Leonard Berg

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimers Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as “definite Alzheimers disease” (AD), “probable AD,” “possible AD,” and “normal brain” to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

Cerebral amyloid deposition and diffuse plaques in ``normal'' aging Evidence for presymptomatic and very mild Alzheimer's disease

The presence of senile plaques in the neocortex of apparently nondemented elderly persons often is accepted as part of normal aging. Alternatively, because cerebral deposition of beta-amyloid may be a key mechanism in the development of Alzheimers disease (AD), the presence of beta-amyloid-containing plaques may represent very early AD. To examine the relationships of cognitively normal aging, very mild dementia of the Alzheimer type, and the presence of neocortical senile plaques, we performed clinicopathologic correlation in 21 longitudinally studied healthy elderly subjects (84.5 +/- 6.6 years old at death). Nine subjects had strikingly high plaque densities in the neocortex; two of these subjects died of head injury before which there was no evidence of cognitive impairment. The other seven subjects with high plaque densities had clinical evidence for very mild cognitive impairment (Clinical Dementia Rating score of 0.5) at some time during their course and mildly impaired psychometric performance at last assessment before death. The remaining 12 subjects had no clinical or psychometric impairment and had few or no neocortical AD lesions. These results suggest that senile plaques may not be part of normal aging but instead represent presymptomatic or unrecognized early symptomatic AD. The high density of senile plaques (predominately of the diffuse subtype) in the cortex of subjects just at the threshold of detectable dementia is consistent with the hypothesis that beta-amyloid deposition is an initial pathogenetic event in the development of AD.

Very mild Alzheimer's disease Informant‐based clinical, psychometric, and pathologic distinction from normal aging

We compare clinicopathologic data from 10 subjects identified in the very mild stage of senile dementia of the Alzheimer type with findings from similar studies in four cognitively normal subjects. We based the diagnosis of very mild dementia in the 10 subjects on informant reports and the judgment of experienced clinicians. Deficits of some psychometric measures of memory, language, and speeded psychomotor performance were observed for these subjects. The histologic markers of Alzheimers disease, including neurofibrillary tangles and both the “diffuse” and classic subtypes of senile plaques, were present in the neocortex in all 10 subjects but essentially were absent in the four controls. These findings indicate that even “questionable” dementia can be diagnostic for Alzheimers disease. Furthermore, because truly normal aging may be unaccompanied by neocortical senile plaques and neurofibrillary tangles, the presence of these lesions should suggest the possibility of clinically undetected Alzheimers disease.

Mild senile dementia of Alzheimer type: research diagnostic criteria, recruitment, and description of a study population.

Clinical investigations of senile dementia of the Alzheimer type require establishment of explicit clinical diagnostic criteria before histological confirmation is possible. Criteria for selection of mildly impaired subjects with senile dementia of Alzheimer type, free of other major disease, are proposed. Problems of recruitment of this select population for a longitudinal study are discussed. A study population with matched healthy control subjects has been enrolled and described. Short term follow-up has provided preliminary support for the diagnostic criteria.

Frequency analysis of the resting awake EEG in mild senile dementia of Alzheimer type

Spontaneous resting electroencephalograms (EEGs) were recorded from 40 subjects with senile dementia of Alzheimer type (SDAT) and 40 individually matched elderly controls at entry into a longitudinal study of SDAT. All of the demented subjects had only a mild degree of dementia, and all were still living in the community. Several measures of EEG activity were calculated, based upon the power spectra of the EEG samples from left and right occipital-to-vertex derivations. Paired t tests showed significant differences between demented and control group means for measures of theta and beta activity, but not for measures of alpha and delta activity. A significant decrease in the average mean frequency in demented subjects was attributed to the combination of decreased beta and increased theta activity. The earliest changes in the resting EEG in SDAT are increased theta and decreased beta power. These changes are not identical to those reported in normal aging, in which a decrease in alpha activity accompanies the changes in theta and beta.

Predictive features in mild senile dementia of the Alzheimer type

Forty-three subjects with mild senile dementia of the Alzheimer type, diagnosed and staged by clinical research criteria, were studied with clinical, psychometric, EEG, visual evoked potential, and CT measures. During the 12 months following entry into the study, 21 subjects progressed to moderate or severe dementia, 21 remained mild, and one was lost to follow-up. Many of the clinical and psychometric measures of impairment were predictive of the progression to moderate or severe dementia. Electrophysiologic and CT measures were not. In a discriminant function analysis, the scores on two measures (the digit symbol subtest of the Wechsler Adult Intelligence Scale and an Aphasia Battery) correctly predicted the stage of dementia 1 year later in 95% of the subjects.

The Progression of Personality Changes in Senile Dementia of the Alzheimer's Type

Passive, agitated, and self‐centered behavioral changes were noted on initial evaluation in two‐thirds, one‐third, and one‐third, respectively, of subjects with mild senile dementia of the Alzheimers type (SDAT). Over a 50‐month follow‐up period, the percentage of patients who exhibited agitated and self‐centered behaviors doubled. The percentage of subjects who demonstrated all three behavioral changes increased from 11% at entry to the study (mild SDAT) to over 50% when the dementia had reached a severe stage. The presence of personality changes at a mild stage of dementia did not predispose subjects to more rapid progression to a more advanced stage of illness.

Analysis of the prion protein gene in thalamic dementia

Thalamic degenerations or dementias are poorly understood conditions. The familial forms are (1) selective thalamic degenerations and (2) thalamic degenerations associated with multiple system atrophy. Selective thalamic degenerations share clinical and pathologic features with fatal familial insomnia, an autosomal dominant disease linked to a mutation at codon 178 of the prion protein (PrP) gene that causes the substitution of asparagine for aspartic acid (178Asn mutation). We amplified the carboxyl terminal coding region of the PrP gene from subjects with selective thalamic dementia or thalamic dementia associated with multiple system atrophy. Three of the four kindreds with selective thalamic dementia and none of the three kindreds with thalamic dementia associated with multiple system atrophy had the PrP 178Asn mutation. Thus, analysis of the PrP gene may be useful in diagnosing the subtypes of thalamic dementia. Moreover, since selective thalamic dementia with the PrP 178Asn mutation and fatal familial insomnia share clinical and histopathologic features, we propose that they are the same disease.

Adult idiopathic communicating hydrocephalus with and without shunting.

The outcome in 37 adult patients with idiopathic communicating hydrocephalus treated by ventriculoatrial shunting is presented. Only 33% showed definite improvement, and no diagnostic procedures accurately predicted the outcome of surgery. These were compared with a control group of 12 patients who were not shunted; 50% of these were stable for up to 36 months. These findings, and the high frequency of serious complications (35%), suggest caution in recommending a shunt procedure.

Behavioral changes in patients with mild senile dementia of the Alzheimer's type

Behavioral changes in 44 subjects with well-characterized mild senile dementia of the Alzheimers type (SDAT) and 16 subjects with only questionable SDAT were compared to a control group of 58 subjects. Answers to both open-ended questions and personality items from the Blessed Dementia Scale were examined. Seventeen items were classified into seven categories by factor analysis and then further categorized into four clinically useful groups: passive, agitated, self-centered, and suspicious. Over 75% of subjects with mild SDAT had behavioral changes compared to 10% of controls. Passive symptoms were the most common, occurring in two-thirds of mild SDAT subjects. Agitated and self-centered symptoms were also common, occurring half as frequently as passive symptoms. Passive symptoms occurred alone in 25% of those with mild SDAT, whereas passive symptoms, together with agitated and/or self-centered symptoms, were present in 11-16% of subjects with mild SDAT. Agitated or self-centered symptoms rarely occurred alone. Characterizing the behavioral symptoms of SDAT is important for their clinical implications and for an approach to understanding brain-behavioral relationships.