L. Barnetson

Relative Roles of Plaques and Tangles in the Dementia of Alzheimer's Disease: Correlations Using Three Sets of Neuropathological Criteria

We have performed a quantitative analysis of the amyloid load (plaques), neuritic plaques and neurofibrillary tangles (NFT) in the frontal, temporal and parietal association cortices of autopsied brains from 49 prospectively evaluated patients with Alzheimers disease (AD) diagnosed according to three sets of published pathological criteria. These patients had been assessed clinically with psychological testing of cognitive abilities within 6 months of death. Correlations were sought between severity of pathological change and cognitive status before death, duration of disease and age at death. Using Khachaturian and CERAD criteria highly positive correlations were obtained between the extent of cognitive deficit and the density of NFT in frontal and parietal lobes. The percentage area of cortex occupied by amyloid in the parietal lobe was correlated to the cognitive deficit only in the CERAD-diagnosed cases. The density of all amyloid plaques (AP) showed no correlation with the extent of cognitive deficit, but the densities of neuritic plaques did correlate with cognitive deficit. Both amyloid load and tangle densities were positively correlated with disease duration. All these correlations were reduced or absent in a subgroup of cases fulfilling the Tierney et al. A3 diagnostic criteria for AD. We found no pathological measure that correlated with the age of patients at death. Amyloid loads and NFT densities showed highly significant but selective positive correlations, the most striking being between temporal lobe NFT density and frontal and parietal lobe amyloid load and between temporal lobe NFT density and frontal and parietal lobe NFT densities. Correlations involving AP density as a measure of amyloid load were almost always less significant than those involving the percentage area of cortex occupied by amyloid, suggesting that the latter measures amyloid load more accurately. However, the highest correlations of NFT densities were with neuritic plaque densities. Overall this study highlights the relevance of neuritic changes (revealed by NFT and neuritic plaques) and the irrelevance of amyloid plaques to the dementia of AD.

Plasma Total Homocysteine and Cognitive Performance in a Volunteer Elderly Population

Case-control studies have demonstrated associations between moderately elevated blood levels of total homocysteine (tHcy) and cerebrovascular disease,1 vascular dementia,2–4 and Alzheimer’s disease.3–5 Clarke et al.3 showed an association between elevated tHcy, low levels of folate and vitamin B12, and histopathologically confirmed Alzheimer’s disease. However, the influence of elevated tHcy levels or its biologic determinants on cognitive performance in the normal elderly and on the development of cognitive impairment or its progression to dementia is not well established. Riggs et al.6 and La Rue et al.7 have suggested that levels of plasma homocysteine, vitamin B12, and folate may exert differential effects on cognitive abilities. Recently, Jensen et al.8 reported negative relationships between elevated tHcy levels (>15 μmol/L) and a broad range of cognitive, quality of life, and psychologic variables in 80-year-old subjects. However, these studies could not assess whether these associations were independent of differences in age, gender, IQ, and depression. Furthermore, it is important to explore the relationship between tHcy and cognitive performance as continuous variables, rather than as dichotomous variables. The aim of this study was to examine the influence of plasma tHcy levels on global cognitive performance in 156 elderly community volunteers.

Accuracy of Clinical Operational Diagnostic Criteria for Alzheimer’s Disease in Relation to Different Pathological Diagnostic Protocols

In this study we analysed the accuracy of two sets of clinical diagnostic criteria, the NINCDS/ADRDA and DSM-III-R, in relation to the currently used pathological diagnostic criteria for Alzheimer’s disease (AD), the Khachaturian criteria, the Tierney A3 criteria and the CERAD protocol. The sensitivity of the individual clinical diagnostic criteria, NINCDS/ADRDA and DSM-III-R, is poor (34–58%) irrespective of the pathological diagnostic criteria applied for the definite diagnosis of AD. The combination of the NINCDS/ADRDA ‘possible’ and ‘probable dementia of the Alzheimer type’ (DAT) categories has a high sensitivity (91–98%). However the combination resulted in very poor specificity (40–61%). Thus, none of the clinical diagnostic criteria is satisfactory. We found similar results when we analysed the predictive value of these clinical diagnostic criteria. The positive predictive value of NINCDS ‘probable DAT’ category and that of the DAT diagnosis by DSM-III-R is very high (89–100%). This makes the use of these categories suitable for research purposes. However, the negative predictive value of both diagnoses is poor (33–63%), making these criteria unsuitable for diagnostic purposes in clinical practice.

The Progression of Alzheimer’s Disease from Limbic Regions to the Neocortex: Clinical, Radiological and Pathological Relationships

Alzheimer’s disease (AD) is characterised by the gradual accumulation of neurofibrillary pathology in selected regions of the brain. Earlier studies indicate that the accumulation of neurofibrillary tangles is associated both with decline in patient’s cognitive performance as well as with medial temporal lobe atrophy on CT scans. There are also indications that progression through the pathological stages of AD is associated with decline in cognitive functions. The results of this study indicate that progression of disease, especially beyond the boundaries of the limbic regions, is associated with marked decline in the cognitive performance of patients suffering from AD. However the clinical manifestations of early pathological stages are not so well defined. We also found that the atrophy of the medial temporal lobe on CT scans is related to the progression of pathology. Atrophy is most apparent when the disease reaches its isocortical stages and is not marked in the limbic stages of the disease. The additive effect of pathologies co-existing with AD is apparent in reduced cognitive scores, while the atrophy of limbic structures, as measured on CT scans, seems to be mainly attributable to AD-related pathology.

Hippocampal Pathology Reflects Memory Deficit and Brain Imaging Measurements in Alzheimers Disease: Clinicopathologic Correlations Using Three Sets of Pathologic Diagnostic Criteria

Neurofibrillary tangles (NFT), neuritic plaques and amyloid load were quantified in sections of the hippocampus at the level of the lateral geniculate body in 41 consecutive cases fulfilling pathological criteria for diagnosis of Alzheimers disease (AD) and coming to autopsy after longitudinal study during life. A strong correlation was found between NFT density in the hippocampus and cognitive impairment scores obtained shortly before death, particularly with scores of memory impairment. Weaker and less consistent correlations were found for hippocampal neuritic plaques and amyloid load with cognitive/memory deficits. No significant correlations were found between hippocampal pathology and either age of onset or disease duration. All three measures of hippocampal pathology were inversely correlated with the minimum medial temporal lobe (MTL) width, a measure of the MTL atrophy made from temporal-lobe-oriented X-ray computed tomography scans performed during life; the strongest correlation being between atrophy of the MTL and NFT density in the hippocampus.

Relationship between Clinical and Radiological Diagnostic Criteria for Alzheimer’s Disease and the Extent of Neuropathology as Reflected by ‘Stages’: A Prospective Study

The distribution of pathology related to Alzheimer’s disease (AD) is not uniform throughout the brain. Sites which have a predilection for the development of Alzheimer-type pathology are the limbic regions and neocortical association areas. The changes in these areas of the brain develop gradually, following a well-determined sequence that allows a pathological staging of the disease process. According to the staging hypothesis, the first pathological alterations develop in the transentorhinal and entorhinal regions. The neurofibrillary pathology then spreads into the hippocampus, but not until the final stages does it affect the neocortex. In this study we analyse the relationship between the pathological stages of AD, according ot the staging hypothesis, and the clinical diagnosis in a prospectively assessed patient group. Prediction of any given pathological stage from the clinical diagnosis was found to be poor. This may be partly due to the fact that additional pathologies can alter the clinical picture and severity of dementia in patients who are only in the initial stages of AD. Nevertheless, the NINCDS-ADRDA clinical criteria had a high sensitivity for detection of AD-related pathology: the ‘probable AD’ category included 22/38 (57.9%) of those in the late isocortical stage, while the ‘possible AD’ category included 19/23 (82.6%) of those in the limbic stage. Using proposed neuro-imaging protocols for improved identification of patients with AD-related pathology, we largely identified subjects in whom the extent of pathology had spread to the neocortex.

Diagnosing Dementia: Interrater Reliability Assessment and Accuracy of the NINCDS/ADRDA Criteria versus CERAD Histopathological Criteria for Alzheimer’s Disease

We investigated the interrater reliability and accuracy of two independent medical doctors in using NINCDS/ADRDA criteria to classify 82 elderly subjects enrolled in OPTIMA, a longitudinal study investigating dementia. Kappa statistics revealed moderate agreement (0.5) in overall classification of dementia type, and almost perfect agreement (0.9) on the absence or presence of dementia. Combining NINCDS/ADRDA ‘possible’ and ‘probable’ Alzheimer’s disease (AD) categories produced substantial agreement (0.7). Comparison with CERAD histopathological criteria for AD showed that combining ‘possible’ and ‘probable’ AD resulted in a high sensitivity and accuracy, but a low specificity. To increase specificity, the NINCDS/ADRDA ‘probable AD’ category should be used alone. An important finding was that the accuracy of diagnoses of AD made from the case notes alone was not different from the diagnoses obtained following active involvement with participants.

Constructional Apraxia in Alzheimer’s Disease: Association with Occipital Lobe Pathology and Accelerated Cognitive Decline

The functional impact and progression of occipital lobe pathology in sporadic late onset Alzheimer’s disease (AD) is barely explored. It is accepted that the primary and association visual areas are affected relatively late, in the neocortical stages of AD. We analysed 60 prospectively assessed AD patients in whom global cognitive deterioration and constructional apraxia were evaluated longitudinally using the CAMDEX. Radioactive immunohistochemistry was used to assess the amount of AD-related pathology in Brodmann areas 18 and 17. Braak staging of each case was also carried out. This study showed that in AD patients constructional apraxia is associated with higher expression of hyperphosphorylated tau. Additionally our findings indicate that early constructional apraxia is a predictor of accelerated cognitive decline in AD.

Leukoaraiosis at Presentation and Disease Progression during Follow‐up in Histologically Confirmed Cases of Dementia

While Alzheimer’s disease and vascular dementia have distinct histopathological features, the combination of both may result in more severe symptoms of dementia.1,2 The effect of concomitant cerebrovascular disease or cerebrovascular risk factors on the clinical course of Alzheimer’s disease is uncertain. Leukoaraiosis, the bilateral symmetrical white matter lucencies visible on computed tomography (CT), is common in very elderly people and in patients with vascular dementia and Alzheimer’s disease.3 Leukoaraiosis is more common among individuals with a prior history of stroke, or cardiovascular risk factors,3 which has prompted many to consider that leukoaraioisis is a radiological correlate of small vessel disease. There is little histopathological evidence to substantiate this and, indeed, the pathological correlates of leukoaraiosis are by no means clear and may well reflect several different processes.4,5 The aim of this longitudinal clinicopathological study was to examine the prevalence of leukoaraiosis on CT at presentation among histological subtypes of dementia and assess their relevance to clinical progression of dementia.

Coexisting pathologies in the brain: influence of vascular disease and Parkinson's disease on Alzheimer's pathology in the hippocampus.

Abstract The finding of more than one coexisting brain pathology in dementia sufferers is not unusual. However, it is unclear how these different diseases may interact or influence the evolution of one another. In this study we analyse the hippocampal expression patterns of hyperphosphorylated tau, paired helical filament (PHF)-related protein, β-amyloid and synaptophysin in a group of Alzheimer’s disease (AD) sufferers with and without additional pathology. Compared to cases with only AD-type pathology we found that the presence of additional vascular disease augmented the accumulation of hyperphosphorylated tau in the CA1 region of the hippocampus without affecting PHF formation in cases with mild AD changes and reduced the extent of PHF formation in the CA2/3 and CA4 regions of the hippocampus in cases with severe AD pathology. We also found that synaptophysin immunoreactivity in the CA4 and dentate gyrus in pure AD was inversely related to the extent of amyloid accumulation but not to neurofibrillary pathology in the same regions. These relationships were lost when additional pathology was present. Memory scores obtained during life correlated closely with hyperphosphorylated tau and PHF-related protein expression in CA1 in pure AD but not in AD with additional pathology. Total amyloid and synaptophysin expression in the hippocampus did not correlate with memory scores in any patient group. Our findings suggest that the interactions of two pathologies in the hippocampus are complex and may differ depending on the stage reached in the evolution of a progressive disease such as AD.