Howard Crystal

Screening for dementia by memory testing

Enhanced cued recall provides a simple and clinically useful memory test for identifying dementia in the elderly. Because this test induces semantic processing and coordinates encoding and retrieval for maximum recall, genuine memory deficits due to impairment of specific memory processes can be distinguished from apparent memory deficits due to use of inefficient strategies or impairment of other cognitive processes. Since genuine memory deficits in the elderly are usually associated with dementia, their identification is highly predictive of clinical dementia. The present study validates the use of enhanced cued recall as a screening test for dementia in 70 aged subjects. All but one person with a pure amnesia were correctly classified. Enhanced cued recall correctly classified 97% of the 120 subjects in this and the previous study. Enhanced cued recall shows learning not revealed by free recall, providing more accurate measurement of memory, and distinguishes demented from nondemented elderly more accurately than either free recall or recognition.

Clinico‐pathologic studies in dementia: Nondemented subjects with pathologically confirmed Alzheimer's disease

We compared neuropsychological findings in 28 longitudinally evaluated elderly subjects with their postmortem neuropathology, including senile plaque and neurofibrillary tangle counts from standardized sections. Nine of the subjects were not demented when evaluated just prior to their death. Numerous cortical senile plaques and other changes of Alzheimers disease (AD) occurred in six of nine nondemented old-old subjects. Five of these six subjects had shown decline on yearly neuropsychological tests but their cognitive impairment was too mild to meet clinical criteria for dementia. Whereas cortical senile plaque count did not distinguish well between demented and nondemented subjects, every subject with numerous cortical neurofibrillary tangles was demented. The nondemented subjects with Alzheimer pathology may have had “preclinical” AD, or numerous cortical plaques may occur in some elderly subjects who would never develop clinical dementia.

A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis.

Cop 1 is a random polymer (molecular weight, 14,000 to 23,000) simulating myelin basic protein. It is synthesized by polymerizing L-alanine, L-glutamic acid, L-lysine, and L-tyrosine. It suppresses but does not induce experimental allergic encephalomyelitis, an animal model of multiple sclerosis. It is not toxic in animals. In a double-blind, randomized, placebo-controlled pilot trial, we studied 50 patients with the exacerbating-remitting form of multiple sclerosis, who self-injected either 20 mg of Cop 1 dissolved in 1 ml of saline or saline alone daily for two years. Six of 23 patients in the placebo group (26 percent) and 14 of 25 patients in the Cop 1 group (56 percent) had no exacerbations (P = 0.045). There were 62 exacerbations in the placebo group and 16 in the Cop 1 group, yielding two-year averages of 2.7 and 0.6 per patient, respectively. Among patients who were less disabled on entry (Kurtzke disability score, 0 to 2), there were 2.7 exacerbations in the placebo group and 0.3 in the Cop 1 group over two years. Among patients who were more affected (Kurtzke disability score, 3 to 6), there was an average of 2.7 exacerbations in the placebo group and 1.0 in the Cop 1 group. Over two years, less disabled patients taking Cop 1 improved an average of 0.5 Kurtzke units; those taking placebo worsened an average of 1.2 Kurtzke units. More disabled patients worsened by 0.3 (Cop 1 group) and 0.4 (placebo group) unit. Irritation at injection sites and rare, transient vasomotor responses were observed as side effects. These results suggest that Cop 1 may be beneficial in patients with the exacerbating-remitting form of multiple sclerosis, but we emphasize that the study is a preliminary one and our data require confirmation by a more extensive clinical trial.

Neuropsychological prediction of dementia and the absence of dementia in healthy elderly persons

Identification of elderly individuals with low and high risk for future dementia has emerged as an important clinical and public health issue. To address this issue, we assessed neuropsychological performance in 317 initially nondemented elderly persons between 75 and 85 years of age and followed them for at least 4 years as part of the Bronx Aging Study. Four measures of cognitive function from the baseline assessment (delayed recall from the Buschke Selective Reminding Test, recall from the Fuld Object Memory Evaluation, the Digit Symbol subtest from the Wechsler Adult Intelligence Scale, and a verbal fluency score) can identify one subgroup with an 85% probability of developing dementia over 4 years and another with a 95% probability of remaining free of dementia. The model achieved an overall positive predictive value of 68%, or three times the base rate, for prediction of the development of dementia in our sample. The overall negative predictive value for prediction of absence of dementia was 88%. Baseline measures of cognitive function, often performed many years before the actual diagnosis of dementia, can provide important information about dementia risk. The group likely to develop dementia becomes a target for preventive or early therapeutic interventions, and the group unlikely to develop dementia can be reassured.

Correlations of synaptic and pathological markers with cognition of the elderly

It has been suggested that the physical basis for dementia is structural or functional loss of synapses. To confirm this finding, we performed an enzyme-linked immunoassay (ELISA) with a monoclonal antibody (EP10) to a synaptophysin-like protein in brain samples from 45 prospectively studied elderly subjects with an average age of 83.3 +/- 10.1 years. We compared the synaptic marker to immunoreactivity with a newly developed PHF antibody (TG3). The cases were selected on the basis of availability of frozen tissue, and included subjects ranging from clinically normal to end-stage dementia. As an initial assessment, we determined Pearson product moment correlations for two clinical measures--the Blessed test of information, concentration, and memory (BICM) and the Fuld object Memory Evaluation (FOME)--with ELISA data and with traditional pathologic markers. We found strong correlations (p < 0.01-0.001) for BICM with brain weight, neuronal loss in the basal nucleus of Meynert (nbM), counts of senile plaques (SP) in the neocortex and hippocampus, and neurofibrillary tangles (NFT) in all areas except the parahippocampal cortex. Except in the occipital lobe, where paired helical filament changes are relatively uncommon, TG3-immunoreactivity also correlated strongly with BICM. Weak correlations (p < 0.05) were found for BICM with EP10-immunoreactivity in only the temporal and parietal lobes. Only the pathologic variables showed any significant correlations with FOME. Because inclusion of normal subjects with few or no pathologic lesions could have been driving the strong correlations with pathologic markers, we limited the analysis to those subjects with dementia (BICM; 8). After making this correction, EP10-immunoreactivity in all cortical areas and the hippocampus correlated better (p < 0.05-0.01) with BICM but not FOME. The present univariate analysis suggests that synaptic markers may not be the best structural correlate of dementia and that markers indicative of cytoskeletal changes, e.g., SP, NFT and PHF protein accumulation, may be better correlates of dementia in the elderly.

Memory impairment on free and cued selective reminding predicts dementia

Objective: To estimate the relative rates of dementia in initially nondemented subjects with and without memory impairment defined by baseline free recall from the Free and Cued Selective Reminding (FCSR) test. Background: Our approach to identifying persons at high risk for future dementia is to show the presence of memory impairment not caused by other cognitive deficits by using a memory test that controls attention and cognitive processing. When the conditions of testing are not adequately controlled, prediction is reduced because age-associated memory deficits due to other cognitive deficits are confused with dementia-associated memory deficits. Methods: Longitudinal evaluation of 264 initially nondemented, elderly community volunteers from the Einstein Aging Study with clinical and psychometric examinations every 12 to 18 months for up to 10 years. Main Outcome Measures: Dementia was defined by an algorithmic definition that required a Blessed Information Memory and Concentration score >8 and clinical evidence of functional decline. Results: Thirty-two incident cases of dementia developed during follow-up. Survival analyses indicated that subjects with impaired free recall at baseline had dementia develop (relative risk = 75.2, 95% CI = 9.9 to 567) over 5 years of follow-up at dramatically higher rates than subjects with intact free recall after adjusting for age, gender, and education. Conclusion: Poor performance on free recall from FCSR predicts future dementia. These findings support the existence of a preclinical phase of dementia characterized by memory impairment, which is present for at least 5 years before diagnosis.

Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease Light and electron microscopic immunocytochemistry of CA2–3 neurites specific to DLBD

Immunocytochemistry with antibodies to ubiquitin is currently the most sensitive method for detecting cortical Lewy bodies, which are a sine qua non for the diagnosis of diffuse Lewy body disease (DLBD), an increasingly recognized form of primary degenerative dementia. In the systematic application of ubiquitin immunocytochemistry to sections of hippocampus from control subjects and patients with a wide spectrum of neurodegenerative diseases, we noted the frequent occurrence of ubiquitin-immunoreactive neurites in the CA2–3 region in DLBD. The nature of these neurites was investigated with immunocytochemistry in DLBD, Alzheimers disease (AD), normal elderly subjects, and Parkinsons disease (PD). Although the number of neurites varied from case to case, they were virtually always detected in DLBD but not in normal, AD, or PD brains. Double immunolabeling studies with anti-ubiquitin demonstrated a small fraction of double-stained neurites with antibodies to neurofilament or Alz-50, but no double staining with an antibody to Alzheimer neurofibrillary tangles. These results are different from those for neurites in AD, which are rarely seen in CA2–3 and which are immunoreactive with all these antibodies. Neuritic degeneration in the CA2–3 region of the hippocampus appears to be a specific histopathologic feature of DLBD.

Women, myocardial infarction, and dementia in the very old

Dementia is a major public health problem among the very old. Available information on incidence and prevalence is sparse and variable; however, there appears to be a higher prevalence among very old women. We present data from a prospective study of initially nondemented community-residing elderly. There were 75 incident dementia cases (up to 7 years of follow-up) of which at least 47% were probable Alzheimers disease. Based on a proportional hazards analysis, women were over 3 times more likely to develop dementia than men despite controlling for baseline demographic, psychosocial, and medical history variables. Poor word fluency and a high normal Blessed test score at baseline were also strong predictors of dementia. We did not find age, head trauma, thyroid disease, or family history of dementia to be risk factors. A new finding is that history of myocardial infarction (MI) is associated with dementia, such that women with a history of MI were 5 times more prone to dementia than those without a history. This observation was not true for men.

Memory and mental status correlates of modified Braak staging

We assessed the relationships of performance on memory and mental status tests and neuropathologic stage of Alzheimers disease as defined by Braak and Braak in 29 patients from a prospective clinicopathologic series. We predicted that memory changes would occur at an earlier Braak stage than mental status changes. Staging was accomplished by matching the topographic distribution of neurofibrillary lesions detected with tau immunocytochemistry to the best fitting diagram published by Braak and Braak. Higher Braak stages were associated with decrements in performance on both memory and mental status tests. As predicted, memory performance declined from stages II to III and mental status did not decline until stages III to IV. The association between memory and Braak stage was unchanged after adjusting for neocortical senile plaques, whereas adjustments for Braak stage eliminated the association between cognitive functioning and amyloid burden. We conclude that Braak staging provides a useful summary of Alzheimers disease neuropathology, which is associated with both memory and mental status performance.

Hippocampal sclerosis: a common pathological feature of dementia in very old (≥80 years of age) humans

In a neuropathological study of 81 brains of prospectively studied subjects of 80 years of age or older at the time of death, 13 cases (16%), including 4 men and 9 women, had hippocampal sclerosis (HpScl) affecting the vulnerable region of the hippocampus. In demented subjects of 80 years of age or older, the frequency of HpScl was even higher, 26%. Cases with HpScl had significantly fewer hippocampal senile plaques (SP) and neurofibrillary tangles (NFT) and parahippocampal NFT than cases without HpScl, but did not differ significantly in any of the other measured pathological parameters. Enzyme-linked analysis of synaptic protein immunoreactivity in a subset of 33 cases demonstrated significant decreases in the hippocampus, but not in frontal, temporal, parietal or parahippocampal cortices. All but 1 of the cases with HpScl had Blessed information, memory and concentration scores (BIMC) of 8 or more, and all were considered to be demented. In some patients memory disturbance was disproportionate to deficits in other cognitive areas. All but 4 of the cases with HpScl had many nonneuritic, amyloid plaques in the neocortex meeting NIA criteria for Alzheimers disease (AD); however, given the advanced age of the subjects, amyloid plaques were considered to represent age-related cerebral amyloid deposition (“pathological aging”) in most cases. Only 3 cases had both many SP and NFT in multiple cortical regions consistent with AD. Another case had brain stem and cortical Lewy bodies consistent with diffuse Lewy body disease (DLBD). A few ballooned neurons were present in the limbic cortices in 3 cases, including one case of dementia with argyrophilic grains (DAG) in limbic and orbital frontal and temporal cortices. The 8 cases without AD, DLBD or DAG included 4 cases in which no other obvious cause of dementia was detected and 4 cases in which HpScl was accompanied by either multiple cerebral infarcts or leukoencephalopathy, or both, that could have contributed to dementia. Patients with HpScl had risk factors, clinical signs and post-mortem pathological findings of cardiovascular disease, but due to the high prevalence of these conditions in very old humans, no significant correlation with HpScl was detected. This study demonstrates that HpScl is a common post-mortem finding in demented, but not normal, elderly subjects. It may contribute to, or be a marker for, the increased risk of dementia in subjects with documented cardiovascular disease or a history of myocardial infarction.