Cognitive and brain imaging measures of Alzheimer's disease

Neurobiology of Aging, Vol. 9, pp. 69-86. PergamonJournals Ltd., 1988.Printed in the U.S.A.

0197.4580/88 $3.00 +°.00

REVIEW

Cognitive and Brain Imaging Measures of Alzheimer's Disease W. H. R I E G E I A N D E. J. M E T T E R Sepulveda VA Medical Center, CA 91343 and U C L A School o f Medicine, Los Angeles, CA

R e c e i v e d 9 July 1987 RIEGE, W. H. AND E. J. METTER. Cognitive and brain imaging measures of AIzheimer's disease. NEUROBIOL AGING 9(1) 69-86, 1988.--Diagnosis of Alzheimer's disease (AD) during life relies upon clinical and neurobehavioral symptoms but is presumptive without microscopic verification of neuropathology. Studies in this review observed considerable heterogeneity in AD symptoms and did not agree on how to detect the earliest symptoms. Problems exist in diagnosis. Differences in symptoms and diagnosis result from how AD is defined neurobehaviorally and on the model used for description. The studies reviewed have been considered under three basic models: A severity (staging) model; a heterogeneity (subtyping) model; and an information processing model. Differences in model intent have resulted in differences in disease description. Brain imaging measures have not invalidated models but add the neural substrate needed to examine correlation of measures within each model. Alzheimer's disease Diagnosis Parietal hypometabolism

Verbal memory

Word fluency

WITH increasing human life span, both the incidence and the prevalence of dementing illness have received increased concern. In many Western societies, the care for dementia has become a public health problem, and a need for early and detailed detection has been underscored by many [68, 95, 119, 195]. The incidence of dementia (half of them Alzheimer's disease--AD) exceeds 2.6% per year in the over age 64 group and increases dramatically for those above age 79 (Katzman, personal communication, 1986). Age-dependent prevalence of 5.8 cases per 100 adults have been reported [186]. From epidemiologicai studies Rocca [186] has extracted an age-specific incidence rate for clinical diagnosis of AD in Europe which increases exponentially with increase in age, with 2.4 cases per 100,000 between age 40 to 60 years and up to 127 cases per 100,000 above age 60. Several studies showed that women had a higher incidence rate as well as prevalence than men and reported shortened survival for patients with AD [5, 186, 200]. Population-based data specific for AD from Rochester, MN indicate an observed-toexpected survival rate of 0.58 and 0.26 at 5 and 10 years, respectively, after disease onset [5]. Research into understanding AD has increased substantially in the last ten years. Efforts were directed to describe the biochemistry [4, 39, 48, 87, 95], the molecular genetics

Heterogeneity

PET brain scan

[47, 94, 157, 186], the pathoanatomy [48, 163, 219] and pathophysioiogy of the disease with hope for eventual treatment and cure. However, studies rely upon adequate diagnosis of AD, on recognizing its clinical features, and on sensitive instruments monitoring disease evolution during life. These points are focus of this review. The first section discusses reports and issues in sensitivity and problems of diagnosis; the second examines evidence in support of neurobehavioral models characterizing AD. The last section considers the role of brain imaging by positron emission tomography (PET) in describing AD dysfunctions and verifying diagnostic testing. DIAGNOSTICCONSIDERATIONS Currently, the diagnosis is based upon progressive loss of memory with inconspicuous onset, a mental status showing cognitive impairments (aphasia, apraxia, agnosia, or impaired abstracting, judgment, or problem-solving), changes in personality or affect, and excluding other causes of dementia. The report of the NINCDS-ADRDA Work Group [139] emphasized that a clinical diagnosis of "probable Alzheimer's disease" (pAD) is the most that can be done "because 20% or more of cases with the clinical diagnosis of

tRequests for reprints should be addressed to Dr. Walter H. Riege, Chief, Memory Research, 116A-6D, Sepulveda VA Medical Center, Sepulveda, CA 91343.

69

70 Alzheimer's disease are found at autopsy to have other conditions and not Alzheimer's disease." In its report, the Task Force on AD [210] recommended in 1984 to "develop standardized diagnostic assessments for Alzheimer's disease" (p. xi) and " . . . biological and/or behavioral markers for the early detection of Alzheimer's disease" (p. xii), as well as " . . . longitudinal assessment instruments capable of reliably measuring behavioral and biological change over multiple points in time." Early detection remains dependent upon clinical criteria, neurobehavioral, and laboratory results to arrive at exclusionary decisions [40]. Most criteria overlap with those spelled out in the DSM III and distinguish Primary Degenerative Dementia (including AD and Pick's disease) from delirium, mental retardation, and the amnestic syndrome. Mild cognitive and brain dysfunctions prevail at an early stage, but these become progressively incapacitating, and may require institutional care at advanced stages. Death usually occurs within 5 to I0 years after deficits are recognized. Despite its distinctive clinical course, neuropsychological studies did not find it easy, in particular in the early stages, to distinguish AD from other conditions that mimic its impairments, including normal aging, depression, multi-infarct dementia, or Parkinsonian dementia. During life, patients carry a diagnosis of probable Alzheimer's Disease (pAD), because a definite diagnosis requires histological verification of characteristic CNS pathology at autopsy [139] or from brain biopsy as well as dementia during life. The usual histopathological criteria for AD have long included a larger than normal number of neuritic plaques (extracellular amyloid filaments) and neurofibriilary tangles in cortical and hippocampal neurons of the brain (see [87]). However, qualitatively similar neuronal lesions occur in smaller numbers during normal aging [199,211]. In patients with histologically proven AD, the clinical rating of dementia severity correlated highly with cell loss (and counts of plaques and neurofibrillary tangles) in large cortical neurons [156] as well as in basal forebrain nuclei [133], but not with AD-reduced choline acetyl transferase levels. Attempts to link the development of AD to the presence of specific neurochemical markers have not been fully successful to date. A familial form of AD (FAD) may be distinguished by genetic linkage to DNA markers on chromosome 21 which would be consistent with autosomal dominant transmission of the disease [157]. (More detailed reviews on genetic markers are found in Davies [47] and Science, Feb. 20, 1987.) F A D seems associated with early onset but is indistinguishable by neurochemical, pathological, clinical [94], and neurobehavioral indices from nonfamiliai AD cases. More than half of the studied cases in an epidemiological survey were not familial [186]. Difficulties in identifying AD stem frequently from the instruments used and the often multifarious symptoms which appear at early stages of the disease. Clinicians and investigators do not seem certain which symptoms appear first. Neurobehavioral indices and brain imaging techniques used in the detection and characterization of Alzheimer's disease patients have not been without dispute, since diagnosis itself is often dependent on those measures which are being evaluated. In addition, many samples of patients under study have been neither comparable in pattern nor in severity of symptoms. The diagnosis of dementia is most often attempted with neurobehavioral rating scales together with history, physical examination and laboratory tests [44]. Alzheimer's disease is

RIEGE A N D METTER diagnosed by exclusion. Vascular causes and depression are excluded by tests (e.g., Hachinski ischemic score <4 or Hamilton Depression score <8). Measures for the clinical differentiation of the dementias include the EEG, CT, and MRI scans which are useful mainly to exclude other diagnoses. To minimize false positives, to uncover risk factors, or to monitor trials with experimental treatments, a diagnosis of AD during life has relied upon combination of neurobehavioral screening, clinical, and laboratory evaluations, which have been found inconsistently accurate. More recently, the clinical acumen in diagnosing AD has improved to 87% [12, 41, 45, 49, 188]. Some of the diagnostic difficulties can be accounted for by three separate models used in the characterization of AD. The first is based upon progressive severity of impairments and describes staging in AD evolution. The second approach is based upon the information processing model and hypothesizes that cognitive deficits can be explained by a breakdown in specific processing stages. This approach does not emphasize diagnosis but interpreting neurobehavioral dysfunctions in AD. The third is focussed on differences in the neurobehaviorai patterns found in pAD patients and argues that the heterogeneity observed among patients results from subgroups which differ in where and to what extent the neuropathology or hypometabolism in the brain interferes with neurobehavior. NEUROBEHAVIORAL DEMENTIA RATING SCALES: THE SEVERITY MODEL Detection of cognitive deficits in early AD requires the probing of multiple areas of cognition [ 110]. Most often used are behavioral rating scales in which prospective patients are evaluated and scored on several activities and skills. It is not yet certain, for example, how to detect the earliest symptoms for AD [152]. Moreover, there are several diverging ways for staging patients throughout the course of the disease that give way to different typologies. Some investigators relied upon comprehensive neurobehavioral guidelines such as the DSM III descriptors or the NINCDSADRDA criteria [139] that suggest staging from "questionable" or " p o s s i b l e " to " p r o b a b l e " to "definite A D " . Others relied upon established rating scales concomitant with neurological and psychiatric-clinical exams. The severity model derives from screening of suspected sample populations and rating those included as mild, moderately, or severely impaired. More than 75% of the screening studies reviewed used the behavioral rating scales. The scales specifically designed to assess or detect AD usually yield quasi-quantitative measures or even only a single global score. Often clinical and psychometric questions are mixed in subdimensions of the scales in which prospective patients are scored on several activities or report of skills. The scores in many scales are merely a summation of checkmarks, simple counting of deficit signs, or ratings along an impairment dimension, so that their measuxes are inherently nonparametric, of unequal interval, and permit only ordinal staging. Only a correlation between the severity of clinical symptoms and other measures of neuropathology confers diagnostic validity to these scales (see [172,192]). Among the screening tests, the mental status questionnaires are most widely used (see Table 1). An early one includes direct questions assessing orientation, calculation, recall of personal information, and the name of the president [194], but there were no questions probing learning, lan-

C O G N I T I O N AND I M A G I N G IN A L Z H E I M E R ' S D I S E A S E guage, or visuo-spatiai abilities. Derived from it are the Short Portable Mental Status Questionnaire (SPMSQ, [164]) and the Mini Mental Status Exam (MMSE, [67]) which includes in its short array of 30 items those that tap language and perceptuo-motor skills. Both questionnaires have the advantage of brief administration and standardized scoring. Although the sensitivity of the MMSE is reportedly adequate for dementia screening, it requires validation against complete neurological and psychiatric examinations in most cases [2]. Almost all confirmed AD cases scored below 24 on first screening, but there were also a number of False Alarms in the community population. This non-specificity requires the MMSE not to be the only screening instrument. When 141 patients labelled as AD by DSM III criteria were evaluated with the MMSE, their scores (from 0-27) correlated negatively ( r = - . 5 0 ) with duration (range 1 to 13 years) of disease since onset [205]. Most difficult were 'recall' items and design copy; only 3% of the cases passed both. Duration of illness and the need to adjust cut-off scores for each item indicated that the sample spanned several stages of AD for which different degrees and patterns of impairment on the MMSE might be expected. Mental status exams were used in over half of the studies reviewed mostly as the precis to clinical tests in presumptive AD diagnosis. In the remaining studies, mental functioning was tapped within dementia rating scales. Mental status exams are known to be influenced by factors such as social class, attention, emotional or communication problems, health, or perceived situation stress. These factors can distort scores and call into question the sensitivity of the instrument. Discrepancies have been noted between mental status exams, severity of brain impairments, and diagnostic interviews by clinicians [210]. The characteristics of some of the recently developed rating scales in use are presented in Table 1, so that only brief descriptions are given. Among the early ones is the Mattis Dementia Rating Scale (DRS, [137]) directed to overcome difficulties of the WAIS and WMS to produce cognitive scores in the severely demented patient. Its five subscales appear constructed with validity for attention, perseveration, visuo-construction, conceptualization, and memory. Items are arranged in order of assumed, but untested difficulty but the scale does not seem accurate in staging of AD [103,159, 214] or in differentiating AD from other dementia [! 14]. By comparison, the Global Deterioration Scale (GDS, [173]) delineates seven stages in Primary Degenerative Dementia. Each stage is defined by both clinical and psychometric evaluation and corresponds to a particular clinical phase in a model of cognitive deterioration. Only the last three phases demarcate early, middle, and late dementia phases. The scale ratings correlated with CT scan rankings (r=.62) of ventricular and sulcal widenings [51] and with PET brain regional metabolic measures [61]. Mild-tomoderate GDS scores of 41 community-dwelling AD patients over a 16-37 month period declined by one or more steps [176] and suggested some predictive validity of the scale. A mental status form of the scale, the Brief Cognitive Rating Scale, found decline with AD duration to be uniform across axes [175]; however, longitudinal studies with neuropsychological monitoring of AD have reported that cognitive functions do not decline at the same rate [190,192]. The AD Assessment Scale (ADAS, [191]) has been used to evaluate dysfunctions characteristic for AD. The dominant impairments in memory, cognition, noncognitive motor and affective functions are tested in one battery, which the

71 authors claim other scales have not done. The 21-item ADAS was standardized on 27 diagnosed AD and 28 healthy elderly controls and is reported to have an inter-rater reliability of 0.96 and test-retest reliability of 0.84. Marked correlation of the ADAS score with ACh in C S F of AD patients ( r = - . 6 3 ) suggested increasing cell loss [151]. At 12-month retest of 12 AD patients with l-year disease duration, the ADAS scores decreased from the already impaired baseline [192]. Word finding and word memory were initially decreased, but orientation was impaired late. Some tests were insensitive to detect impairment, either because AD functioned already at very low levels in these tasks or were not yet impaired [192,202]. Thus, the stage at which patients are grouped for study and the specificity of scales to detect impairments, plus the interval used for retesting, all determined the rate of decline observed. Most rating scales enable the clinician to probe several cognitive aspects and also ask for his clinical expertise in judging the relevance and significance of specific deficit signs. Rating scales, therefore, cannot be completely objective or quantified. This is also seen in the Clinical Dementia Rating (CDR) scale [100]. The CDR considers global staging from normal to dementing signs, and its questions leading to the patient's abilities in six component areas (Memory, Orientation, Problem-solving, Community affairs, Home and hobbies, and Personal Care) are asked of both the patient and his/her collateral. The SPMSQ, the Face-Hand test [105], the Boston Diagnostic Aphasia Exam (BDAE), and the Hamilton Depression scale contribute to the final global score from 0, 0.5, 1, 2, to 3. These are ordinal and descriptive only, and impairments do not increase to the same degree from one category to the next. A strictly clinical Differential Diagnosis Inventory [41] uses ratings that selectively weight features separating AD on the basis of cognitive and motor functions from non-AD. The Inventory gives highest scores to impaired cognition (memory, language, visuo-spatial skills, abstracting) and to normal motor functions, and the authors report complete accuracy in retrospective, but not yet a prospective study. Neither severity, nor dementia differentiation, nor AD subgrouping can be evaluated, although differential diagnosis is aided by a flow-chart approach [40]. However, verbal output, mental status, and motor praxis, together with MMSE scores determine AD diagnosis and leave other cognitive functions (learning or nonverbal memory) unconsidered. An inherent weakness of rating scales lies in their superficial probing and variable weighting of unequal aspects of cognition which are then reflected in a single score. Information about specific deficits is lost and cognition becomes considered as a unitary dimension. Scales were not based upon views of cognitive decline in dementia but rather reflect the clinical intuitions of the originator as well as borrowing from earlier scales [37]. Scales have been found valid when staging severity in advanced cases but often lack sensitivity when carried out in general hospital population. The mental status test [ 105] and SPMSQ, for example, were able to identify 96% without, but only 55% with senile dementia in a community sample [64]. By comparison the MMSE was more sensitive, correctly classifying 82% without but 87% with dementia [2]. Low intellect or low education may confound screening. None of these scales have proved completely satisfactory in aiding early identification of AD or differentiating it from other causes of dementia, and some questions about disease evolution remain. Within the staging model the scales do not seem to agree on the emergence of

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TABLE

1

CHARACTERISTICS OF SELECTED DEMENTIA SCREENING INSTRUMENTS Mental Status T e s t s Mini-Mental State Exam, MMSE (Folstein, 1975)

Short Portable Mental Status Quest., S P M S Q (Pfeiffer, 1975)

D e m e n t i a Rating Scale, DRS (Mattis, 1976)

Brief description

30 items, 30 points max, Orientation, recall, attention, language, copy design [67]

10 items, m a x o f 10 errors, Orientation, m e m o r y , serial subtraction [164]

5 subscales: Pts: Attention 37 Perseveration 37 Construction 6 Conceptualiz. 39 Memory 25 Max points = Most items in decr. order of diff. [137]

Cutoff

<~ 24 23 22 21

> 4 errors [21,164]

No set cutoff, Mean (dement) = 80 [34] Normal Dementia Contr. Mild Moder. >130 101-130 80-100 [103] -93-129 62-87 [114] -95-117 71-87 [158] 141 131 110 [89]

Reliability

Test-retest: r = .80 [208] Normal = .85 Dementia = .90 Delirious = .56 [2]

Test-retest: r = .82 [164]

Test-retest: r = .97, subscale r ' s = .61 to .94 [34] Split-half = .90 [801

Sensitivity Specificity

For cutoff = 22, Sensitivity = .83, Specificity = .86 [2] Classification accuracy = 87% [112]

Sensitivity = .54 Specificity = .97 Predictive value = .49 [21]

Staging in Dementia

Scores correlate with G D S [32] and with duration since onset [205]

No, but scores predict decrease in C D R [10]; separate normal from mod-severe but not from mild dementia [11,100]

Differential Diagnosis

Dementia/depression [138,171], Dement/Parkinsons only together w/ clinical e x a m [99]

Strengths and Limitations

Relatively equal scoring and cutoff - - H i g h false positives in low educ, Black, or old [2] - - M o d e r to A d v a n c e d d e m e n t i a is not well discriminated [172]

Instrument

[41] [67,172] [2] [170]

Subscales distinguish normal from mild: recall, word rec, orientat; and mild from moderate: attention, orientat, recog. [214] No: Mild p A D = mild n o n - p A D [114]

- - D i d not separate more severe dementia stages [I00] - - R a c e and educ affect scores [167] - - F a l s e neg = .46 [21]

- - L i t t l e agreement on cutoff or ranges - - C o r r e l w / f r o n t a l C B F and somatostatin C S F [204]

AND METTER

COGNITION AND IMAGING IN ALZHEIMER'S DISEASE

33

TABLE I (Continued) Clinical Rating Scales Clinical Dementia Rating, CDR (Berg, 1982)

Dementia Rating Scale, DRS (Blessed, 1968)

Global Deterioration Scale, GDS (Reisberg, 1983)

Ratings from healthy to severe combine 6 categories: memory, orientation, judgement, community affairs, home and hobbies, personal care; from pat. and collateral [1 l]

22 items, 28 points max, Rates ADL, personality, habits from medical records and collaterals [17]

Descriptive rating of 7 clinical phases of cognitive deterioration based on patient interview [173]

0 = healthy 0.5 = questionable I = mild dementia 2 = moderate dementia 3 = severe dementia

0 = full normal function 28 = extreme incapacity [17]

1-2 = normal 3--4 = confusional stages 5-7 = dementia [172]

Test-retest: overall = .87, worse over time as predicted [ 1 0 0 ] Interrater: .89 [I00] .86 [202]

Test-retest (1 year):

Test-retest (4 years): Normal = .9 ! unchanged, pAD's declined by one or more phases [51,172]

No change Normal 80% Mild 60% Moder 73% [58]

Specificity: Stages 2-6 r = .92 with MMSE [172]

Ratings recognized Healthy/Questionable/ Mild dement [100]; correlate w / o t h e r dementia ratings [11]

Correlates w/CDR r = .74, but does not reliably assign stage [I00] or detect mild dementia

7 stages: Normal--Very Severe Decline [172]

Cannot be used alone to separate types of dementia [172]

pAD scored below functional psychotic, delirious and physically ill [17]

Cannot be used alone. See [172] for detailed inclusion/exclusion criteria

--Useful over wider range of severity than scales based on less global measures [10] --Staging has little predictive value~[100]

- - L e s s sensitive than CDR for severe dementia [ 100] --Diagnostic accuracy depends on info. from med charts and collaterals [58] --Reliability decreased as severity incr [58]

--Useful for staging, given accurate clinical diagnosis of AD [172] - - N o reliable patterning of deficits

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features characteristic for decline. In the GDS, for example, language difficulties and problems in social competence are not prominent until the next to the last of the seven stages, whereas the CDR considers verbal memory and ability to handle home affairs impaired already in the mild or moderate stages, and a four-stage model by Constantinides (in [135]) considers personality and affective changes characteristic for an early stage. Other screening instruments, while sharing the criterion of orderly and progressive decline, also do not agree on the number and definable deficits of stages. The rating scales that delineate staging in AD were not designed to examine the heterogeneity in symptoms. Measures of subtypes, on the other hand, differ in the importance of symptoms. An example of this is given by Mayeux and associates [138] who extracted four subgroups of AD from 121 cases on the basis of clinical symptoms and their progression over 4 years. The subgroups differed in severity on initial and on later testing with the MMSE and in myoclonus and extrapyramidal signs, but memory functions were not considered important for grouping [32,138]. This subgrouping contrasts with the viewpoint [41] that impaired verbal memory and intellect, but normal motor function, provide criteria for diagnosing AD.

I N F O R M A T I O N PROCESSING S K I L L S

Patients assigned the provisonal diagnosis of AD often exhibit disparate profiles of impaired and spared functions. The borderland between early dementing signs and changes seen in normal aging is neither firmly defined nor consistent. A large number of studies attest that memory difficulties are the earliest clinical signs in pAD [60, 67, 135, 152, 214], whereas difficulties in language or in visuo-perceptual functions are sporadic or appear in later stages of the disease. Deficits in memory are not the result of impairment in a single function, as some screening or mental-status scales seem to assert, but are characterized by difficulties in one or several component processes that may leave others intact. In the early stage, for example, autobiographical or remote memory and memory for procedures (knowing how) may be unscathed, while new information is not well retained [108]. Theoretical models of memory processing have attempted to define the components; a linear information processing model may be representative [106]. It postulates that a person guides information flow through a series of stages each requiring several processing steps. Input follows the sensory, pre-attentive memory through primary (short-term) memory to secondary memory [216] which may be conceptualized as repository of newly acquired information in contrast to tertiary (remote or semantic) memory where welllearned or personal information is thought to be lodged. In addition, the information to be remembered may be defined by modality (e.g., verbal-nonverbal, visual, auditory, tactual), by the extent of effort in processing [217], or by coding or retrieving processes involved. Difficulty at any stage creates characteristic patterns that have been claimed to assist diagnosis. The difficulties in secondary verbal memory described for the elderly [167], for example, separate them from early pAD in whom pervasive impairments in primary and secondary verbal and nonverbal memory are observed [108]. Moreover, early pAD in contrast to normal elderly cannot take advantage of attributes in information that are ordinarily used in encoding [218]. Their learning and recall is not facilitated by repeating information, reminding of forgot-

ten information, providing automatic organization by repeating words again and again, or presenting semantic cues [109,217], although some covert associations of semantic material can be retained as shown by reading speed of familiar and unfamiliar sentences [154]. From the standpoint of instrument review, tasks that emerge as sensitive to AD and specific to a cognitive function are consistent with a hypothesis of breakdown in semantic memory and knowledge [136]. Semantic memory itself is a term that refers to the "storage and retrieval of knowledge of objects, words, facts, concepts, and the relationship between them," and its information constitutes the common pool of knowledge not unique to the individual [209]. Deficits in verbal learning, in coding of words for retrieval, in word finding or naming of words within a category [7,159] figure prominently in profiles of early pAD. In fact, word fluency and verbal paraphasias may aid in the diagnosis of Alzheimer's disease [40]. Weingartner and colleagues [217,218] observed that recall of categorized words presented difficulties for 14 mildly impaired pAD. Patients did not discriminate related from unrelated words or impose relation upon to-be-remembered unrelated words presented together, although matched controls had no recall problems even a week later. Early pAD could not match abstract pictorial drawings with printed words representing objects or actions [ 136] and were deficient in naming of low frequency, but not of high frequency objects in confrontation [40,159]. The word fluency problems of mild AD in generating words within a category but not to a given letter dissociated them from moderate-to-severely impaired AD [159] and from Huntington's or Korsakoff amnesic patients [27]. Their rate of producing correct words decreased with increase in dementia severity [159,193], and they have difficulties in learning paired associates or in naming designs [189]. However, the mild pAD in contrast to moderate pAD were able to recognize relational attributes to words, sort words within superordinate categories [159], judge the affective meaning of words [136,218], or use vocabulary in free speech, that is, in processes that do not require to form new memories or do not rely upon access to a detailed network of semantic associations. It appears as if the image coding has been disrupted in information input and recall. This breakdown in semantic knowledge had been already proposed by Warrington [215] who argued on the basis of extensive testing of agnosic impairments in three patients with diagnosis of cerebral atrophy of vascular origin or of unknown cause, that deficits characterize a specific defect in semantic memory both in visual and verbal domains. The agnosia observed in Warrington's patients was restricted to recognition of objects (including visual representations of objects and faces) and to recognition of attributes of words. Warrington suggested that the findings support a view of hierarchical structuring in the semantic memory system in which concepts are ordered as in a 'thesaurus' by superordinate and subordinate categories (p. 652). Patients describe the object often by the superordinate cla,ss word (e.g., h a m m e r - - s o m e kind of tool), while subordinate associations are dropped out, and semantic recognition errors usually refer to the same superordinate category (e.g., d o n k e y - horse). Other investigators confirm amply that pAD have great difficulty generating words from categories, and answers can be non-specific or lacking detail [40, 136, 218]. A different approach to interpreting memory deficits in early pAD within an information processing model has recently been proposed by Jorm [104]. Based upon the two

C O G N I T I O N AND I M A G I N G IN A L Z H E I M E R ' S D I S E A S E

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TABLE 2 STUDIES SHOWINGSPECIFIC NEUROPSYCHOLOGICALTESTS SENSITIVE IN SEPARATINGPROBABLE ALZHEIMER'S DISEASE PATIENTS Early or Mild From: Test Verbal Memory Word list lrng Select. reminding Paired-assoc Delay recogn Story recall Semantic Knowledge Word flncy (lettrs) Word flncy (category) Stroop task Word finding WAIS VIQ Visual-Spatial Face recognition Design recognition Design reprod

Controls

[218] [158,218] [20, 104, 149]

Mod.-Severe

[20, 214. 218]

[135]

Attention

[214]

[15, 83, 149]

[151

[20, 126, 135, 222] [ 154] [126]

[74] [160]

[20] [1141 [ 15,1041 [20,135]

[114]

[22, 104. 223] [212]

Visuo-Mot & Probl Solv WAIS PIQ WAIS block design •Bender gestalt Trailmaking

pAD From Other Dementias

Subgroups of pAD

[158]

[20,218]

[20, 27. 136, 159] [1141 [ 135,136]

Mod.-Severe From Control

[1351

[27] [114]

[!35] [1351 [65.1551

[223, 224] [15.20] [126,135] [20, 78, 126] [20] [20]

[201

[78,160]

[1551 [135,1551

[212]

Orientation

processing systems hypothesized by Schneider and Shiffrin [198], Jorrn suggests that early pAD are impaired in controlled but not in automatic processing of information in memory. Controlled processing (CP), which requires attentional capacity, is called upon with processing of new or complex information and is considered effortful [88]. Automatic processing (AP), by comparison, demands little attentional resource or elaboration and is little affected by other processing demands. Learning is transition from CP to AP, both are considered to occupy opposite endpoints of a continuum [198]. Evidence from a review of tests sensitive to early pAD shows that tasks which demand learning, forming new associations between elements in long-term storage, or organizing information for retrieval, that is, in CP, not only separate pAD from healthy but also differentiate stages of severity of dementia. Mild pAD had problems in tests, such as paired associate learning [20, 149, 189], naming objects, forms, or masked pictures [189, 214, 218]i recall of story detail or sequence [20, 212, 218], repeating sentences of low frequency [189], or recognizing semantic associations [6,218]. A pAD deficit in CP is also implicated from early difficulties in learning definitions for unfamiliar words [221], understanding simple proverbs [215], or in the free recall of the first-presented words [148] or pictures in lists [221]. In continuous recognition of unfamiliar faces, Ferris [62] had found no deficits in early pAD but Wilson and others [222] reported that 29 mild pAD had lower scores on such a

[ 15]

task than 41 age-matched controls; the deficit was not attributable to faulty perception of faces nor to response bias. When emotional expression was to be detected in faces, the pAD failed also [22]. The recall of famous faces or incidents from remote memory is poor; when the task is modified by giving the names to which famous faces had to be matched, the early pAD scored higher than moderately impaired pAD but still below norm [180]. In contrast, cognitive performances of early or mild pAD remain unaffected in tests that seem to rely on AP, such as matching visual forms, naming colors, letters, or body parts [114,189], in vocabulary or in reading of familiar sentences [154]. With cued recall the pAD produced as many words from learned lists as normals [153]. They were able to express themselves fluently [215] and to refer back and forth to events in their lives, although detail may be confused. However, these preserved processes are often impaired at later stages when AP becomes compromised. The screening tests (SPMSQ and DRS) that fail to detect early dementia impairments usually tap items of AP that are well learned; the MMSE, on the other hand, contains several items of CP and AP so that stages may be defined. A hypothesis of early pAD inpairment in CP but not AP is compelling but diagnostically not sufficiently descriptive, since other conditions may simulate the CP impairments [104]; decreases in CP tasks were also associated with high arousal, depression, and aging [88]. It is more likely that the specific

76 and gradual breakdown in semantic memory network and network forming underly the memory difficulties in pAD and explain them. Some recent investigations have considered separating AD deficits by the multiple processes known to be involved in normal memory functioning. Wilson and associates [220] found verbal memory more disrupted than visual memory. Learning of words or names but not story retrieval improved with treatment by AChE inhibitors physostigmine [207] or tacrine [203]. Whether encoding or retrieving functions are disrupted was investigated by Ober and others [158] in 12 mild pAD (MDS score 95-117) and 5 moderate pAD (MDS score 71-87). Both groups had severe impairments on the selective reminding task; the mild, however, recalled more immediately reminded items than previously presented items, indicating problems with encoding into secondary memory. The moderate, on the other hand, had even lower recall but showed more items stored than recalled on any given trial, indicating retrieval failure. This was explained in part as perseveration of only a few items in short-term memory, in part as allocating limited processing resources (attention) to encoding only a few items consistently. The mild cannot process just-presented and previously-presented items simultaneously, representing a deficit in short-term memory, which later is overshadowed by limited retrieval ability. Memory is most severely affected as AD progresses, but impairments in both verbal and non-verbal primary memory are mild early in the course [23, 108, 147]. Secondary memory is characteristically deficient across modality, type of input or retrieval. Word recognition deficits were correlated with difficulties in naming and in verbal imagery [109], and pAD patients were also found impaired in their use of visual context as a memory aid [26,38]. Degree of impairment in paired-associate learning of shopping-list words [222], geometric forms [38], or story recall [108] was correlated with degree of cerebral atrophy seen on CT [51,107]. In tertiary memory, measured often with tests of recognition of famous faces, events, or recall of autobiographical data, early pAD patients were inconsistent in recall of detail and considerably impaired in verbal fluency [38]. The WAIS test profile for separating AD from other dementia did not produce the alleged sensitivity even in 41 moderately severe pAD [66], and only the VIQ and Picture Completion (abstracting) distinguished between 12 pAD and 12 MID equated for age and education [132]. In summary, the neurobehavioral instruments outlined have gained some limited diagnostic validity. Many of the screening batteries give only superficial insight into the patient's cognitive abilities, few are adequate for monitoring therapy or disease progression, and most characterize a patient by counts on cognitive loss but cannot differentiate AD from other dementia. Within the severity model, screening tests provide descriptive scores on at best ordinal staging of the disease; however, the heterogeneity of symptoms is not described. Tests concerned with the information-processing skills of a patient can be considerably more relevant to the clinical profile needed for diagnosis. It may be useful, then, after screening of a suspected patient with the MMSE and a dementia rating scale, to probe cognitive functions more in detail. An inclusive neuropsychological profde would tap the patient's abilities (a) to scan his semantic memory (Word Fluency to categories and to letters), (b) to retain and recall logically organized information (Recall of story, of sentences after interpolated inter-

RIEGE AND METTER ference, or of pictures) and to learn a list of words (Paired associates, selective reminding), and (c) to solve visuoconstructive or sequential problems (Block design, Ravens colored Progressive Matrices, Memory-for-Designs, Benton VRT, or Symbol-Digit substitution). Common condition for cognitive deficits in AD to be detected seems to be tasks that probe the ability to form new memories or to have access to a network of meaning. Although the mosaic of cognitive impairments is not easily described, tapping characteristically impaired memory functions in AD assists diagnosis, and some hold that tasks specific to the motor system need also be considered [32,138].

THE HETEROGENEITYMODEL Studies reviewed agree that the AD symptoms do not fit a uniform or common pattern but display heterogeneous profiles. This heterogeneity may reflect the existence of subgroups with overlapping patterns of symptoms. From this position, investigators have attempted to categorize patients into more homogeneous subtypes [135]. Some of the apparent distinctions focused on early and late onset of symptoms [18,32], but this subtyping may be variable from study to study. In addition, the pAD patient is by the nature of the disease a poor autobiographer, and the surrogate historian, usually the spouse, does not always have shared information on onset of signs, cognitive lapses, or medical history. The early-late onset dichotomy does not seem useful in screening, although early-onset AD have been reported to show a wider range of brain structural and neurotransmitter damage than late-onset AD even when disease duration is taken into account [18,195]. The early-onset AD seemed to be associated with more pronounced parietal hypometabolism [85], with language impairments, myoclonus and extrapyramidal signs [32,138], although the latter are neither considered diagnostic nor characteristic for AD [41]. The contention that AD presents not one but several different subtypes has been supported with evidence of qualitatively different profiles of cognitive impairments [32,138], different patterns of cerebral hypometabolism [76, 135, 141], or of separating a familial subtype from a 'sporadic' AD [47]. Subgroup models, however, while accepting progressive decline, do not agree with the notion of homogenous disintegration and posit separate clusters of symptoms with unequal pattern and rate of decline. Diagnosis of AD by exclusion also introduces sample heterogeneity. In fact, profiles of impaired and spared functions have called into question whether a common symptom complex can be defined [130]. Investigators have proposed that the heterogeneity might be explained either by patients being observed from different stages, from different subtypes, or from both. The two models, staging and subtyping, are complementary. Many dementia rating scales exclude subtyping and f o l o w the dicta of the staging model which hypothesizes that a progressive decrease ~in function over time denotes an increase in symptom severity and that the increase is relatively continuous and orderly but allows the pattern of symptoms to change or new ones to emerge [173]. Differences in the pattern of symptoms imply differences in brain regions affected by AD. We argue that the heterogeneity of symptoms observed among patients reflects subgroups that differ in where and to what extent in the brain the neurophysiological dysfunctions interfere with neurobe-

COGNITION AND IMAGING IN A L Z H E I M E R ' S DISEASE havior. The heterogeneity model gains from the link between these two neurofunctional indices. For this, however, a measure is required of the degree of function remaining in brain regions thought related with the cognitive impairments. Estimates of the regional cerebral metabolic rate of glucose utilization (rCMRGIc) have fit this role in a number of studies and have been found sensitively correlated with early signs of cognitive deficits in AD. The CMRGIc measure has indicated that hypometabolic lesions are often earlier, larger, and more distributed than anatomical lesions in AD, even than those determined at autopsy [166].

BRAIN IMAGINGIN AD Currently a number of techniques are used to image brain structure and function. These include x-ray computed tomography (CT), magnetic resonance imaging (MRI), xenon blood flow with multiple detectors, single photon emission computed tomography (SPECT), positron emission tomography (PET), brain electrical activity mapping (BEAM), and mapping of brain evoked potentials. This array of measures may estimate activity, structures, metabolism, blood flow, and neurotransmitter receptor distributions and their review is beyond the purpose of this paper. Studies are reviewed which examine neurophysiological indices from PET in relation to neurobehavioral indices. Regional cerebral metabolic rate of glucose use (rCMRGIc) in AD was most often estimated with PET and the use of F18-Fluoro-2-deoxyglucose (FDG) [165,166]. If rCMRGlc is assumed to be a measure of the function of a specific brain region (i.e., the index of neuronal and dendritic activity), then the cross-sectional image of the brain FDG metabolism presents a functional map of brain activity in regions of interest [165]. By using oxygen 15 in several forms, regional cerebral blood flow (rCBF) and oxygen metabolism by the brain have also been measured. Such measures produce different functional maps; however, there has been relatively acceptable agreement among rCBF, CMRO2, and CMRGIc indices. Studies using PET with FDG have examined predominantly the relation of brain and cognitive functions. With this technique it has been possible to visualize changes in brain regional metabolism in normal aging [123,144, 169, 181,183] and in degenerative dementia [9, 29, 63, 75, 121, 124, 143]. To observe CMRGlc deficits requires comparison with healthy aging persons. A number of studies have examined aging, rCBF, oxygen and glucose metabolism. Some found age decrease in global and regional measurements [117,183], while others have noted no such decreases [50,56]. Cerebral oxygen consumption is not significantly lowered with age [125], but overall glucose utilization by the brain, as well as that of Broca's region [183], were reported to decrease gradually with increasing age [123]. The presence or size of age differences in rCMRGIc have not always been confirmed [52], however, in AD the rCMRGIc are corcmonly compared with those of age-matched healtl~y persons. The use of PET scanners in evaluating CMRGIc in AD has relied on relatively high resolution so that reliably detimed regions can be assessed, because partial volume effects may be smaller with higher resolution systems. The CMRGlc, then, may be a more representative index of cortical alteration than that of other brain imaging measures. Since AD is known to be predominantly a cortical disease, the pattern of rCMRGIc alterations could be sensitive corn-

77 ponents of a clinical diagnostic prof'de. The most common observation to date is the presence of relative decreases in cortical glucose metabolism in pAD [52,118], as well as in CMRO2 or CBF [72,73]. This was seen predominantly in temporo-parietal but also in frontal regions. As the disease progresses, dysfunctions appear to advance from superior parietal to parietal to temporal and then to frontal regions. The pattern of low metabolism in brain of pAD has been observed and confirmed by several different laboratories and may reflect lower rates of FDG phosphorylation f'wst in temporal-parietal, later also in frontal regions [75, 118, 178]. The distribution of metabolic declines follows the pattern and magnitude of pathology found at autopsy. Studies using FDG-PET in evaluating pAD agree not only that glucose metabolism is reduced but also that the pattern of regional hypometabolism is not consistent from patient to patient. Average levels were reduced [116,118] relative to age-matched normals by 47% in parietal and in dorsolateral occipital cortex, 28% in frontal, temporal, and calcarine occipital cortices, and only 12% in caudate and thalamus [119]. Pathologic AD reductions in CMRGIc are most prominent in temporal-parietal structures. They are least severe in deep nuclei, particularly in caudate and thalamus [24], or cerebellum. Reduction of choline acetyl transferase follows a similar distribution [46]. The pattern of diminished glucose utilization in AD is neither always uniform nor symmetric in hemispheres. Patients with early or mild dementia were found to have metabolic rates that overlapped with control subjects, while severe dementia was associated with marked metabolic decline (see Table 3). However, even early AD categorized as mild with questionable dementia (CDR=0.5) were separated from elderly controls by the ratio of the parietal to caudatethalamus (P/C-TH) CMRGIc [118,180]. In general, the extent of dementia and regional P/C-TH ratio were marginally and negatively correlated as AD progressed. Studies examining the interregional metabolic differences [75, 76, 141, 142] reported that antero-posterior changes were more prominent than left-right hemispheric differences, although others noted the reverse [52]. From cluster analysis of 18 mild-to-moderate AD and 23 controls, Metter and associates [142] found three groups best characterized by differences in the frontal/temporo-parietal ratio and global glucose metabolism but not by left-right ratio measures. Friedland and others [75] reported that the differences in anterior/posterior CMRGIc ratio in brains of I0 diagnosed pAD were more prominent than the left/right ratio, although the verbal IQ and the Mattis Dementia Rating score were correlated with the left frontal/right frontal ratio, the Performance IQ with right/left temporal-parietal ratio. Brain protein synthesis was investigated with methionine [25] and muscarinic receptors imaged with SPECT-(lzaI)QNB [96] in AD. The brain protein synthesis rate was diminished by 18% in frontal regions of borderline demented AD patients who showed no CT abnormalities; this diminution was correlated with the extent of their memory impairments. Moreover, the oxygen metabolism of the AD brain was reduced when examined with the nitrous oxide method by measuring the arterial-venous difference in oxygen concentration. Frackowiak and associates [72] using continuous oxygen inhalation in mild-to-moderate demented patients found a decrease in global and regional CMRO~ which paralleled changes in CBF [73]. The greatest changes were observed in the parietal and temporal regions. In severe dementia the frontal regions also showed a profound decrease.

78

RIEGE AND METTER TABLE 3 IMAGINGSTUDIES SEPARATINGPROBABLE ALZHEIMER'S DISEASE FROM OTHER GROUPS Early or Mild From: Controls PET Hi frontal Temporal

Probable AD From:

Mod.-Severe

[89] [30*, 134, 179]

Parietal

[57, 70, 89, 134, 166, 179]

Global P/CT CT

[30] [180] [79]

SPECT RCBF EEG

[73]

[331

Controls

[42, 44, 49, 54, 57, 70, 72, 179] [8*, 30", 42, 44, 49, 54, 57, 70, 72, 76*, 134] [42, 44, 49, 57, 70, 72, 85, 134] [30, 42, 70, 72] [42,44] [1, 45, 50, 51, 63, 79, 128] [19, 27, 102] [3, 72, 73, 226] [33]

Other Dementias

[8]

[166,179] [8] [8, 116, 120, 178] [59,201] [27,81]

*Combined Temporal and Parietal areas. CORRELATIONSOF BRAIN IMAGINGAND COGNITIVE MEASURES Equally important is the question how characteristic metabolic relationships between brain regions are for AD, that is, how do regions correlate with function when AD sets in. Individual brain regions do not function in isolation but rather in relationship to other regions. Correlational analyses [146] examining 26 regional CMRGIc measures in 31 normal persons revealed strong correlations (l) for homologous regions in each hemisphere; (2) among the superior/middle frontal gyri, inferior parietal and the occipital cortex; and (3) between inferior frontal, posterior temporal, and thalamic regions. Comparison with behavioral measures indicated that the frontal-parietal-occipital correlations appeared to be involved in visual memory and decision making, while the third, the inferior set of correlations seemed involved with recall of sentences, story, or pictures [178]. Horowitz and others [97] found very similar regional relationships. Some investigators reported that language or visuo-constructive deficits in selected pAD patients corresponded to asymmetry in resting CMRGIc [69], while others did not [43], or report highly variable distribution patterns o f CMRGlc [76]. The fight frontal/left frontal CMRGlc ratio was negatively correlated with verbal IQ scores, indicating mainly left frontal hypometabolism [75]. A hypothesis of coupling of resting brain metabolism with mental functions has been both supported [69, 90, 179, 183] and discounted [85,91] in normal aging as well as in earlyto-moderate AD. Bitten and associates [14] had already reported that mental abilities correlated positively with CMR for oxygen in older men with asymptomatic disease, but not in optimally healthy, older men. The advance of fineresolution PET-FDG imaging has allowed investigators to corroborate this finding. In mild, and more so in moderate AD, specific brain structural and metabolic indices were correlated to some cognitive measures sensitive to degree of dementia [69, 90, 183]. More consistent are reports of relatively localized hypometabolism in periSylvian regions associated with cognitive deficits. Both are more pronounced in advanced [63]

than in mild pAD [49]. The left and right parietal and sometimes superior frontal regions show in their metabolic indices marked relation to tests of immediate and delayed story recall, PA learning, or mental status scores and GDS [49, 63, 85]. Not all studies, however, used homogenous patient samples, or age- and education-matched controls, or adjusted correlations for multiple comparisons or metabolic measures for high regional intercorrelations. Correlations with absolute measures of CMRGIc were not always detected [30,43], and only the CMRGlc corrected for whole brain activity or the fight-left asymmetries seem to discover correlations to specific cognitive deficits [43,179]. Reports agree that even in mild-to-moderate pAD, verbal abilities, such as word finding [59], word learning [178], or WAIS Verbal IQ [28,29], are associated with left hemisphere CMRGIc, in particular, with temporo-parietal and posterior frontal regions. Neither metabolic nor cognitive deficits are uniform, however, and not all patients with mild-tomoderate pAD displayed verbal deficits associated with left temporo-pafietal hypometabolism [44] or visuo-constructive impairments correlated with low right CMRGic. It has been suggested [44] that a threshold of metabolic reduction in temporo-parietal regions must be met before neuropsychological deficits are observed. There is no agreement as yet which deficits appear first in AD. Evidence for "initial reduction in parietal l o b e . . , prior to neuropsychological changes" from serial assessment of one patient [42] seems as sparse as that for the reverse [43], although deficits in verbal coding and decrease in the sensitive parietal/caudatethalamus ratio may coincide in early pAD [182]. The variability in early neuropsychological and in m~tabolic deficits is considerable [108] and the AD " a p p e a r s to be protean" [43] in the signs which emerge first. In spite of the heterogeneity in neurobehavioral indices in AD, several studies report the expected correlation of verbal memory and naming impairments with left periSylvian CMRGIc and of visuo-constructive dysfunctions with right parietal metabolism [30, 69, 179]. From this, some investigators have argued that metabolic hemispheric asymme-

C O G N I T I O N A N D I M A G I N G IN A L Z H E I M E R ' S D I S E A S E tries, in particular, in parietal regions, reflect subgrouping in AD, and the correlations with either language or apraxic impairments were cited in support [43, 69, 135]. Moreover, the metabolic left-right asymmetry scores of resting CMRGIc were correlated with difference scores between language and visuo-practic tests in patients with mild-to-moderate AD but not in optimally healthy men [43,91]. In pAD patients, the interregional correlations seemed to be enhanced [141], and even in questionable AD, visual memory difficulties were correlated with hypometabolism expressed in the parietal/caudate-thalamus ratio already in mild pAD [182]. The cognitive performances of 18 pAD were >1 S.D. below norm [178] and a subgroup with exaggerated right hypometabolism had lower scores in non-verbal visual and auditory memory. Another subgroup with proportionately lower left parietal metabolism had lower recognition memory for words or text; they had difficulty in continuous recognition of easy as well as complex items, reflecting coding difficulties. The frontal correlation with immediate memory seen in controls was lost in pAD. However, the hippocampal regions were not singled out as focus of memory deficits in pAD [178]. Components of a neurobehavioral function may not always relate to the same region. In mild-to-moderate AD, the design drawing and memory (Rey-Osterrieth and Benton Visual Retention tests) were right-parietal localized, while performance in whole-body praxis (e.g., stand up, jump) correlated with left fronto-temporal CMRGIc and representational praxis (e.g., put finger under your chin, etc.) was related to right fronto-temporal CMRGlc [29]. Similarly, abilities to accurately mimic or to pantomine movements were lower in pAD and correlated with right parietal or left frontal metabolism, respectively [71]. In addition, several reports have shown correlations between linear CT widening of lateral and third ventricles and impairment in cognitive and memory functions of pAD [51, l0 l]. Ventricular dilatation was associated with extent of cognitive impairments [52, l01 ] on tests of memory for words or sequences, although linear measurements were not as revealing as rank ordering of CT images [52] or volumetric transformations [1].

DIFFERENTIATINGAD FROM OTHER DEMENTIA PET imaging appeared to be equally useful in differentiating AD from other dementias. Although AD and MID have similarly reduced global and regional CMRGlc measures [8, 116, 118], the patterns of regions with reduced CMRGIc were distinctly different. Metabolic deficits in AD were more general, affecting many cortical areas or at least large regions. MID subjects showed scattered focal defects throughout the cortex and white matter that led to global and regional metabolic reductions. On closer inspection, regions away from the MID lesion may show normal metabolic rates [116]. In MID, lesions missed by CT were detected by F D G [118]. Patients with pAD, MID, or ddpression (D) are often clinically confused. Linear measures on CT of cortical atrophy and lesions separate the pAD from MID or probable vascular dementia [59] and correlate with the degree of dementia. Moreover, a parietal to either caudate-thalamus or to cerebellum CMRGIc ratio has been shown to sensitively distinguish between AD, MID, and controls [116,120] and depression [178]. Multivariate discriminant analyses with rCBF [161] and with FDG-PET [178,184] produced AD separation

79 with >80% accuracy. In pAD, hypometabolism was bilateral but varied between hemispheres 15-24% Whereas in MID and D asymmetry varied no more than 10%. Global CMRGIc did not distinguish between the groups. However, rCBF changes preceded multi-infarct and followed the onset of AD dementia [187]. Cohen and others [35,36] using a slant angle camera with iodoamphetamine measuring qualitative blood flow, demonstrated that AD could be differentiated from MID despite the limited tomographic resolution of the system [82]. Brain metabolic changes in pAD have not been easy to distinguish from those in the Parkinsonian brain. A number of studies have examined C B F in Parkinson's disease (PD) with the xenon method [13,84], rCBF and LCMRO2 with multiple detectors [129] or with PET [127,162], or glucose metabolism with PET [118, 122, 196]. In general, a decline of about 10% in global CBF, CMRO2, and CMRGIc has been found not to the extent observed in AD patients. Some studies did not, while others noted a decrease in parietal cortex, or a loss in the normal hyperfrontal pattern where frontal rCBF is greater than temporo-parietal rCBF [143]. When regional CMRGIc were expressed as ratio to the sum of all rCMRGIc, these 'reference ratios' were lower in all regions of pAD than in those of PD patients [115]. The number of regional intercorrelations was decreased in PD but increased in pAD. This was reflected in left-to-right frontal and temporal correlations indicating parallel hemispheric decline in pAD [141,143]. The pattern of intercorrelations separated disease entities [145]. Patients with fronto/parietal lowering seemed to have had the disease somewhat longer [141]. In both pAD and PD, hypometabolism was most severe in parietal and almost normal in cerebellar regions; the parietal/cerebellar ratio distinguished* both patient groups from controls [llS]. Patients with slowly progressing aphasia but no dementing signs have been described [93,140]. It is not agreed whether a distinct syndrome or early and highly focal AD or Pick's disease are detected. Chawluk and associates [31] studied two such patients with FDG-PET and found profound left temporo-parietai hypometabolism in the absence of significant global abnormalities. Pick's disease has rarely been studied with physiological imaging. These patients differed from AD with the presence of prominent frontal decline in rCBF [185]. The blood flow changes correlated with clinically present frontal lobe signs.

CONCLUDING COMMENTS Studies reviewed agree that there are specific dysfunctions both in cognitive and brain metabolic indices of early probable Alzheirner's disease. These were neither explicit nor consistent from patient to patient. Neuropsychological tests to define component processes were preferred to tests of overall cognition, so that deficit patterns might be compared with measures of brain regional deficits from imaging. Metabolic and cognitive indices were not always correlated in healthy elderly, but were linked already in the early stage of AD, particularly, in parietal hemispheric asymmetry measures or the P/C-TH ratio. Studies reviewed also lead to a hypothesis of heterogenous dysfunctions. This heterogeneity seemed reflected in two ways, one, in the degree and variable pattern of cognitive deficits; two, in the relatively specific but inconsistent number of test instruments found sensitive to detect them.

80 The first is recognized in the methodological problems of patients included for study. Part of the heterogeneity is explained by the diagnosis by exclusion, part results from the often small sample sizes of studies, from including patients of different severity stages or duration, or non-AD patients in the symptom reports. The second aspect of a heterogeneity hypothesis is seen in the diverse approaches of dementia screening scales that have variable success with diagnostic sensitivity. Although they tap several areas of neurobehavior, the dementia scales at best permit ordinal staging along an elusive severity dimension, but do not assist diagnosis by early deficit signs, differentiating the categories of dementia, or subtyping of AD, as is implied by a heterogeneity hypothesis. Scales did not permit investigators to describe which deficit signs appear first. Neurobehavioral tests of information processing were more specific to characteristic deficits. Studies agreed that encoding, storing, and later retrieving of new verbal or complex associations become exceedingly more difficult with progressive AD severity. Performances on tasks asking for learning or recall of word pairs, story or sequences, for naming, for generating words from categories, or for reproduction of designs from memory were diminished by up to three standard deviations below that of normal elderly. They aid diagnostic differentiations. Such deficits have been explained by a failure in effortfui processing compared with automatic processing or by a breakdown in the semantic memory system. An AD loss of subordinate detailing and of associations within the hierarchical structuring of the semantic memory system was supported by several findings although the model presupposes dominant semantic coding of information. The bottom-to-top loss in semantic structuring would describe the paradoxical observations by several investigators that AD have considerable difficulties in

RIEGE AND METTER generating words from categories but not to given letters. Such breakdown seems to resemble a reverse developmental staging. More relevant to the question for tests sensitive to AD deficits are reports of verbal memory and naming impairments correlated with regions of low brain glucose utilization, in particular, in temporo-parietal and sometimes posterior frontal regions. Such correlations verify the use of either measure in monitoring of AD. A restricted resolution of the PET scanner in several studies may have resulted in correlations assigned to large brain regions, but a dichotomy of correlation between verbal functions and left hemisphere, visuo-practic memory and right hemisphere metabolic indices is postulated though not always supported. There appears to be more evidence for similar correlations of dichotomized cognitive scores with the right-left asymmetries in regional hemispheric metabolism or with a frontal/parietal ratio. If confirmed, different patients with different asymmetries or ratio scores might form different subgroups for which cognitive deficit patterns would provide needed validation. Thereby, the heterogeneity in both measures would be reduced. It is not unlikely that the combination of specific cognitive tests and regional CMRGIc improve the clinical sensitivity needed for AD diagnosis. At present, testing was done in most studies at only one point in time which only implies that instruments had predictive validity. Multivariately combined and repeated use of these measures can confirm this. ACKNOWLEDGEMENTS The authors thank Dr. J. O. Harker and A. B. Lanto for their essential contributions to the preparation of the review. The work was supported by the Veterans Administration Medical Research.

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DISEASE

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