Laurel A. Beckett

Natural history of mild cognitive impairment in older persons

Background Cognitive abilities of older persons range from normal, to mild cognitive impairment, to dementia. Few large longitudinal studies have compared the natural history of mild cognitive impairment with similar persons without cognitive impairment. Methods Participants were older Catholic clergy without dementia, 211 with mild cognitive impairment and 587 without cognitive impairment, who underwent annual clinical evaluation for AD and an assessment of different cognitive abilities. Cognitive performance tests were summarized to yield a composite measure of global cognitive function and separate summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. The authors compared the risk of death, risk of incident AD, and rates of change in global cognition and different cognitive domains among persons with mild cognitive impairment to those without cognitive impairment. All models controlled for age, sex, and education. Results On average, persons with mild cognitive impairment had significantly lower scores at baseline in all cognitive domains. Over an average of 4.5 years of follow-up, 30% of persons with mild cognitive impairment died, a rate 1.7 times higher than those without cognitive impairment (95% CI, 1.2 to 2.5). In addition, 64 (34%) persons with mild cognitive impairment developed AD, a rate 3.1 times higher than those without cognitive impairment (95% CI, 2.1 to 4.5). Finally, persons with mild cognitive impairment declined significantly faster on measures of episodic memory, semantic memory, and perceptual speed, but not on measures of working memory or visuospatial ability, as compared with persons without cognitive impairment. Conclusions Mild cognitive impairment is associated with an increased risk of death and incident AD, and a greater rate of decline in selected cognitive abilities.

Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment

In Alzheimers disease (AD), loss of cortical and hippocampal choline acetyltransferase (ChAT) activity has been correlated with dementia severity and disease duration, and it forms the basis for current therapies. However, the extent to which reductions in ChAT activity are associated with early cognitive decline has not been well established. We quantified ChAT activity in the hippocampus and four cortical regions (superior frontal, inferior parietal, superior temporal, and anterior cingulate) of 58 individuals diagnosed with no cognitive impairment (NCI; n = 26; mean age 81.4 ± 7.3 years), mild cognitive impairment (MCI; n = 18; mean age 84.5 ± 5.7), or mild AD (n =14; mean age 86.3 ± 6.6). Inferior parietal cortex ChAT activity was also assessed in 12 subjects with end‐stage AD (mean age 81.4 ± 4.3 years) and compared to inferior parietal cortex ChAT levels of the other three groups. Only the end‐stage AD group had ChAT levels reduced below normal. In individuals with MCI and mild AD, ChAT activity was unchanged in the inferior parietal, superior temporal, and anterior cingulate cortices compared to NCI. In contrast, ChAT activity in the superior frontal cortex was significantly elevated above normal controls in MCI subjects, whereas the mild AD group was not different from NCI or MCI. Hippocampal ChAT activity was significantly higher in MCI subjects than in either NCI or AD. Our results suggest that cognitive deficits in MCI and early AD are not associated with the loss of ChAT and occur despite regionally specific upregulation. Thus, the earliest cognitive deficits in AD involve brain changes other than simply cholinergic system loss. Of importance, the cholinergic system is capable of compensatory responses during the early stage of dementia. The upregulation in frontal cortex and hippocampal ChAT activity could be an important factor in preventing the transition of MCI subjects to AD.

Individual differences in rates of change in cognitive abilities of older persons.

The authors examined change in cognitive abilities in older Catholic clergy members. For up to 6 years, participants underwent annual clinical evaluations, which included a battery of tests from which summary measures of 7 abilities were derived. On average, decline occurred in each ability and was more rapid in older persons than in younger persons. However, wide individual differences were evident at all ages. Rate of change in a given domain was not strongly related to baseline level of function in that domain but was moderately associated with rates of change in other cognitive domains. The results suggest that change in cognitive function in old age primarily reflects person-specific factors rather than an inevitable developmental process.

Prevalence of Parkinsonian Signs and Associated Mortality in a Community Population of Older People

BACKGROUNDnOlder people frequently have signs of parkinsonism, but information about the prevalence of parkinsonism and mortality among those with the condition in the community is limited.nnnMETHODSnA stratified random sample of 467 residents of East Boston, Massachusetts, 65 years of age or older, were given structured neurologic examinations. Using uniform, specified combinations of parkinsonian signs, we estimated the prevalence of four categories of signs--bradykinesia, gait disturbance, rigidity, and tremor--and of parkinsonism, defined as the presence of two or more categories. We did not study Parkinsons disease because it could not be distinguished from other conditions that can cause parkinsonism. Proportional-hazards models were used to compare the risk of death among people with and those without parkinsonism.nnnRESULTSnOne hundred fifty-nine persons had parkinsonism, 301 did not, and 7 could not be classified. The overall prevalence estimates were 14.9 percent for people 65 to 74 years of age, 29.5 percent for those 75 to 84, and 52.4 percent for those 85 and older. With a mean follow-up period of 9.2 years, 124 persons with parkinsonism (78 percent) and 146 persons without (49 percent) died. Adjusted for age and sex, the overall risk of death among people with parkinsonism was 2.0 (95 percent confidence interval, 1.6 to 2.6) times that among people without. Among people with parkinsonism, the presence of gait disturbance was associated with an increased risk of death.nnnCONCLUSIONSnParkinsonism is very common among people over the age of 65, and its prevalence increases markedly with age. Parkinsonism is associated with a twofold increase in the risk of death, which is strongly related to the presence of a gait disturbance.

Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease.

Oxidative stress may play a role in neurologic disease. The present study examined the relation between use of vitamin E and vitamin C and incident Alzheimer disease in a prospective study of 633 persons 65 years and older. A stratified random sample was selected from a disease-free population. At baseline, all vitamin supplements taken in the previous 2 weeks were identified by direct inspection. After an average follow-up period of 4.3 years, 91 of the sample participants with vitamin information met accepted criteria for the clinical diagnosis of Alzheimer disease. None of the 27 vitamin E supplement users had Alzheimer disease compared with 3.9 predicted based on the crude observed incidence among nonusers (p = 0.04) and 2.5 predicted based on age, sex, years of education, and length of follow-up interval (p = 0.23). None of the 23 vitamin C supplement users had Alzheimer disease compared with 3.3 predicted based on the crude observed incidence among nonusers (p = 0.10) and 3.2 predicted adjusted for age, sex, education, and follow-up interval (p = 0.04). There was no relation between Alzheimer disease and use of multivitamins. These data suggest that use of the higher-dose vitamin E and vitamin C supplements may lower the risk of Alzheimer disease.

Level of education and change in cognitive function in a community population of older persons

In a community population of persons over the age of 65, cognitive function was assessed using brief performance tests on two occasions 3 years apart. Those with fewer years of formal education consistently had greater declines in cognitive function, independently of age, birthplace, language of interview, occupation, and income. These prospective findings suggest that low educational attainment or a correlate predicts cognitive decline. It is not clear, however, whether this relation represents a direct effect of education on future cognition, whether education might be related to occurrence of a disease leading to cognitive decline in older persons, or whether education might be a surrogate for some variable not included in the study.

Entorhinal Cortex β-Amyloid Load in Individuals with Mild Cognitive Impairment

Abstract The deposition of β-amyloid within the entorhinal cortex (EC) may play a key role in the development of mild cognitive impairment (MCI) in the elderly. To examine the relationship of β-amyloid deposition to MCI, EC tissue immunostained for this protein was quantitated from a cohort of aged Catholic religious clergy with a clinical diagnosis of MCI and compared to those with no cognitive impairment (NCI) and Alzheimers disease (AD). β-amyloid staining was seen in 12 of the 20 NCI, in 10 of 12 MCI, and in all 12 AD cases within the EC. β-amyloid immunoreactivity displayed two patterns within the EC: (1) a crescent-shaped band within layers 3–4 or (2) bilaminar staining mainly within layers 2–3 and 5–6. Ten cases failed to display any detectable β-amyloid imunoreactivity. Despite the heterogeneity of β-amyloid loads within the clinical groups, decomposing an analysis of variance revealed a significant difference across groups in mean β-amyloid load within the EC based upon a linear trend analysis. Multiple comparisons testing revealed that NCI individuals had a significantly lower mean β-amyloid load (1.32) than AD individuals (4.55). The MCI individuals had a mean intermediate (2.60) load between NCI and AD, but not statistically distinguishable from the mean for either NCI or AD. Spearman rank correlation showed a trend for decreasing MMSE with increasing amyloid load that failed to reach statistical significance. Since many NCI cases displayed β-amyloid loads equal to or greater than that seen in some MCI and some AD cases, it is mostly likely that deposition of this protein is not the sole pathogenic event underlying cognitive impairment in the elderly.

Progression of gait disorder and rigidity and risk of death in older persons

Background: Bradykinesia, gait disturbance, rigidity, and tremor are common motor signs in old age. All of these signs are associated with increased morbidity and mortality, but the extent to which they are progressive is unknown. Methods: Study participants were 787 older Catholic clergy members without clinically diagnosed PD, related conditions, or dementia at baseline. They were evaluated annually for up to 7 years, with >95% follow-up participation by survivors. Evaluations included administration of a modified version of the motor portion of the Unified PD Rating Scale (UPDRS), from which previously established measures of the global UPDRS and four specific motor signs were derived. Scores represent the percent of the total possible UPDRS score obtained. Results: At baseline, the global UPDRS score ranged from 0 to 36.3 (mean ± SD, 7.3 ± 6.4). It increased by an average of 0.69 unit per year during follow-up, with more rapid progression in older persons, but there was wide variability with no progression in 21% of subjects and annual increases of up to 8.23 units in the remaining 79%. Of 129 persons who died, 106 had follow-up UPDRS data. In a proportional hazards model, risk of death was associated with both the level of the global UPDRS score at baseline and the annual rate of progression (both p < 0.001). Overall, risk of death in subjects who had some worsening of the global UPDRS score was 2.93 times the rate among those without progression (95% CI, 1.32–6.50). Gait disorder/postural reflex impairment and rigidity worsened, but bradykinesia and tremor did not. Risk of death was associated with worsening of gait/posture but not with the other signs. Conclusion: Gait disorder and rigidity, as assessed with the modified UPDRS, are usually progressive in old age. Both the severity of the gait disorder and its rate of progression are strongly associated with risk of death.

Terminal decline in cognitive function

Background: Impending death is thought to be associated with age-related cognitive decline, but this association has not been well studied. Methods: Participants were 763 older Roman Catholic nuns, priests, and brothers without dementia at baseline. They completed an average of 5.6 annual evaluations (range 2 to 9), with >95% follow-up participation in survivors. Each evaluation included administration of 19 cognitive function tests from which previously established measures of global cognition (mean = 0.108, SD = 0.502) and specific cognitive functions were derived. In a series of change point random effects models, the average point before death when rate of cognitive decline changed was identified, and rates of cognitive decline before and after the optimal change point were estimated, controlling for the effects of age, sex, and education. Results: There were 122 deaths during the observation period. Those who died had lower global cognitive function at baseline than survivors (by 0.103 unit; p = 0.03), and beginning about 43 months before death, their annual rate of global cognitive decline sharply accelerated from an annual loss of 0.026 to 0.173 unit, a more than sixfold increase. Results were comparable in analyses that controlled for baseline health and disability. Terminal cognitive decline was evident in nearly all of those who died, but at highly variable rates. Remarkably little cognitive decline was evident in survivors. Decline in episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability also greatly increased about 3 to 6 years prior to death. Conclusion: On average, cognitive decline sharply accelerates in the last years of life.

Metric properties of nurses' ratings of parkinsonian signs with a modified Unified Parkinson's Disease Rating Scale

We evaluated the ability of nurse clinicians to assess parkinsonian signs in older persons with a modified version of the motor section of the Unified Parkinsons Disease Rating Scale (UPDRS). After completing a structured training protocol, three nurse clinicians and a neurologist with expertise in movement disorders administered a modified UPDRS to 75 older persons. The nurses repeated the assessment about 3 weeks later. Inter-rater agreement and short-term temporal stability were estimated for each item, the total modified UPDRS score, and for summary measures of bradykinesia, postural reflex impairment, rigidity, and tremor, and a global parkinsonian sign score. We performed our assessment in Catholic religious communities in the Chicago area, using consecutive subjects at four communities participating in the Religious Orders Study, a longitudinal, clinical-pathologic study of older persons. Our results showed that nurses were not a significant source of variability, with intraclass correlations exceeding 0.97 for all items, and they showed good to excellent agreement with the neurologist for most modified UPDRS items. Correlations between nurses and neurologist exceeded 0.90 for the total modified UPDRS, ranged from 0.76 to 0.95 for the four parkinsonian domain scores, and exceeded 0.90 for the global parkinsonian sign score. Nurses showed fair to good agreement with themselves over the 3-week interval for most modified UPDRS items. Correlations over the 3-week interval exceeded 0.90 for the total modified UPDRS score, ranged from 0.70 to 0.95 for the four domain scores, and exceeded 0.90 for the global parkinsonian sign score. Ratings of parkinsonian signs by nurse clinicians corresponded closely to those of a neurologist with expertise in movement disorders and showed good inter-rater agreement and temporal stability. With appropriate training, nurse clinicians can reliably administer the modified UPDRS.