Statistical Methods for Health Care Research

Background Mild cognitive impairment (MCI) is considered to be a transitional stage between aging and Alzheimer disease (AD). Objective To determine whether MCI represents early-stage AD by examining its natural history and neuropathologic basis. Design A prospective clinical and psychometric study of community-living elderly volunteers, both nondemented and minimally cognitively impaired, followed up for up to 9.5 years. Neuropathologic examinations were performed on participants who had undergone autopsy. Setting An AD research center. Participants All participants enrolled between July 1990 and June 1997 with Clinical Dementia Rating (CDR) scores of 0 (cognitively healthy; n = 177; mean age, 78.9 years) or 0.5 (equivalent to MCI; n = 277; mean age, 76.9 years). Based on the degree of clinical confidence that MCI represented dementia of the Alzheimer type (DAT), 3 subgroups of individuals with CDR scores of 0.5 were identified: CDR 0.5/DAT, CDR 0.5/incipient DAT, and CDR 0.5/uncertain dementia. Main Outcome Measure Progression to the stage of CDR 1, which characterizes mild definite DAT. Results Survival analysis showed that 100% of CDR 0.5/DAT participants progressed to greater dementia severity over a 9.5-year period. At 5 years, rates of progression to a score of CDR 1 (or greater) for DAT were 60.5% (95% confidence interval [CI], 50.2%-70.8%) for the CDR 0.5/DAT group, 35.7% (95% CI, 21.0%-50.3%) for the CDR 0.5/incipient DAT group, 19.9% (95% CI, 8.0%-31.8%) for the CDR 0.5/uncertain dementia group, and 6.8% (95% CI, 2.2%-11.3%) for CDR 0/controls. Progression to greater dementia severity correlated with degree of cognitive impairment at baseline. Twenty-four of the 25 participants with scores of CDR 0.5 had a neuropathologic dementing disorder, which was AD in 21 (84%). Conclusions Individuals currently characterized as having MCI progress steadily to greater stages of dementia severity at rates dependent on the level of cognitive impairment at entry and they almost always have the neuropathologic features of AD. We conclude that MCI generally represents early-stage AD.

https://www.cbsnews.com/htdocs/pdf/alzheimer.pdf

Mild cognitive impairment represents early-stage Alzheimer disease.

The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were ∼650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by ∼90%, and the number of neurons in layer IV decreased by ∼70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging.

https://www.jneurosci.org/content/jneuro/16/14/4491.full.pdf

Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease

The distribution and density of neurofibrillary tangles and amyloid plaques was studied in a unique series of cases whose premortem cognitive status had been assessed with the Clinical Dementia Rating (CDR), including 39 nondemented cases (CDR 5 0; age, 51‐ 88 years), 15 very mildly demented cases (CDR 5 0.5), and 8 severely demented (CDR 5 3) cases. The initial formation of tangles and plaques in healthy aging appeared to be independent of each other. Tangles were found in all the nondemented cases, especially in hippocampal and parahippocampal areas; the average tangle concentration increased exponentially with age. In contrast, plaques were absent in some brains up to age 88, and the earliest plaque formation in other cases occurred in the neocortex, in patches of diffuse plaques. Widely distributed neuritic as well as diffuse plaques throughout neocortex and limbic structures characterized a further group of nondemented cases. In these cases there was also a substantial increase over other nondemented cases, both in the number of tangles and in the rate of increase in tangles with age, suggesting an interaction between amyloid and neurofibrillary change at this stage. Such cases closely resemble CDR 5 0.5 cases, and it is proposed they represent “preclinical” Alzheimer’s disease. Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 1999;45:358 ‐368 It is generally recognized that the incidence of Alzheimer’s disease (AD) is age related, increasing exponentially after the sixth decade of life. 1 Neurofibrillary tangles and b-amyloid plaques are commonly reported to occur in the brains of aged individuals, even without clinical criteria for AD. 2‐ 4 Despite this, recent studies have suggested that when AD or other disorders are carefully excluded, aging itself may not result in substantial cognitive or neuronal loss. 5‐7 In contrast, even the mildest stage of dementing change may indicate the presence of AD, as supported by sufficient plaques and tangles for pathological diagnosis of the disease, 8,9 and substantial neuronal loss in vulnerable areas such the entorhinal cortex 6 . To define the pattern of tangle and plaque formation during healthy aging, it is necessary to identify and study individuals without even very slight cognitive or memory impairment. We have an opportunity to study these issues, because of availability of a unique series of nondemented and very mildly demented cases who were assessed with the Clinical Dementia Rating (CDR). 10 This instrument is sensitive enough to identify nondemented cases accurately, as well as to recognize the earliest clinically detectable stage of AD (CDR 5

Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease

The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques-which are frequently surrounded by dystrophic neurites-and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.

/pdf/epidemiology-of-alzheimer-disease-4jbouco1i1.pdf

Epidemiology of Alzheimer disease

The Internet (electronic mail and the World Wide Web) may provide new opportunities for communication that can help older adults avoid social isolation. This randomized controlled trial assessed the psychosocial impact of providing Internet access to older adults over a five-month period. One hundred volunteers from four congregate housing sites and two nursing facilities were randomly assigned to receive Internet training or to a wait list control group. The pre & post measures included the UCLA Loneliness scale, modified CES Depression scale, a measure of locus of control, computer attitudes, number of confidants, and overall quality of life. Participants received nine hours of small group training in six sessions over two weeks. Computers were available for continued use over five months and the trainer was available two hours/week for questions. At the end of the trial, 60% of the intervention group continued to use the Internet on a weekly basis. Although there was a trend toward decreased loneliness and depression in intervention subjects compared to controls, there were no statistically significant changes from baseline to the end of trial between groups. Among Internet users (n = 29) in the intervention group there were trends toward less loneliness, less depression, more positive attitudes toward computers, and more confidants than among intervention recipients who were not regular users (n = 19) of this technology. Most elderly participants in this trial learned to use the Internet and the majority continued to use it on a weekly basis. The psychosocial impact of Internet use in this sample suggested trends in a positive direction. Further research is needed to determine more precisely, which older adults, residing in which environmental contexts are more likely than others to benefit from this rapidly expanding information and communication link.

A randomized controlled trial of the psychosocial impact of providing internet training and access to older adults.

OBJECTIVE: To describe weight loss in relation to the severity of Alzheimer's disease (AD), to identify confounders that might account for weight loss, and to investigate the association of weight change with mortality.



METHODS: This study included 666 subjects with AD from the Consortium to Establish a Registry for Alzheimer's Disease, a longitudinal study of subjects with AD studied for ≤6 years. Body weight was measured on entry and at annual follow-up examinations as part of standardized clinical assessments. Hierarchical linear models were used to estimate weight change per change in stage of AD, as measured by the Clinical Dementia Rating scale, and to assess the impact of possible confounders on the tendency for weight loss. Linear correlation of the trajectories of weight and CDR over time were used to determine the association between weight change and stage change. The association between weight change and mortality was modeled using the Cox proportional hazards model.



RESULTS: Each change in stage of AD was associated with an estimated average weight loss of nearly 2 lb (P = .0001). The correlation between change in stage of AD and weight change was statistically significant (r = −0.09, P = .005), which indicates a greater tendency toward weight loss with progression of AD. Weight loss of 2:5% in any year before death was a significant predictor of mortality. When weight loss in the year before death or censoring was analyzed as a continuous variable, it was a significant predictor of mortality. Additionally, the relative risk of death increased as weight loss increased. In contrast, weight gain decreased the risk of mortality.



CONCLUSION: The risk of weight loss tends to increase with severity and progression of AD. Weight loss is a predictor of mortality among subjects with AD, whereas weight gain appears to have a protective effect.

The Association of Weight Change in Alzheimer's Disease with Severity of Disease and Mortality: A Longitudinal Analysis

Rationale: Acute nicotine injections have been found to improve attentional performance in patients with Alzheimer’s disease (AD), but little is known about chronic nicotine effects. Objective: The present study was undertaken to evaluate the clinical and neuropsychological effects of chronic transdermal nicotine in Alzheimer’s disease subjects over a 4-week period. Methods: The double-blind, placebo controlled, cross-over study consisted of two 4-week periods separated by a 2-week washout period. Patients wore the nicotine patch (Nicotrol®) for 16 h a day at the following doses: 5 mg/day during week 1, 10 mg/day during weeks 2 and 3 and 5 mg/day during week 4. The eight subjects had mild to moderate AD and were otherwise healthy. Results: Nicotine significantly improved attentional performance as measured by the Conners’ continuous performance test (CPT). There was a significant reduction in errors of omission on the CPT which continued throughout the period of chronic nicotine administration. The variability of hit reaction time (reaction time for correct responses) on the CPT was also significantly reduced by chronic nicotine. Nicotine did not improve performance on other tests measuring motor and memory function. Conclusions: The sustained improvement in attention found in this study with nicotine dermal patches is encouraging. However, the lack of detected effects of nicotine treatment on other cognitive and behavioral domains in this study leaves questions concerning the clinical impact of nicotinic treatment in Alzheimer’s disease. The modest size of this study limited statistical power which may have been needed to detect more subtle but clinically significant cognitive effects. Higher doses of nicotine, other nicotinic ligands or combination treatment of nicotine with other therapies may be efficacious for producing broader therapeutic effects.

Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease

The clinical course of advanced dementia.

The Internet offers new opportunities for communication that can help older adults avoid social isolation. Although elders may need more time and assistance in learning computer systems, many are embracing this new technology. There is growing potential not only for recreation and communication through the Internet but also the delivery of services. This study examines the feasibility of providing Internet and electronic mail access to older adults in a retirement community and the extent to which this improves psychosocial well-being. In contrast to members of a comparison group, a trend toward decreased loneliness was observed among participants. In addition, the number of computer-related problems decreased and use of the applications increased throughout the study. These preliminary results support the feasibility of implementing computer-based interventions with the potential of improving psychosocial well-being among older adults.

Heidi K. White

Papers

A randomized controlled trial of the psychosocial impact of providing internet training and access to older adults.

The Association of Weight Change in Alzheimer's Disease with Severity of Disease and Mortality: A Longitudinal Analysis

Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease

The clinical course of advanced dementia.

Surfing the Net in Later Life: A Review of the Literature and Pilot Study of Computer Use and Quality of Life