James A. Mortimer

Hippocampal volume as an index of Alzheimer neuropathology Findings from the Nun Study

ObjectiveTo determine whether hippocampal volume is a sensitive and specific indicator of Alzheimer neuropathology, regardless of the presence or absence of cognitive and memory impairment. MethodsPostmortem MRI scans were obtained for the first 56 participants of the Nun Study who were scanned. The area under receiver operating characteristic curves, sensitivity, specificity, and positive and negative predictive values were used to assess the diagnostic accuracy of hippocampal volume in predicting fulfillment of Alzheimer neuropathologic criteria and differences in Braak staging. ResultsHippocampal volume predicted fulfillment of neuropathologic criteria for AD for all 56 participants (p < 0.001): 24 sisters who were demented (p = 0.036); 32 sisters who remained nondemented (p < 0.001), 8 sisters who remained nondemented but had memory impairment (p < 0.001), and 24 sisters who were intact with regard to memory and cognition at the final examination prior to death (p = 0.003). In individuals who remained nondemented, hippocampal volume was a better indicator of AD neuropathology than a delayed memory measure. Among nondemented sisters, Braak stages III and VI were distinguishable from Braak stages II or lower (p = 0.001). Among cognitively intact individuals, those in Braak stage II could be distinguished from those in stage I or less (p = 0.025). ConclusionVolumetric measures of the hippocampus may be useful in identifying nondemented individuals who satisfy neuropathologic criteria for AD as well as pathologic stages of AD that may be present decades before initial clinical expression.

Relationship of motor symptoms to intellectual deficits in Parkinson disease

We studied 60 patients with idiopathic Parkinson disease with motor and neuropsychologic tests to ascertain whether the severity of motor symptoms was associated with the degree of neuropsychologic deficit. Significant correlations were found between the severity of bradykinesia and impaired performance on tests assessing visual-spatial reasoning and psychomotor speed. More severe tremor was associated with better performance on a spatial orientation memory test. These relationships remained when age, age at onset, and self-rated depression were controlled. The findings suggested that cognitive impairment may result from the same subcortical lesions that cause motor symptoms.

Correlates of Cognitive Function in Middle-Aged Adults

The Atherosclerosis Risk in Communities Study administered cognitive function tests to more than 14,000 middle-aged adults in 1990–1992. The battery included the Delayed Word Recall test, the Digit Symbol Subtest of the Wechsler Adult Intelligence Scale-Revised, and the Controlled Oral Word Association (Word Fluency) test. Test performance was correlated positively with education level, negatively with age, was better in women than in men, and better in managers/professionals compared with other occupations. After controlling for these factors, race and community, the findings most consistent for both sexes were that Delayed Word Recall was negatively associated with depressive symptoms, diabetes, and fibrinogen level; the Digit Symbol Subtest was associated with marital status, negatively associated with depressive symptoms, smoking status, fibrinogen level, and carotid intima-media thickness, and positively associated with alcohol drinking and FEV1; and the Word Fluency test was positively associated with marital status, alcohol drinking, sports participation, and FEV1. Most of these cross-sectional results were in the predicted direction and have biologic plausibility, but mean differences between extreme categories were small (generally on the order of 0.1 to 0.2 of a standard deviation). Longitudinal study is warranted to evaluate whether small differences in middle-age lead to larger, clinically meaningful deficits with aging.

Head Circumference, Education and Risk of Dementia: Findings from the Nun Study

To examine the prevalence of dementia associated with having a smaller brain, lower education or both of these characteristics, 294 Catholic sisters were assessed annually for dementia. Sixty participants died and their brains were evaluated to determine fulfillment of neuropathological criteria for Alzheimer‘s disease (AD). Lower educational attainment and the interaction of smaller head circumference with lower education were associated with the presence of dementia, controlling for age and the presence of one or more apolipoprotein E-e4 alleles. By contrast, neither low educational attainment nor head circumference was significantly associated with fulfillment of neuropathological criteria for AD. Individuals having both low education and small head circumference were four times as likely to be demented as the rest of the sample. The findings suggest that higher education and larger head size, alone or in combination, may reduce the risk of expressing dementia in late life.

Dementia in Parkinson disease: A neuropsychological analysis

An extensive set of neuropsychological measures was administered to 60 Parkinsons disease patients and age-, sex-, and education-matched controls in order to investigate the nature and prevalence of the cognitive deficit in the disease. Parkinsonian patients performed significantly poorer on all measures with the exception of tests for apraxia and object recognition, and on a test of vocabulary knowledge. Discriminant analysis of the test data revealed that over 93% of patients are impaired relative to matched controls, but that assigning a prevalence rate for dementia in the disease may be difficult due to the continuous distribution of cognitive deficits.

Early-life Risk Factors for Alzheimer Disease

Research findings obtained over the past 20 years suggest that Alzheimer disease (AD) may have its origins in early life. In this review, we consider the evidence for early-life risk factors for this illness. We propose that risk factors that predict neuropathology are largely distinct from those related to the clinical expression of Alzheimer disease. Early-life risk factors for pathology include genes, chromosomal abnormalities, head injury, insulin resistance, and inflammation. With regard to risk factors for clinical expression of Alzheimer disease, six general groups of childhood exposures are reviewed: (1) perinatal conditions, (2) early-life brain development, (3) early-life body growth, (4) early-life socioeconomic conditions, (5) environmental enrichment, and (6) cognitive reserve. The literature reviewed suggests that risk of Alzheimer disease is probably not determined in any single time period but results from the complex interplay between genetic and environmental exposures throughout the life course. Enhancement or preservation of brain or cognitive reserve could delay the onset of Alzheimer disease and in some cases prevent the disease from occurring altogether.

Complete ascertainment of dementia in the Swedish Twin Registry: the HARMONY study

The purpose of this report is to describe the Study of Dementia in Swedish Twins (known as HARMONY), including procedures for complete ascertainment of all cases of Alzheimers disease (AD) and other dementias in 14,435 individuals aged 65 and older from the national Swedish twin registry. Telephone cognitive screening identified 11.5% as positive for cognitive dysfunction. Clinical diagnoses were completed for 1557 individuals, including individuals who screened positive, their twin partners, and a sample of normal controls. Estimated prevalence of dementia ranged from 1.4% for age 65-69 to 29.2% for age 90 and older. Concordance rates for Alzheimers disease were 59% for monozygotic twins, 32% for like-sexed, and 24% for unlike-sexed dizygotic twins. Among monozygotic twins where both twins had Alzheimers disease, the within pair difference in age of onset ranged from both becoming demented in the same year to 7 years difference in onset.

Very Early Detection of Alzheimer Neuropathology and the Role of Brain Reserve in Modifying Its Clinical Expression

Numerous studies show that the pathology of Alzheimer’s disease is present decades before a clinical diagnosis of dementia can be made. Given the likelihood that agents will become available that reliably delay onset and/or slow progression of Alzheimer’s disease, it will be important to detect preclinical Alzheimer’s disease as early as possible for maximal treatment effect. Detection of individuals by sensitive cognitive measures provides one way to identify people who are at high risk of developing clinical Alzheimer’s disease. However, it is likely that those with considerable brain or cognitive reserve will be able to mask cognitive deficits until very close to the onset of the dementia, rendering such cognitive measures insensitive. Optimum biomarkers for Alzheimer’s disease therefore need to target the severity of underlying brain pathology independently of brain reserve. Findings are presented showing the importance of higher education and larger brain size in masking the underlying disease pathology.

Exercise therapy for Parkinson's disease

The outcomes of two different 12-week exercise programs were assessed by machine measurements of motor signs, tests of grip strength, motor coordination and speed, and neurophysiologic determinations of long-latency stretch responses in two groups of Parkinson patients matched for age, sex and stage of disease. The programs tested included an exercise program developed by the United Parkinson Foundation and a program of upper body karate training. Outcomes of these programs were similar. The majority of patients in both groups showed improvements in gait, tremor, grip strength and motor coordination on tasks requiring fine control. In one task involving whole body coordination there was a decline in function, while muscle rigidity was unchanged. The findings suggest that exercise is a useful adjunct to pharmacologic therapy.

Potentially modifiable risk factors for dementia in identical twins

The purpose of this study was to test nongenetic factors that might explain discordance for dementia in monozygotic twin pairs. Risk factors included education, engaged lifestyle in midlife, and early life circumstances indexed by tooth loss, short adult height, and parental social class.