many years limit the diagnostic value of AD-related neuropathologic findings: (a) these pathologic features are also noted in normal aging, and (b) these pathologic features are not uniquely seen in AD. Although Alois Alzheimer had initially believed that the neurofibrillary tangles, which he described in his classic case description, and the senile plaques, which had already been known to occur in association with senile dementia, would not be present in the brains of normal elderly persons, work in the early decades of the 20th century demonstrated that this was not true (see Wilkins & Brody, 1969, for a review; Grunthal, 1927; Gellerstedt, 1933). All of the cerebral pathology seen in AD could also be seen in the brains of ostensibly healthy aged persons. Similarly, the pathologic features associated with AD can be found in other disorders. To cite only a few examples: Amyloid deposits in the brain are known to be a feature of hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) (Levy et al., 1990), an uncommon hereditary disorder; ß-amyloid deposition has been observed in the brains of nonaged persons within days following severe head injury (Roberts et al., 1991); and neurofibrillary tangles similar to or identical to those seen in AD occur in progressive supranuclear palsy, dementia pugilistica, and even myotonic dystrophy (Bancher et al., 1987; Kiuchi et al., 1991).

Because the neuropathologic features of AD are not pathognomonic of this condition and, most importantly, appear to overlap with those of normal aging, the emphasis in AD diagnosis has been placed on the magnitude of AD-associated pathology in the brain in confirming or supporting a diagnosis of AD. Classical studies of Tomlinson and colleagues in the late 1960s and early 1970s had shown relatively strong correlations between the counts of senile plaques in the brain and counts of neurofibrillary tangles and the magnitude of dementia assessed antemortem (Tomlinson et al., 1968, 1970). These and subsequent studies resulted in considerable weight being placed on neuropathologic diagnosis in consensus definitions of AD. The result has been attempts to standardize the process of the neuropathologic diagnosis of AD (Khachaturian, 1985; Mirra et al., 1991). The most ambitious and well studied of these attempts at neuropathologic diagnostic standardization has been that of the CERAD (summarized by Mirra in this issue) (Mirra, 1997 [this issue]). The CERAD criteria have been recommended as a diagnostic protocol for AD in multicenter brain banking (Bogdano-vic & Morris, 1995). This protocol includes an illustrated guidebook and semiquantitative ratings of plaque and tangle frequency in specified brain regions. The result is a score with levels of certainty of AD diagnosis.

The CERAD studies have indicated an absence of interrater reliability among neuropathologists for quantitative plaque and tangle counts, which has also been noted in other investigations (Chui et al., 1993; Duyckaerts et al., 1990; Mirra et al., 1994, 1997 [this issue]). However, when semiquantitative rather than quantitative procedures are used, better results have been obtained by the CERAD investigators. The diagnostic accuracy of the CERAD semiquantitative procedures is reported as follows: The clinical diagnosis of AD was confirmed in 88% of cases and attributed to other conditions in 12% of cases (Mirra, 1997 [this issue]), although it should be noted that necessarily these data appeal to clinical diagnosis as a standard. The CERAD procedures have shown modest correlations with the severity of dementia as measured with the MMSE.

An understanding of the role of neuropathology in AD diagnosis must necessarily be informed by a knowledge of further findings and controversies. One of these controversies is that the essential presence of either major neuropathologic lesion remains a subject of debate. For example, numerous neocortical plaques have been found in a subgroup of aged persons with normal mental status (Katzman et al., 1988), and amyloid burden does not increase and the number of plaques does not correlate with the severity of AD (Gomez-Isla et al., 1997; Terry, 1997).

A more classical study had examined the essential nature of neurofibrillary pathology in AD. Terry and colleagues reported in 1987 that 30% of a series of cases with typical clinical presentation and course of AD and an otherwise typical AD neuropathologic picture lacked neocortical neurofibrillary tangles, although neurofibrillary tangles were present in the hippocampus (Terry et al., 1987).

Despite acknowledged controversy, a reasoned view of the nature of neuropathologically evident change in AD, as it is presently understood, can be offered. Braak and Braak have described an increasingly recognized view of the nature and evolution of AD brain pathology (Braak & Braak, 1991a, 1991b, 1992, 1994, 1997b). They state "the first changes are typically neurofibrillary tangles and neuropil threads." These appear initially, according to Braak and Braak, in the transentorhinal region of the medial temporal lobe. Subsequently, in accordance with these observations, the neurofibrillary pathology spreads to the hippocampus and, ultimately, the neocortex. Braak and Braak distinguish six stages of neuropathologic evolution, of which the first two stages are transentorhinal and occur before the advent of clinically manifest symptoms. Subsequent neuropathologic stages have been termed limbic and neocortical. Braak and Braak view the terminology "senile plaque" as obsolete and as referring to both amyloid deposits and neuritic plaques, the latter of which also contain neurofibrillar material. In any event, they do not view these structures as presently useful for staging the magnitude of pathology in AD.

The observations of Braak and Braak are consistent with other recent observations that indicate linear loss of volume of specific hippocampal brain regions with the clinical and temporal advance of AD (Bobinski et al., 1995; Simic et al., 1997). Accompanying these volume changes, in the same hippocampal regions, are increments in the percentages of neurons with neurofibrillary changes and progressive decrements in the absolute number of neurons in the same hippocampal regions. These neuronal losses, which appear to be linear with the temporal and clinical progression of AD, are so substantial that up to approximately 90% of neurons in particular hippocampal brain regions are lost over the 22-year potential course of clinically manifest AD (Bobinski et al., 1997). Similar findings have been noted recently in brain association areas. Specifically, in a study of the superior temporal nucleus, Gomez-Isla and colleagues have found dramatic neuronal losses that correlated with the number of neurofibrillary tangles and the duration and severity of AD (Gomez-Isla et al., 1997). The amyloid burden did not correlate with AD disease progression in any of these studies.

However, another relatively recent study using a computer-based image analysis of the cross-sectional area of the brain occupied by ß-amyloid immunopositive deposition found a strong correlation between cognitive impairment and amyloid burden in the entorhinal cortex (Cummings & Cotman, 1995).

Apart from the relatively well-studied neuropathology just reviewed, other neuropathologic changes also occur in AD, including changes in synaptic density and changes in non-neuronal structures such as the white matter (Brun & Englund, 1986; Davies et al., 1987; Scheff et al., 1990).

Peripheral Markers

Over the past few years, a number of in vivo techniques for the improved diagnosis and tracking of AD have been identified. These miscellaneous approaches may be subsumed under the general category "peripheral markers." These include diagnostic markers present in the blood, cerebrospinal fluid (CSF), and other body tissues. Also included in this category are less well-known physiologic approaches to AD diagnosis, tracking, and assess-ment, including cognition-independent neurologic markers such as neurologic reflexes and motor assessments.

The best-known peripheral markers are genetic markers for AD. The presently known genetic markers are of two types. The first of these are specific genetic predisposing factors for AD. Three specific genetic AD mutations that are potentially identifiable have been discovered to date. These are mutations in the APP (Goate et al., 1991; Mullan et al., 1992) and two mutations that have been termed presenilin 1 (PS1) and presenilin 2 (PS2) (Sherrington et al., 1995; Levy-Lahad et al., 1995; Rogaev et al., 1995). Although these mutations are robust markers for an early onset of AD, they occur very infrequently. Roses and Saunders (1997 [this issue]) note that "taken together, all of the known APP, PS1, and PS2 mutation families. . . amount to about 100 families worldwide." Another form of genetic mutation that is recognized as an early predisposing factor for AD is trisomy of the 21st chromosome, which results in Down’s syndrome. Down’s syndrome, in turn, is known to be associated with AD occurring at a relatively early age. Although the mechanism of the association of Down’s syndrome with AD is not known, it is known that the APP is encoded in the long arm of chromosome 21 (Goldgaber et al., 1987; Kang et al., 1987; Tanzi et al., 1987).

Another category of genetic marker for AD, which, for the present, uniquely applies to late-life AD, i.e., by far the most common form of AD, is the apolipoprotein E genotype. Apolipoproteins are molecules responsible for lipid transport in various organs. Three different subtypes of the apolipoprotein E allele are inherited: apolipoprotein E epsilon 2 (APOE-e2), APOE-e3, and APOE-e4 subtypes. Persons who carry one or more copies of the APOE-e4 allele are at increased risk for the development of AD. This increased risk has been confirmed repeatedly and is dramatic. Studies have indicated that persons who inherit two copies of the apolipoprotein E e4 genotype (i.e., who are homozygous) have approximately eight times the risk of developing AD as persons who do not inherit any copies of the APOE-e4 allele (Corder et al., 1993; Poirier et al., 1993). Persons with a single copy of the APOE-e4 allele are also at increased risk for the development of AD (odds ratios have varied between 2.2 and 4.4) (National Institute on Aging/Alzheimer’s Association Working Group, 1996). Persons with the APOE-e2 allele are at lower risk for the development of AD (Corder et al., 1994).

Of the six APOE genotypes, APOE-e3/3 is the most common, at least in European ancestry populations, and of the three APOE alleles, e3 is the most common. However, the APOE-e4 allele is also common, representing approximately 15% of APOE alleles. Consequently, approximately 30% of European ancestry populations carry at least one copy of the e4 allele, so the increased risk of AD associated with this allele affects a substantial proportion of the population. In association with the increased risk of AD, the APOE-e4 allele is associated with an earlier age of onset of AD. A recent multisite study found that individuals with two copies of the APOE-e4 allele had a mean age of onset of AD of 66 years, in comparison with a mean age of onset of 72 years for persons with either one APOE-e4 allele or no copies of the APOE-e4 allele (Blacker et al., 1997). Nevertheless, it must be emphasized that "some APOE-e4 carriers survive to old age and remain cognitively intact" (National Institute on Aging/Alzheimer’s Association Working Group, 1996).

Other peripheral markers of AD pathology are under investigation. An example of numerous efforts along these lines are in vivo studies of known AD-related pathologic elements. For instance, one of the major neuropathologic elements in AD is the neurofibrillary tangle, which is composed of paired helical filaments (PHFs). As already noted, these PHFs contain two principal elements, the tau protein and ubiquitin. Both of these elements are present in the CSF. Furthermore, levels of tau are increased in the CSF of AD patients in comparison with controls (Vandermereen et al., 1993; Vigo-Pelfrey et al., 1995). These increases in CSF tau appear to be, to some extent, age-related. Additionally, increased levels of ubiquitin have also been found in the CSF of AD patients (Kudo et al., 1994; Wang et al., 1991), although, interestingly, the increase in ubiquitin levels does not appear to be age-related. Despite these interesting pathologic findings, for various reasons, including overlap with ostensibly age-related controls, these tau and ubiquitin pathologic markers that are elevated in AD and present in the CSF are not being advocated for use as diagnostic markers at the present time (Iqbal and Grundke-Iqbal, 1997 [this issue]). Others have reported diagnostically promising relationships between CSF tau and levels of the beta amyloid protein in CSF, which will have to be verified in further studies (Motter et al., 1995).

Relatively novel approaches to AD diagnosis are also being pursued. For example, reflex testing is a sensitive indicator of nervous system integrity and is universally used among physicians to assess neurologic change. Indeed, the reflex hammer is one of the major icons associated in the public’s mind with physicians in general and with neurologists in particular. Reflex changes have been known to occur late in the course of AD (Huff et al., 1987).

Another series of observations has indicated that many of the clinical changes in AD recapitulate inversely, the normal human developmental pattern from infancy to the adult (Reisberg et al., 1986, 1990). So-called developmental neurologic reflexes have also been known to occur in aged patients (Paulson & Gottlieb, 1968) and, especially, in AD (Franssen et al., 1991, 1993; Huff et al., 1987). Recently, pathologic substrates in AD have been uncovered that parallel the observed clinical and neurologic developmental observations in AD. Specifically, Braak and Braak (1996, 1997a) have noted that the pattern of AD neurofibrillary change reverses the pattern of myelogenesis in normal development. Franssen and associates have exploited this knowledge of neurologic reflex changes in AD, and of developmental inverse clinicopathologic relationships in AD, to elucidate specific in vivo pathologic markers of AD course. For example, Franssen and colleagues have recently reported that by measuring developmental reflexes using a standardized clinical rating scale (Franssen, in Burns, 1993), these reflexes can serve as sensitive markers of specific points in the course of AD. Specifically, they have reported that the overt occurrence of a sucking, grasping, or the plantar extensor reflex differentiates AD patients who have deficiencies in basic activities of daily living but are not yet incontinent from permanently incontinent AD patients who are deficient in basic activities of daily living but still ambulatory, with a specificity, sensitivity, and overall accuracy of greater than 85% (Franssen et al., 1997). Consequently, these neurologic reflexes appear to emerge at a particular point in the progression of AD pathology, just as they disappear at characteristic points in the course of infancy and early childhood development.

Other work by Franssen and associates indicates that neurologic reflexes and release signs, which are not necessarily developmentally associated, can serve as early, cognition-, education-, and culture-independent markers of the advent of AD, as well as measures for charting the entire course of AD. For example, Franssen and colleagues reported significant increments in measures of deep tendon reflexes (i.e., the biceps, triceps, quadriceps, and gastrocnemius-soleus reflexes), and in what they termed nociceptive release signs (i.e., the snout reflex, the glabellar blink reflex, and the palmomental reflex), in patients with mild memory impairment (GDS stage 3), in comparison with normal controls (Franssen et al., 1991). When they combine five categories of neurologic reflex and release sign measures, representing 14 individual measures, a very robust relationship is noted with the course of aging and AD. For example, the Pearson correlation of these neurologic reflex and release sign measures with MMSE scores is greater than .7, whereas the correlation of these measures with the FAST staging procedure is .8 (Franssen & Reisberg, 1994, 1997 [this issue]).

Kluger and associates (1997a, 1997b [this issue]) have taken another novel approach to the diagnosis of AD. Brain disease is, of course, often accompanied by motor changes. In the case of stroke, normal-pressure hydrocephalus, Huntington’s chorea, and numerous other neurologic diseases, these motor changes are very dramatic and overt. Motor changes have also long been recognized as concomitants of AD (Reisberg et al., 1983). Kluger and associates have utilized computerized measurements of complex motor tasks, such as head tracking, in the early diagnosis of AD. They find that the accuracy of these complex motor tasks in distinguishing normal controls from subjects with mild cognitive impairment, and the accuracy in distinguishing normal controls from subjects with early AD, is comparable to the accuracy obtained with a psychometric battery of tests (Kluger et al., 1997a, 1997b [this issue]). Because these measures are ostensibly free of the influences of cognition, education, and culture, the motor assessments would appear to have advantages over psychometric measures in the early diagnosis of AD.

Conclusion

Procedures for the improved diagnosis of AD have advanced continuously over the past three decades. A variety of clinical approaches inform the diagnosis of AD. These include standard clinical differential diagnostic procedures, mental status and neuropsychologic assessment, functional and global evaluations, neuroimaging and electrophysiology, neuropathologic assessments, and peripheral markers. Clinicians who diagnose AD need to be somewhat aware of the merits and the current state of development of each of these diagnostic approaches.

Many approaches to AD diagnosis that are relatively well developed at the present juncture were unknown, or not generally known, in 1984, when the landmark criteria of McKhann and colleagues were published. For example, Lewy body dementia was not seen as an important entity in differential diagnosis, and genotypic risk factors and markers were unknown a decade ago. In general, many diagnostic approaches have become more focused and specific over the past several years. For example, apart from overt decrements in mental status and cognition, specific patterns of functional, neurologic, and behavioral change have been identified that can inform diagnosis. Similarly, apart from general neuropathologic changes, specific kinds of changes, evolving in specific ways, have been described in association with the neuropathologic evolution of AD.

A very similar evolution has occurred in the knowledge of the neuroimaging changes in AD. Atrophy and change can now be visualized in specific regions, which can be much more informative than a general view of brain atrophy alone.

Clearly, AD can be described at the present time as a very characteristic clinicopathologic process that is amenable to diagnosis. The advent of improved treatment and management makes the proper, and state-of-the-art, diagnosis of AD a clinical imperative in all medical settings. Concurrently, improved information regarding existing diagnostic procedures and their relevance and applicability in diverse clinical and cultural settings must continue to accrue.

Special Meeting Work Group Participants and Affiliations

(1) Participants, in addition to the authors, were as follows: Harry Allen, Manchester Royal Infirmary, Manchester, UK; Luigi Amaducci, University of Florence, Florence, Italy; David Ames, Institute of Psychiatry, London, UK; Stefanie Auer, New York University Medical Center, New York, NY, USA; Franz Baro, Katholieke Universiteit Leuven, Broeders van Liede, Belgium; Felix Bermejo, Hospital Universitario, Madrid, Spain; Heiko Braak, J.W. Goethe University, Frankfurt am Main, Germany; Jane Byrne, University of Manchester, Manchester, UK; Edmond Chiu, University of Melbourne, Kew, Victoria, Australia; Jorge Costa e Silva, World Health Organization, Geneva, Switzerland; Peter Davies, Albert Einstein College of Medicine, Bronx, NY, USA; Mony de Leon, New York University Medical Center, New York, NY, USA; Davangere Devanand, Columbia University, New York, NY, USA; Timo Erkinjuntti, University of Helsinki, Helsinki, Finland; Sanford Finkel, Northwestern University Medical School, Chicago, IL, USA; Marshal Folstein, New England Medical Center, Boston, MA, USA; Françoise Forette, University Paris V, Paris, France; Emile Franssen, New York University Medical Center, New York, NY, USA; Serge Gauthier, McGill Centre for Studies in Aging, Verdun, Quebec, Canada; Nori Graham, Royal Free Hospital, London, UK; Richard Ham, State University of New York Health Science Center at Syracuse, NY, USA; Jane Hecker, Repatriation General Hospital, Daw Park, South Australia, Australia; Ulrich Hegerl, Ludwig-Maximilians-Universität München, Munich, Germany; Akira Homma, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; Khalid Iqbal, NYS Institute for Basic Research, Staten Island, NY, USA; Kim A. Jobst, Radcliffe Infirmary Trust, Oxford, UK; Cees Jonker, Vrye Universiteit, Amsterdam, The Netherlands; Alan Kluger, New York University Medical Center, New York, NY, USA; Amos Korczyn, Tel-Aviv University, Ramat-Aviv, Israel; Alexander Kurz, Technisch Universität München, Munich, Germany; Knüt Laake, Ullevaal Hospital, Oslo, Norway; Hans Lauter, Psychiatrische Klinik, Munich, Germany; Brian Lawlor, St. James’s Hospital, Dublin, Ireland; Hartmut Lehfeld, Psychiatrische Klinik mit Poliklinik der Universität Erlangen-Nurnberg, Erlangen, Germany; Raymond Levy, Institute of Psychiatry, London, UK; Suzanne Mirra, Emory University School of Medicine, Decatur, GA, USA; William Molloy, Henderson Hospital, Hamilton, Ontario, Canada; John Morris, Washington University, St. Louis, MO, USA; Jordi Peña-Casanova, Barcelona, Spain; Ronald C. Petersen, Mayo Clinic, Rochester, MN, USA; Leonid Prilipko, World Health Organization, Geneva, Switzerland; Stanley Rapoport, National Institutes of Health, Bethesda, MD, USA; Burton V. Reifler, Bowman Gray School of Medicine, Winston-Salem, NC, USA; Karen Ritchie, Inserm Equipe "Vieillissement Cognitif," Montpellier, France; Allen Roses, Duke University Medical Center, Durham, NC, USA; Hannes B. Stähelin, Kantonsspital, Basel, Switzerland; Saskia Teunisse, Amsterdam, The Netherlands; Marco Trabucchi, University of Rome, Rome, Italy; Frans Verhey, Maastricht, The Netherlands; Gunhild Waldemar, National University Hospital, Rigshospitalet, Copenhagen, Denmark; Jean Wertheimer, Hôpital Psychogériatrique, Lausanne, Switzerland; and Peter Whitehouse, University of Cleveland, Cleveland, OH, USA.

References

Allen, N. H. P., Gordon, S., Hope, T., & Burns, A. (1996). Manchester and Oxford universities scale for the psychopathological assessment of dementia. British Journal of Psychiatry, 169, 293-307.

Alzheimer, A. (1907). Uber eine eigenartige Erkrankung der Hirnrinde [About a peculiar disease of the cerebral cortex]. Allgemeine Zeitschrift fur Psychiatrie und PsychischGerichtliche Medizin, 64, 146-148.

American Psychiatric Association. (1980). Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: Author.

American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders (3rd ed.-rev.). Washington, DC: Author.

American Psychiatric Association. (1994). Diag-nostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author.

Auer, S. R., Sclan, S. G., Yaffee, R. A., & Reisberg, B. (1994). The neglected half of Alzheimer disease: Cognitive and functional concomitants of severe dementia. Journal of the American Geriatrics Society, 42, 1266-1272.

Bancher, C., Lassmann, H., Budka, H., Grundke-Iqbal, I., Iqbal, K., et al. (1987). Neurofibrillary tangles in Alzheimer’s disease and progressive supranuclear palsy: Antigenic similarities and differences. Acta Neuropathologica, 74, 39-46.

Becker, J. T., Huff, F. J., Nebes, R. D., Holland, A., & Boller, F. (1988). Neuropsychological function in Alzheimer’s disease: Pattern of impairment and rates of progression. Archives of Neurology, 45, 263-268.

Berg, L., McKeel, D. W., Jr., Miller, J. P., Baty, J., & Morris, J. C. (1993). Neuropathological indexes of Alzheimer’s disease in demented and nondemented persons aged 80 years and older. Archives of Neurology, 50, 349-358.

Berg, L., Miller, J. P., Baty, J., Rubin, E. H., Morris, J. C., et al. (1992). Mild senile dementia of the Alzheimer type. 4. Evaluation of intervention. Annals of Neurology, 31, 242-249.

Berg, L., Miller, J. P., Storandt, M., Duchek, J., Morris, J. C., et al. (1988). Mild senile dementia of the Alzheimer type: 2. Lon itudinal assessment. Annals of Neurology, 23, 477-484.

Besthorn, C., Forstl, H., Geiger-Kabisch, C., Sattel, H., Gasser, T., et al. (1994). EEG coherence in Alzheimer disease. Electro-encephalography and Clinical Physiology, 90, 242-245.

Blacker, D., Haines, J. L., Rodes, L., Terwedow, H., Go, R. C. P., et al. (1997). ApoE-4 and age at onset of Alzheimer’s disease: The NIMH genetics initiative. Neurology, 48, 139-147.

Bobinski, M., Wegiel, J., Tarnawski, M., Reisberg, B., de Leon, M. J., et al. (1997). Relationships between regional neuronal loss and neurofibrillary changes in the hippocampal formation and duration and severity of Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 56, 414-420.

Bobinski, M., Wegiel, J., Wisniewski, H. M., Tarnawski, M., Reisberg, B., et al. (1995). Atrophy of hippocampal formation subdivisions correlates with stage and duration of Alzheimer disease. Dementia, 6, 205-210.

Bogdanovic, N., & Morris, J. H. (1995). Diagnostic criteria for Alzheimer’s disease in multicentre brain banking. In: Neuropathological diagnostic criteria for brain banking. Biomedical and Health Research Series (pp. 20-29). IOS Press.

Braak, H., & Braak, E. (1991a). Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathology, 1, 213-216.

Braak, H., & Braak, E. (1991b). Neuro-pathological stageing of Alzheimer-related changes. Acta Neuropathologica, 82, 239-259.

Braak, H., & Braak, E. (1992). The human entorhinal cortex: Normal morphology and lamina-specific pathology in various disease. Neuroscience Research, 15, 6-31.

Braak, H., & Braak, E. (1994). Pathology of Alzheimer’s disease. In D. B. Calne (Ed.), Neurodegenerative diseases (pp. 585-613). Philadelphia: WB Saunders.

Braak, H., & Braak, E. (1996). Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathologica, 92, 197-201.

Braak, H., & Braak, E. (1997a). Aspects of cortical destruction in Alzheimer’s disease. In B. T. Hyman, C. Duyckaerts, & Y. Christen (Eds.), Connections, cognition and Alzheimer’s disease (pp. 1-16). Berlin: Springer-Verlag.

Braak, H., & Braak, E. (1997b). Staging of Alzheimer-related cortical destruction. International Psychogeriatrics, 9(Suppl. 1), 257-261.

Brun, A., & Englund, E. (1986). A white matter disorder in dementia of the Alzheimer type: A pathoanatomical study. Annals of Neurology, 19, 253-262.

Burke, W. J., Miller, J. P., Rubin, E. H., Morris, J. C., Coben, L. A., et al. (1988). Reliability of the Washington University Clinical Dementia Rating (CDR). Archives of Neurology, 45, 31-32.

Burns, A. (1990). Cranial computed tomography in dementia of the Alzheimer type. British Journal of Psychiatry, 157, 10-15.

Burns, A., Folstein, S., Brandt, J., & Folstein, M. (1990a). Clinical assessment of irritability, aggression, and apathy in Huntington and Alzheimer’s disease. The Journal of Nervous and Mental Disease, 178, 20-26.

Burns, A., Jacoby, R., & Levy, R. (1991a). Progression of cognitive impairment in Alzheimer’s disease. Journal of the American Geriatrics Society, 39, 39-45.

Burns, A., Jacoby, R., & Levy, R. (1990b). Psychiatric phenomena in Alzheimer’s disease. I: Disorders of thought content. British Journal of Psychiatry, 157, 72-76.

Burns, A., Jacoby, R., & Levy, R. (1990c). Psychiatric phenomena in Alzheimer’s disease. II: Disorders of perception. British Journal of Psychiatry, 157, 76-81.

Burns, A., Jacoby, R., & Levy, R. (1990d). Psychiatric phenomena in Alzheimer’s disease. III: Disorders of mood. British Journal of Psychiatry, 157, 81-86.

Burns, A., Jacoby, R., & Levy, R. (1990e). Psychiatric phenomena in Alzheimer’s disease IV: Disorders of behaviour. British Journal of Psychiatry, 157, 86-94.

Burns, A., Jacoby, R., Philpot, M., & Levy, R. (1991b). CT in Alzheimer’s disease—Methods of scan analysis: Comparison with normal controls and clinico-radiological correlations. British Journal of Psychiatry, 159, 609-614.

Burns, A., & Pearlson, G. (1994). Computed tomography. London: Chapman and Hall.

Burns, A., Philpot, M. P., Costa, D. C., Ell, P. J., & Levy, R. (1989b). The investigation of Alzheimer’s disease with single photon emission tomography. Journal of Neurology, Neurosurgery and Psychiatry, 52, 248-253.

Burns, A., Tune, L., Steele, C., & Folstein, M. (1989a). Positron emission tomography in dementia—A clinical review. International Journal of Geriatric Psychiatry, 4, 67-72.

Chui, H. C., Tierney, M., Zarow, C., Lewis, A., Sobel, E. M., et al. (1993). Neuropathologic diagnosis of Alzheimer disease: Interrater reliability in the assessment of senile plaques and neurofibrillary tangles. Alzheimer Disease and Associated Disorders, 7, 48-54.

Coben, L. A., Danziger, W. L., & Berg, L. (1983). Frequency analysis of the resting awake EEG in mild senile dementia of Alzheimer type. EEG Clinical Neurophysiology, 55, 372-380.

Cohen-Mansfield, J., Marx, M. S., & Rosenthal, A. S. (1989). A description of agitation in a nursing home. Journal of Gerontology, 44, M77-M84.

Cohen-Mansfield, J., Marx, M. S., Werner, P., & Freedman, L. (1992). Temporal patterns of agitated nursing home residents. International Psychogeriatrics, 4, 197-206.

Convit, A., de Leon, M. J., Tarshish, C., De Santi, S., Tsui, W., et al. (1997). Specific hippocampal volume reductions in individuals at risk for Alzheimer’s disease. Neurobiology of Aging, 18, 1-9.

Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., et al. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature and Genetics, 7, 180-184.

Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261, 921-923.

Cummings, B. J., & Cotman, C. W. (1995). Image analysis of ß-amyloid load in Alzheimer’s disease and relation to dementia severity. Lancet, 346, 1524-1528.

Cummings, J. L. (1985). Organic delusions: Phenomenology, anatomical correlations, and review. British Journal of Psychiatry, 146, 184-197.

Cummings, J. L., & Benson, D. F. (1983). Laboratory aids in the diagnosis of dementia. In J. L. Cummings & D. F. Benson (Eds.), Dementia—A clinical approach (pp. 285-308). Boston: Butterworths.

Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A., et al. (1994). The neuropsychiatric inventory: Comprehensive assessment of psychopathology in dementia. Neurology, 44, 2308-2314.

Cummings, J. L., Miller, B., Hill, M., & Neshkes, R. (1987). Neuropsychiatric aspects of multi-infarct dementia and dementia of the Alzheimer type. Archives of Neurology, 44, 389-393.

Dahlbeck, S. W., McCluney, K. W., Yeakley, J. W., Fenstermacher, M. J., Bonmati, C., et al. (1991). The interuncal distance: A new MR measurement for the hippocampal atrophy of Alzheimer disease. American Journal of Neuroradiology, 12, 931-932.

Davies, C. A., Mann, D. M. A., Sumpter, P. Q., & Yates, P. O. (1987). A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. Journal of Neurological Sciences, 78, 151-164.

DeCarli, C., Kaye, J., Horowitz, B., & Rapoport, S. (1990). Critical analysis of the use of CT to study human brain in ageing and dementia of the Alzheimer type. Neurology, 40, 872-873.

de Leon, M. J., Ferris, S. H., George, A., Reisberg, B., Christman, D. R., et al. (1983). Computed tomography and positron emission transaxial tomography evaluations of normal aging and Alzheimer’s disease. Journal of Cerebral Blood Flow and Metabolism, 3, 391-394.

de Leon, M. J., Ferris, S. H., George, A. E., Reisberg, B., Kricheff, I., et al. (1980). Computed tomography evaluations of brain behavior relationships in senile dementia of the Alzheimer’s type. Neurobiology of Aging, 1, 60-69.

de Leon, M. J., George, A. E., Golomb, J., Tarshish, C., Convit, A., et al. (1997). Frequency of hippocampus atrophy in normal elderly and Alzheimer’s disease patients. Neurobiology of Aging, 18, 1-11.

de Leon, M. J., George, A. E., Stylopoulos, L. A., Smith, G., & Miller, D. C. (1989). Early marker for Alzheimer’s disease: The atrophic hippocampus. Lancet, 2, 672-673.

de Leon, M. J., Golomb, J., George, A. E., Convit, A., Tarshish, C. Y., et al. (1993). The radiologic prediction of Alzheimer’s disease: The atrophic hippocampal formation. American Journal of Neuroradiology, 14, 897-906.

Devanand, D. P., Miller, L., Richards, M., Marder, K., & Bell, K. (1992). The Columbia University scale for psychopathology in Alzheimer’s disease. Archives of Neurology, 49, 371-376.

Drevets, W. C., & Rubin, E. H. (1989). Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type. Biological Psychiatry, 25, 39-48.

Dura, J. R., Haywood-Niler, E., & Kiecolt-Glaser, J. K. (1990). Spousal caregivers of persons with Alzheimer’s and Parkinson’s disease dementia: A preliminary comparison. The Gerontologist, 30, 332-336.

Duyckaerts, C., Delaere, P., Hauw, J., Abbamondi-Pinto, A. L., Sorbi, S., et al. (1990). Rating of the lesions in senile dementia of the Alzheimer type: Concordance between laboratories. Journal of the Neurological Sciences, 97, 295-323.

Erkinjuntti, T., Lee, D. H., Gao, F., Steenhuis, R., Eliasziw, M., et al. (1993). Temporal lobe atrophy on magnetic resonance imaging in the diagnosis of early Alzheimer’s disease. Archives of Neurology, 50, 305-310.

Erzigkeit, H. (1989). The SKT—A short cognitive performance test as an instrument for the assessment of clinical efficacy of cognition enhancers. In M. Bergener & B. Reisberg (Eds.), Diagnosis and treatment of senile dementia (pp. 164-174). Berlin: Springer-Verlag.

Esquirol, J. E. D. (1838). Des maladies mentales [Diseases of the mind]. Paris: Balliere.

Flicker, C., Ferris, S.H., & Reisberg, B. (1991). Mild cognitive impairment in the elderly: Predictors of dementia. Neurology, 41, 1006-1009.

Flicker, C., Ferris, S. H., & Reisberg, B. (1993a). A longitudinal study of cognitive function in elderly persons with subjective memory complaints. Journal of the American Geriatrics Society, 41, 1029-1032.

Flicker, C., Ferris, S. H., & Reisberg, B. (1993b). A two-year longitudinal study of cognitive function in normal aging and Alzheimer’s disease. Journal of Geriatric Psychiatry and Neurology, 6, 84-96.

Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatry Research, 12, 189-198.

Fontaine, S., & Nordberg, A. (1996). Brain imaging. In S. Gauthier (Ed.), Clinical diagnosis and management of Alzheimer’s disease (pp. 83-105). London: Martin Dunitz.

Forstl, H., & Hentscel, F. (1997). Electrophysiology and neuroimaging. In R. Jacoby & C. Oppenheimer (Eds.), Psychiatry in the elderly (pp. 178-192). London: Oxford University Press.

Forstl, H., Zerfass, R., Geiger-Kabisch, C., Sattel, H., Besthorn, C., et al. (1995). Brain atrophy in normal aging and Alzheimer’s disease. British Journal of Psychiatry, 167, 739-746.

Foster, J. R., Sclan, S., Welkowitz, J., Boksay, I., & Seeland, I. (1988). Psychiatric assessment in medical long-term care facilities: Reliability of commonly used rating scales. International Journal of Geriatric Psychiatry, 3, 229-233.

Fox, N. C., Freeborough, P. A., & Rossor, M. N. (1996). Visualisation and quantification of rates of atrophy in Alzheimer’s disease. Lancet, 348, 94-97.

Frackowiak, R. S. J., Pozzilli, C., Legg, N. J., DuBoulay, G. H., Marshall, J., et al. (1981). Regional cerebral oxygen supply and utilization in dementia—A clinical and physiological study with oxygen-15 and positron tomography. Brain, 104, 753-778.

Franssen, E. H. (1993). Neurologic signs in ageing and dementia. In A. Burns (Ed.), Aging and dementia, A methodological approach (pp. 144-174). London: Edward Arnold.

Franssen, E. H., Kluger, A., Torossian, C. L., & Reisberg, B. (1993). The neurologic syndrome of severe Alzheimer’s disease: Relationship to functional decline. Archives of Neurology, 50, 1029-1039.

Franssen, E. H., & Reisberg, B. (1994). Cognition-independent neurologic markers of the course of Alzheimer’s disease (AD) [Abstract]. Neurobiology of Aging, 15, S7.

Franssen, E. H., & Reisberg, B. (1997). Neurologic markers of the progression of Alzheimer’s disease. International Psychogeriatrics, 9(Suppl. 1), 297-306.

Franssen, E. H., Reisberg, B., Kluger, A., Sinaiko, E., & Boja, C. (1991). Cognition-independent neurologic symptoms in normal aging and probable Alzheimer’s disease. Archives of Neurology, 48, 148-154.

Franssen, E. H., Souren, L. E. M., Torossian, C. L., & Reisberg, B. (1997). Utility of developmental reflexes in the differential diagnosis and prognosis of incontinence in Alzheimer disease. Journal of Geriatric Psychiatry and Neurology, 10, 22-28.

Frisoni, G. B., Rozzini, R., Bianchetti, A., & Trabucchi, M. (1993). Principal lifetime occupation and MMSE score in elderly persons. Journal of Gerontology: Social Sciences, 48, S310-S314.

Ganguli, M., Ratcliff, G., Huff, J., Belle, S., Kancel, M. J., et al. (1990). Serial sevens versus world backwards: A comparison of the two measures of attention from the MMSE. Journal of Geriatric Psychiatry and Neurology, 3, 203-207.

Geaney, D., Soper, N., Shepstone, B., & Cowan, P. (1990). Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer’s disease. Lancet, 335, 1484-1487.

Gélinas, I., Gauthier, L., Wood-Dauphinee, S., Gauthier, S., Bellavance, F., et al. (1995). Assessment of functional disability in Alzheimer’s disease [Abstract]. CJOT Conference Supplement, 62, 15.

Gellerstedt, N. (1933). Our knowledge of cerebral changes in normal involution of old age. Upsala-Lak/Foren Forh, 38, 193.

Gemmell, H. G., Sharp, P., Smith, F., & Besson, J. A. (1989). Cerebral blood flow measured by SPECT as a diagnostic tool in the study of dementia. Psychiatry Research, 27, 327-329.

Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature, 349, 704-706.

Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U., & Gajdusek, D. C. (1987). Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science, 235, 877-880.

Gomez-Isla, T., Hollister, R., West, H., Mui, S., Growdon, J. H., et al. (1997). Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Annals of Neurology, 41, 17-24.

Gottlieb, G. L., Gur, R. E., & Gur, R. C. (1988). Reliability of psychiatric scales in patients with dementia of the Alzheimer type. American Journal of Psychiatry, 45, 857-859.

Grunthal, E. (1927). Clinical and anatomical investigations on senile dementia. Zeitschrift Fur die gesampte Neurologie und Psychiatrie, 111, 763.

Hartmaier, S. L., Sloan, P. D., Guess, H. A., & Koch, G. G. (1994). The MDS Cognition Scale: A valid instrument for identifying and staging nursing home residents with dementia using the minimum data set. Journal of the American Geriatrics Society, 42, 1173-1179.

Huff, F. J., Boller, F., Luchelli, F., Querriera, R., Beyer, J., et al. (1987). The neurologic examination in patients with probable Alzheimer’s disease. Archives of Neurology, 44, 929-932.

Hughes, C. P., Berg, L., Danziger, W. L., Coben, L. A., & Martin, R. L. (1982). A new clinical scale for the staging of dementia. British Journal of Psychiatry, 140, 566-572.

Hunter, R., McLuskie, R., Wyper, D., Patterson, J., Christie, J., et al. (1989). The pattern of functional related regional cerebral blood flow investigated by SPECT with 99 mTc HMPAO in patients with presenile Alzheimer’s disease and Korsakoff’s psychosis. Psychological Medicine, 19, 847-855.

Ichimiya, A., Herholz, K., Mielke, R., Kessler, J., Slansky, I., et al. (1994). Difference of region cerebral metabolic patterns between presenile and senile dementia of Alzheimer type. Journal of Neurological Sciences, 123, 11-17.

Iqbal, K., & Grundke-Iqbal, I. (1997). Elevated levels of t and ubiquitin in brain and cerebrospinal fluid in Alzheimer’s disease. International Psychogeriatrics, 9(Suppl. 1), 289-296.

Jacobs, J. W., Bernhard, M. R., Delgado, A., & Strain, J. F. (1977). Screening for organic mental syndromes in the mentally ill. Annals of Internal Medicine, 80, 40-46.

Jobst, K. A., Smith, A. D., Barker, C. S., Wear, A., King, E. M., et al. (1992b). Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal cortex in patients with a clinical and pathological diagnosis of Alzheimer’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 33, 190-194.

Jobst, K. A., Smith, A. D., Szatmari, M., Molyneux, A., Esiri, M. E., et al. (1992a). Detection in life of confirmed Alzheimer’s disease using a simple measurement of medial temporal lobe atrophy by computed tomography. Lancet, 340, 1179-1184.

Kahn, R. L., Goldfarb, A. I., Pollack, M., & Peck, A. (1960). Brief objective measures for the determination of mental status in the aged. American Journal of Psychiatry, 117, 326-328.

Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., et al. (1987). The precursor of Alzheimer’s disease amyloid ßA4 protein resembles a cell-surface receptor. Nature, 325, 733-736.

Katzman, R., Terry, R., DeTeresa, R., Brown, T., Davies, P., et al. (1988). Clinical, pathological, and neurochemical changes in dementia: A subgroup with preserved mental status and numerous neocortical plaques. Annals of Neurology, 23, 138-144.

Kennedy, A. M., Frackowiak, R. S. J., Newman, S. K., Bloomfield, P. M., Seaward, J., et al. (1995). Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer’s disease. Neuroscience Letters, 186, 17-20.

Kertesz, A., Polk, M., & Carr, T. (1990). Cognition and white matter changes on magnetic resonance imaging in dementia. Archives of Neurology, 47, 387-391.

Khachaturian, Z. S. (1985). Diagnosis of Alzheimer’s disease. Archives of Neurology, 42, 1097-1105.

Khachaturian, Z. S. (1997, July/August). Plundered memories. The Sciences, pp. 20-25.

Kidd, M. (1963). Paired helical filaments in electron microscopy in Alzheimer’s disease. Nature, 197, 192-193.

Kiuchi, A., Otsuka, N., Namba, Y., Nakano, I., & Tomonaga, H. (1991). Presenile appearance of abundant Alzheimer’s neurofibrillary tangles without senile plaques in the brain in myotonic dystrophy. Acta Neuropathologica, 82, 1-5.

Kluger, A., Gianutsos, J. G., Golomb, J., Ferris, S. H., George, A. E., et al. (1997a). Patterns of motor impairment in normal aging, mild cognitive decline, and early Alzheimer’s disease. Journal of Gerontology: Psychological Sciences, 52B, P28-P39.

Kluger, A., Gianutsos, J. G., Golomb, J., Ferris, S. H., & Reisberg, B. (1997b). Motor/psychomotor dysfunction in normal aging, mild cognitive decline, and early Alzheimer’s disease: Diagnostic and differential diagnostic features. International Psychogeriatrics, 9(Suppl. 1), 307-316.

Kondo, J., Honda, T., Mori, H., Hamada, Y., Miura, R., et al. (1988). The carboxyl third of tau is tightly bound to paired helical filaments. Neuron, 1, 827-834.

Kudo, T., Iqbal, K., Ravid, R., Swaab, D. F., & Grundke-Iqbal, I. (1994). Alzheimer disease: Correlation of cerebrospinal fluid and brain ubiquitin levels. Brain Research, 82, 1-7.

Lawton, M. P., & Brody, E. (1969). Assessment of older people: Self-maintaining and instrumental activities of daily living. The Gerontologist, 9, 179-186.

Lerner, A. J., Koss, E., Patterson, M. B., Ownby, R. L., Hedera, P., et al. (1994). Concomitants of visual hallucinations in Alzheimer’s disease. Neurology, 44, 523-527.

Levy, E., Carman, M. D., Fernandez-Madrid, I. J., Power, H., Lieberburg, I., et al. (1990). Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral haemorrhage, Dutch type. Science, 248, 1124-1126.

Levy, M. L., Cummings, J. L., Fairbanks, L. A., Bravi, D., Calvani, M., et al. (1996). Longitudinal assessment of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer’s disease. American Journal of Psychiatry, 153, 1438-1443.

Levy-Lahad, E., Wijsman, E. M., Nemens, E., Anderson, L., Goodard, K. A., et al. (1995). A familial Alzheimer’s disease locus on chromosome 1. Science, 269, 970-973.

Matsubayashi, K., Shimada, K., Kawamoto, A., & Ozawa, T. (1992). Incidental brain lesions on magnetic resonance imaging and neurobehavioural functions in the apparently healthy elderly. Stroke, 23, 175-180.

McCulla, M. M., Coats, M., Van Fleet, N., Duchek, J., Grant, E., et al. (1989). Reliability of clinical nurse specialists in the staging of dementia. Archives of Neurology, 46, 1210-1211.

McDonald, W., Krishnan, K., Doraiswamy, P. M., & Figiel, G. S. (1991). Magnetic resonance findings in patients with early onset Alzheimer’s disease. Biological Psychiatry, 29, 799-810.

McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., et al. (1984). Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA work group under the auspices of Department of Health & Human Services Task Force on Alzheimer’s disease. Neurology, 34, 939-944.

Mirra, S. S. (1997). Neuropathological assessment of Alzheimer’s disease: The experience of the Consortium to Establish a Registry for Alzheimer’s Disease. International Psychogeriatrics, 9(Suppl. 1), 263-268.

Mirra, S. S., Gearing, M., McKeel, D., Crain, B., Hughes, J., et al. (1994). Interlaboratory comparison of neuropathology assessments in Alzheimer’s disease: A study of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Journal of Neuropathology and Experimental Neurology, 53, 303-315.

Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., et al. (1991). The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology, 41, 479-486.

Molloy, D. W., Alemayehu, E., & Roberts, R. (1991). Reliability of a standardized Mini-Mental State Examination compared with the traditional Mini-Mental State Examination. American Journal of Psychiatry, 148, 102-105.

Mori, H., Kondo, J., & Ihara, Y. (1987). Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science, 235, 1641-1644.

Morris, J. C. (1993). The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology, 43, 2412-2414.

Morris, J. C., Edland, S., Clark, C., Galasko, D., Koss, E., et al. (1993). The consortium to establish a registry for Alzheimer’s disease (CERAD). Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer’s disease. Neurology, 43, 2457-2465.

Morris, J. C., Ernesto, C., Shaefer, K., Coats, M., Leon, S., et al. (1997). Clinical dementia rating (CDR) training and reliability protocol: The Alzheimer Disease Cooperative Study Unit experience. Neurology, 48, 1508-1510.

Morris, J. C., McKeel, D. W., Storandt, M., Rubin, E. H., Price, J. L., et al. (1991). Very mild Alzheimer’s disease: Informant-based clinical, psychometric, and pathological distinction from normal aging. Neurology, 41, 469-478.

Morris, J. C., Storandt, M., McKeel, D. W., Rubin, E. H., Price, J. L., et al. (1996). Cerebral amyloid deposition and diffuse plaques in "normal" aging: Evidence for presymptomatic and very mild Alz-heimer’s disease. Neurology, 46, 707-719.

Mortimer, J. A., Ebbitt, B., Jun, S., & Finch, M. D. (1992). Predictors of cognitive and functional progression in patients with probable Alzheimer’s disease. Neurology, 42, 1689-1696.

Motter, R., Vigo-Pelfrey, C., Kholodenko, D., Barbour, R., Johnson-Wood, K., et al. (1995). Reduction of b-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Annals of Neurology, 38, 643-648.

Mullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., et al. (1992). A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of ß-amyloid. Nature Genetics, 1, 345-347.

Murden, R. A., McRae, T. D., Kaner, S., & Bucknam, M. E. (1991). Mini-mental state exam scores vary with education in blacks and whites. Journal of the American Geriatrics Society, 39, 149-155.

National Institute on Aging/Alzheimer’s Association Working Group. (1996). Apolipoprotein E genotyping in Alz-heimer’s disease. Lancet, 347, 1091-1095.

Neary, D., Snowden, J. S., Northen, B., & Goulding, P. (1988). Dementia of frontal lobe type. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 353-361.

O’Brien, J., Desmond, P., Ames, D., Schweitzer, I., Tuckwell, V., et al. (1994). The differentiation of depression from dementia by temporal lobe magnetic resonance imaging. Psychological Medicine, 24, 633-640.

Oppenheim, G. (1994). The earliest signs of Alzheimer’s disease. Journal of Geriatric Psychiatry and Neurology, 7, 118-122.

Patterson, M. B., Mack, J. L., Neundorfer, M. M., Martin, R. J., Smyth, K. A., et al. (1992). Assessment of functional ability in Alzheimer’s disease: A review and a preliminary report on the Cleveland Scale of Activities of Daily Living. Alzheimer Disease and Associated Disorders, 6, 145-163.

Paulson, G., & Gottlieb, G. (1968). Developmental reflexes: The reappearance of foetal and neonatal reflexes in aged patients. Brain, 91, 37-52.

Perry, G., Friedman, R., Shaw, G., & Chau, V. (1987). Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proceedings of the National Academy of Sciences, USA, 84, 3033-3036.

Pfeiffer, E. A. (1975). Short portable mental status questionnaire for the assessment of organic brain deficit in the elderly. Journal of the American Geriatrics Society, 23, 433-441.

Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., Bertrand, P., et al. (1993). Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet, 342, 697-699.

Prichep, L. S., John, E. R., Ferris, S. H., Reisberg, B., Alper, K., et al. (1994). Quantitative EEG correlates of cognitive deterioration in the elderly. Neurobiology of Aging, 15, 85-90.

Prinz, P. N., & Vitiello, M. V. (1989). Dominant occipital (alpha) rhythm frequency in early stage Alzheimer’s disease and depression. EEG and Clinical Neurophysiology, 73, 427-432.

Rapoport, S. I. (1991). Positron emission tomography in Alzheimer’s disease in relation to disease pathogenesis: Critical review. Cerebrovascular and Brain Metabolism Reviews, 3, 297-335.

Redlich, E. (1898). Ueber miliare sklerose der Hirnrinde bei seniler Atrophie [Miliary sclerosis of the cerebral cortex in senile atrophy]. Jahrbucher F Psych u Neurol, 17, 208-216.

Reisberg, B. (1986). Dementia: A systematic approach to identifying reversible causes. Geriatrics, 41, 30-46.

Reisberg, B., Borenstein, J., Salob, S. P., Ferris, S. H., Franssen, E. H., et al. (1987). Behavioral symptoms in Alzheimer’s disease: Phenomenology and treatment. Journal of Clinical Psychiatry, 48(Suppl.), 9-15.

Reisberg, B., Ferris, S. H., de Leon, M. J., & Crook, T. (1982). The Global Deterioration Scale for assessment of primary degenerative dementia. American Journal of Psychiatry, 139, 1136-1139.

Reisberg, B., Ferris, S. H., & Franssen, E. H. (1986). Functional degenerative stages in dementia of the Alzheimer’s type appear to reverse normal human development. In C. Shagass et al. (Eds.), Biological psychiatry 1985 (Vol. 7, pp. 1319-1321). New York: Elsevier Science.

Reisberg, B., Ferris, S. H., Franssen, E. H., Shulman, E., Monteiro, I., et al. (1996). Mortality and temporal course of probable Alzheimer’s disease: A five-year prospective study. International Psychogeriatrics, 8, 291-311.

Reisberg, B., Franssen, E. H., Sclan, S. G., Kluger, A., & Ferris, S. H. (1989). Stage specific incidence of potentially remediable behavioral symptoms in aging and Alzheimer’s disease: A study of 120 patients using the BEHAVE-AD. Bulletin of Clinical Neurosciences, 54, 95-112.

Reisberg, B., London, E., Ferris, S. H., Borenstein, J., Scheier, L., et al. (1983). The Brief Cognitive Rating Scale: Language, motoric, and mood concomitants in primary degenerative dementia. Psychopharmacology Bulletin, 19, 702-708.

Reisberg, B., Pattschull-Furlan, A., Franssen, E. H., Sclan, S., Kluger, A., et al. (1990). Cognition-related functional, praxis and feeding changes in CNS aging and Alzheimer’s disease and their developmental analogies. In K. Beyreuther & G. Schettler (Eds.), Molecular mechanisms of aging (pp. 18-40). Berlin: Springer-Verlag.

Reisberg, B., Sclan, S. G., Franssen, E., de Leon, M. J., Kluger, A., et al. (1993). Clinical stages of normal aging and Alzheimer’s disease: The GDS staging system. Neuroscience Research Communications, 13(Suppl. 1), 551-554.

Reisberg, B., Sclan, S. G., Franssen, E. H., Kluger, A., & Ferris, S. H. (1994). Dementia staging in chronic care populations. Alzheimer Disease and Associated Disorders, 8, S188.

Roberts, G. W., Gentleman, S. M., Lynch, A., & Graham, D. I. (1991). ßA4 amyloid protein deposition in brain after head trauma. Lancet, 338, 1422-1423.

Rockwell, E., Jackson, E., Vilke, G., & Jeste, D. V. (1994). A study of delusions in a large cohort of Alzheimer’s disease patients. American Journal of Geriatric Psychiatry, 2, 157-164.

Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., et al. (1995). Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature, 376, 775-778.

Rosen, J., & Zubenko, G. S. (1991). Emergence of psychosis and depression in the longitudinal evaluation of Alzheimer’s disease. Biological Psychiatry, 29, 224-232.

Rosen, W. G., Mohs, R. C., & Davis, K. L. (1984). A new rating scale for Alzheimer’s disease. American Journal of Psychiatry, 141, 1356-1364.

Roses, A. D., & Saunders, A. M. (1997). Apoli-poprotein E genotyping as a diagnostic adjunct for Alzheimer’s disease. International Psychogeriatrics, 9(Suppl. 1), 277-288.

Rubin, E. H., & Kinscherf, D. A. (1989). Psychopathology of very mild dementia of the Alzheimer type. American Journal of Psychiatry, 146, 1017-1021.

Rubin, E. H., Morris, J. C., & Berg, L. (1987). The progression of personality changes in senile dementia of the Alzheimer’s type. Journal of the American Geriatrics Society, 35, 721-725.

Salmon, D. P., Thal, L. J., Butters, N., & Heindel, W. C. (1990). Longitudinal evaluation of dementia of the Alzheimer type: A comparison of 3 standardized mental status examinations. Neurology, 40, 1225-1230.

Saxton, J., McGonigle-Gibson, K. L., Swihart, A. A., Miller, V. J., & Boller, F. (1990). Assessment of the severely impaired patient: Description and validation of a new neuropsychological test battery. Psychological Assessment: A Journal of Consulting and Clinical Psychology, 2, 298-303.

Scheff, S. W., DeKosky, S. T., & Price, D. A. (1990). Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiology of Aging, 11, 29-37.

Sclan, S. G., & Reisberg, B. (1992). Functional assessment staging (FAST) in Alzheimer’s disease: Reliability, validity and ordinality. International Psychogeriatrics, 4(Suppl. 1), 55-69.

Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., et al. (1995). Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer’s disease. Nature, 375, 754-760.

Simchowicz, T. (1910). Histologische studien uber die senile demenz [Histologic studies of senile dementia]. Histopathology, 4, 267.

Simic, G., Kostovic, I., Winblad, B., & Bogdanovic, N. (1997). Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease. Journal of Comparative Neurology, 379, 482-484.

Small, G. W., Mazziotta, J. C., Collins, M. T., Baxter, L. R., Phelps, M. E., et al. (1995). Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. Journal of the American Medical Association, 273, 942-947.

Soininen, H., Partinen, V. J., Helkala, E. L., & Riekkinen, P. J. (1982). EEG findings in senile dementia and normal ageing. Acta Neurologica Scandinavica, 65, 59-70.

Stern, Y., Alexander, G. E., Prohovnik, I., Stricks, L., Link, B., et al. (1995). Relationship between lifetime occupation and parietal flow: Implications for reserve against Alzheimer’s disease pathology. Neurology, 45, 55-60.

Tangalos, E. G., Smith, G. E., Ivnik, R. J., Petersen, R. C., Kokmen, E., et al. (1996). The Mini-Mental State Examination in general medical practice: Clinical utility and acceptance. Mayo Clinic Proceedings, 71, 829-837.

Tanzi, R. E., Gusella, J. F., Watkins, P. C., Bruns, G. A., St. George-Hyslop, P., et al. (1987). Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science, 235, 880.

Tariot, P. N., Mack, J. L., Patterson, M. B., Edland, S. D., Weiner, M. F., et al. (1995). The behavior rating scale for dementia of the consortium to establish a registry for Alzheimer’s disease. American Journal of Psychiatry, 152, 1349-1357.

Teri, L., Hughes, J. P., & Larson, E. B. (1990). Cognitive deterioration in Alzheimer’s disease: Behavioral and health factors. Journal of Gerontology, 45, 58-63.

Teri, L., Larson, E., & Reifler, B. (1988). Behavioral disturbance in dementia of the Alzheimer’s type. Journal of the American Geriatrics Society, 36, 1-6.

Terry, R. D. (1997). The pathology of Alzheimer’s disease: Numbers count. Annals of Neurology, 41, 7.

Terry, R. D., Hansen, L. A., DeTeresa, R., Davies, P., Tobins, H., et al. (1987). Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles. Journal of Neuro-pathological and Experimental Neurology, 46, 262-268.

Teunisse, S., Derix, M. M. A., & van Crevel, H. (1991). Assessing the severity of dementia. Patient and caregiver. Archives of Neurology, 98, 274-277.

Tombaugh, T. N., & McIntyre, N. J. (1992). The Mini-Mental State Examination: A comprehensive review. Journal of the American Geriatrics Society, 40, 922-935.

Tomlinson, B. E., Blessed, G., & Roth, M. (1968). Observations on the brains of non-demented old people. Journal of Neurological Sciences, 7, 331-356.

Tomlinson, B. E., Blessed, G., & Roth, M. (1970). Observations on the brains of demented old people. Journal of Neurological Sciences, 11, 205-242.

Uhlmann, R. F., & Larson, E. B. (1991). Effect of education on the Mini-Mental State Examination as a screening test for dementia. Journal of the American Geriatrics Society, 39, 876-880.

Vandermereen, M., Mercken, M., Vanmechelen, E., Six, J., Van de Voorde, A., et al. (1993). Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. Journal of Neurochemistry, 61, 1828-1834.

Vigo-Pelfrey, C., Seubert, P., Barbour, R., Blomquist, C., Lee, M., et al. (1995). Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer’s disease. Neurology, 45, 788-793.

Wang, G. P., Iqbal, K., Bucht, G., Winblad, B., Wisniewski, H. M., et al. (1991). Alzheimer’s disease: Paired helical filament immunoreactivity in cerebrospinal fluid. Acta Neuropathologica (Berlin), 82, 6-12.

Weiner, M. F., Williams, B., & Risser, R. C. (1997). Assessment of behavioral symptoms in community-dwelling dementia patients. American Journal of Geriatric Psychiatry, 5, 26-30.

Weiss, B. D., Reed, R., Kligman, E. W., & Abyad, A. (1995). Literacy and performance on the Mini-Mental State Examination. Journal of the American Geriatrics Society, 43, 807-810.

Wilkins, R. H., & Brody, I. A. (1969). Alzheimer’s disease. Archives of Neurology, 21, 109-110.

Wischik, C. M., Novak, M., Edwards, P. C., Klug, A., Tichelaar, W., et al. (1988b). Structural characterization of the core of the paired helical filament of Alzheimer disease. Proceedings of the National Academy of Sciences, USA, 85, 4884-4888.

Wischik, C. M., Novak, M., Thogersen, H. C., Edwards, P. C., Runswick, M. J., et al. (1988a). Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proceedings of the National Academy of Sciences, USA, 85, 4506-4510.

World Health Organization. (1992). The ICD-10 classification of mental and behavioral disorders. Geneva, Switzerland: Author.

Wragg, R. E., & Jeste, D. V. (1989). Overview of depression and psychosis in Alzheimer’s disease. American Journal of Psychiatry, 146, 577-587.

Yesavage, J. A., Poulsen, S. L., Sheik, J., & Janke, E. (1988). Rate of change of common measures of impairment in senile dementia of the Alzheimer’s type. Psychopharmacology Bulletin, 24, 531-534.

Reprinted from International Psychogeriatric Volume 9, Supplement 1.