Magnus A. McGee

Staging of Cytoskeletal and β-Amyloid Changes in Human Isocortex Reveals Biphasic Synaptic Protein Response during Progression of Alzheimer’s Disease

We have examined the relationships between dementia, loss of synaptic proteins, changes in the cytoskeleton, and deposition of beta-amyloid plaques in the neocortex in a clinicopathologically staged epidemiological cohort using a combination of biochemical and morphometric techniques. We report that loss of synaptic proteins is a late-stage phenomenon, occurring only at Braak stages 5 and 6, or at moderate to severe clinical grades of dementia. Loss of synaptic proteins was seen only after the emergence of the full spectrum of tau and beta-amyloid pathology in the neocortex at stage 4, but not in the presence of beta-amyloid plaques alone. Contrary to previous studies, we report increases in the levels of synaptophysin, syntaxin, and SNAP-25 at stage 3 and of alpha-synuclein and MAP2 at stage 4. Minimal and mild clinical grades of dementia were associated with either unchanged or elevated levels of synaptic proteins in the neocortex. Progressive aggregation of paired helical filament (PHF)-tau protein could be detected biochemically from stage 2 onwards, and this was earliest change relative to the normal aging background defined by Braak stage 1 that we were able to detect in the neocortex. These results are consistent with the possibility that failure of axonal transport associated with early aggregation of tau protein elicits a transient adaptive synaptic response to partial de-afferentation that may be mediated by trophic factors. This early abnormality in cytoskeletal function may contribute directly to the earliest clinically detectable stages of dementia.

Population norms for the MMSE in the very old Estimates based on longitudinal data

Objective To report the percentile distribution of Mini-Mental State Examination (MMSE) scores in older people by age, sex, and education level, estimated from longitudinal data, after correcting for loss due to dropout. Methods The Cambridge City over 75 Cohort is a population-based study of a cohort of 2106 subjects age 75 years and older at study entry followed up over 9 years. At each of the four waves, cognitive function was assessed using MMSE. Based on these data, the relationship between age and MMSE score was modeled. Percentile distributions by age, sex, and education level were provided using inverse probability weighting to correct for dropouts. Results Performance on MMSE was related to age in men and women. In women, at age 75, MMSE score ranged from 21 (10th percentile) to 29 (90th percentile). At age 95, the range was 10 (10th percentile) to 27 (90th percentile). The upper end of MMSE distribution was slightly modified with age, whereas the lower end of the distribution was very sensitive to age effect. A similar pattern was observed in both sexes. Conclusion These findings provide norms for MMSE scores in subjects age 75 years and older from longitudinal population-based data. Such norms can be used as reference values to determine where an individuals score lies in relation to his or her age, sex, and education level.

DECLINE ACROSS DIFFERENT DOMAINS OF COGNITIVE FUNCTION IN NORMAL AGEING) RESULTS OF A LONGITUDINAL POPULATION! BASED STUDY USING CAMCOG

Dementia is an important cause of disability in the elderly. There is evidence that cognitive impairment in dementia is on a continuum with cognitive impairment in the non‐demented elderly. In order to investigate this possibility, we need detailed knowledge about the population distribution of cognitive function and change in cognitive function. The aim of this study is to describe the change in different domains of cognitive function over 4 years in a population‐based sample of non‐demented elderly people, and to investigate the effect of sociodemographic variables and baseline cognitive function on change in each of the cognitive domains. Respondents from two group general practice lists (n=503) were interviewed using the Cambridge Cognitive Examination (CAMCOG) at the incidence wave of the Cambridge City Over‐75 Cohort Study and after a mean time period of 3.9 years. One hundred and thirty five of 212 non‐demented subjects seen at follow‐up completed the CAMCOG at both interviews. The annual rate of change in total CAMCOG score was −1.6 points per year (p<0.001). There was statistically significant decline in all of the CAMCOG subscales. Greater decline in the Memory subscale was associated with less education (p=0.03). Greater decline in the Attention/Calculation subscale was associated with manual social class (p=0.05). Greater decline in the Perception subscale was associated with older age (p=0.03). Decline in specific cognitive domains may indicate a reversible phase of cognitive impairment and deserves further investigation. Copyright

Neuropathological Findings in the Very Old: Results from the First 101 Brains of a Population-based Longitudinal Study of Dementing Disorders

Abstract: We report a unique longitudinal epidemiological study of cognitive decline in the elderly population of the city of Cambridge, UK. A population sample of people aged 75 and over was surveyed between 1984–1996 (n= 2,616) and followed 2.4, 6, and 9 years later. CAMDEX diagnostic criteria were used for clinical assessment, and the neuropathological protocol (in 101 cases) was based on the CERAD method, with additional features to allow Braak staging of neurofibrillary pathology. The main findings are of the heterogeneity of lesions to be found in very old populations, and the existence of considerable overlap in the pathologies found in the demented and nondemented. It seems that white matter (ischemic) pallor an amyloid angiopathy, as well as neuritic plaques, neurofibrillary tangles and Lewy body formation are all lesions that increase the likelihood of dementia.

Examination of the validity of the hierarchical model of neuropathological staging in normal aging and Alzheimer's disease.

Abstract The neuropathological staging model of Alzheimer’s disease proposed by Braak and Braak [Acta Neuropathol (1991) 82 : 259] requires that the evolution of neurofibrillary pathology follows a predictable pattern that can be ordered in a regular regional hierarchy. We have operationalized the neuropathological staging system to permit testing of its validity. Forty-two cases were derived from an epidemiological study of cognitive function in an elderly population for which post-mortem brain tissue was collected. Cases with neuropathological diagnoses other than Alzheimer’s disease and normal aging were excluded. Neurofibrillary tangle counts were determined in all cortical laminae and regions used for staging. There was a significant correlation between the overall extent of neurofibrillary pathology and the number of regions affected. There were frequent order violations in the proposed hierarchy: 19 instances (45%) involving entorhinal and transentorhinal cortices, and 16 instances (38%) involving CA1 of hippocampus and entorhinal cortex. Only 6 out of 42 cases conformed in all regions to the expected hierarchy. Nevertheless, 90% of the cases had 2 order violations or less, supporting the approximate validity of the hierarchy.

Estimating the true extent of cognitive decline in the old old

OBJECTIVE: To measure cognitive change using a brief measure over a period of 9 years and to adjust for attrition in the sample.

The relationship between clinical dementia and neuropathological staging (Braak) in a very elderly community sample

The neuropathological staging model proposed by Braak and Braak (1991) implies that the evolution of neurofibrillary pathology follows a predictable sequence and can be ordered in a regular regional hierarchy. A total of 42 cases of an elderly population sample, which had been prospectively clinically assessed, were examined. Clinical diagnosis was made according to the CAMDEX criteria, and the sample reported here did not include cases were vascular dementia according to the criteria proposed by Chui et al. (1991). The neuropathological staging procedure was applied as originally proposed by Braak and Braak (1991). In addition, in all cortical laminae and regions which are essential for the staging model neurofibrillary tangles were quantified. Demented cases had significantly more areas involved and more advanced neuropathological stages. Cases with stages 1–3 tended to be non-demented, and cases with stages 4–6 tended to be demented. However, there was a considerable degree of overlap and no clear-cut threshold could be established. This brings into question the diagnostic value of the staging model.

Lewy Body Variant of Alzheimer's Disease: Selective Neocortical Loss of t-SNARE Proteins and Loss of MAP2 and α-Synuclein in Medial Temporal Lobe

Lewy bodies (LBs) appear in the brains of nondemented individuals and also occur in a range of neurodegenerative disorders, such as dementia with Lewy bodies (DLB) and Parkinsons disease. A number of people with a definite diagnosis of Alzheimers disease (AD) also exhibit these intraneuronal inclusions in allo- and/or neocortical areas. The latter, referred to as Lewy body variant of AD (LBV), bears a clinical resemblance to AD in terms of age at onset, duration of illness, cognitive impairment, and illness severity. Since the presence of LBs is accompanied by neuronal cytoskeleton changes, it is possible that the latter may influence neuronal connectivity via alterations to the synaptic network. To address this, we examined the expression of synaptic proteins (synaptophysin, syntaxin, SNAP-25, and α-synuclein) and two cytoskeletal proteins (tau and MAP2) in the brain tissue of subjects enrolled in a population-based autopsy study (n = 47). They were divided into groups with no memory problems (control group, n = 15), LBV (n = 5), AD devoid of LBs (n = 17), cerebrovascular dementia (n = 3), and mixed dementia (n = 7). The LBV and AD groups had a similar degree of cognitive impairment and neuropathological staging in terms of Braak staging and CERAD score. In comparison with the control group and the dementia groups without LBs, the LBV group had significantly lower levels of syntaxin and SNAP-25 (23%) in the neocortex, and depletion of MAP2 (64%), SNAP-25 (34%), and α-synuclein (44%) proteins in the medial temporal lobes. These findings suggest that the t-SNARE complex deficit present in LBV may be associated with the presence of LB-related pathology and may explain the more profound cholinergic loss seen in these patients.