A D Smith

The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease

The Hordaland Homocysteine Study (HHS) is a population-based study of more than 18,000 men and women in the county of Hordaland in Western Norway. The first investigation (HHS-I) took place in 1992-93, when the subjects were aged 40-67 y. In 1997-99, a follow-up study (HHS-II) of 7,053 subjects was carried out. In this large population, plasma levels of total homocysteine (tHcy) are associated with several physiologic and lifestyle factors and common diseases. Increasing age, male sex, smoking, coffee consumption, high blood pressure, unfavorable lipid profile, high creatinine, and the MTHFR 677C > T polymorphism are among the factors associated with increased tHcy levels; physical activity, moderate alcohol consumption, and a good folate or vitamin B-12 status are associated with lower tHcy levels. Subjects with raised tHcy levels have increased risk of cardiovascular morbidity, cardiovascular and noncardiovascular mortality, and are more likely to suffer from depression and from cognitive deficit (elderly). Among women, raised tHcy levels are associated with decreased bone mineral density and increased risk of osteoporosis. Women with raised tHcy levels also have an increased risk of having suffered from pregnancy complications and an adverse pregnancy outcome. Significant associations between tHcy and clinical outcomes are usually observed for tHcy levels > 15 micromol/L, but for most conditions, there is a continuous concentration-response relation with no apparent threshold concentration. Overall, the findings from HHS indicate that a raised tHcy level is associated with multiple clinical conditions, whereas a low tHcy level is associated with better physical and mental health.

Cell cycle markers in the hippocampus in Alzheimer’s disease

Abstract Using immunohistochemistry we have analysed the nuclear expression of cyclins A, B, D, and E in neurones in the hippocampi of control subjects and patients suffering from various neurodegenerative disorders including Alzheimer’s disease (AD). Cyclins A and D could not be detected but varying degrees of cyclin E expression were found in all patient groups including control subjects. Cyclin B expression was not detected in control subjects but it was expressed in the subiculum, dentate gyrus and CA1 region in patients with AD-type pathology and in the CA2 region and the dentate gyrus of cases of Pick’s disease. These reults suggest that some neurones may have re-entered the cell cycle. The expression of cyclin E without cyclin A expression may indicate an arrest in G1 with the possibility of re-differentiation and exit from G1 to G0. The expression pattern of cyclin E indicates that re-entry into the cell cycle is possible even in control patients, but it is accentuated in patients with AD-related pathology. However, cyclin B was only expressed in AD patients and occurred in areas that were severely affected by pathology. Neurones with cyclin B-reactive nuclei in AD were AT8 positive but did not contain fully developed tangles. In neurones, where cyclin B is expressed, it would appear that the G1/S checkpoint has been bypassed and that the cell cycle is arrested in G2. It is proposed that these neurones do not have the opportunity for subsequent re-differentiation. Since factors known to be present in G2 seem to be responsible for microtubule destabilisation and hyperphosphorylation of tau we hypothesise that cell cycle disturbances may be important in the pathogenesis of AD.

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.

Detection in life of confirmed Alzheimer's disease using a simple measurement of medial temporal lobe atrophy by computed tomography

The medial temporal lobe of the brain is important for normal cognitive function, notably for memory, and is the region with the most extensive pathological change in Alzheimers disease (AD). We wanted to find out if atrophy of the medial temporal lobe could be detected in life in patients in whom a diagnosis of AD was subsequently established histopathologically. The minimum width of the medial temporal lobe, measured by temporal-lobe-oriented computed tomography (CT) about one year before death, in 44 patients with a histopathological diagnosis of AD (cases) was nearly half (0.56 of the median) that in 75 controls of the same age with no clinical evidence of dementia (95% confidence interval 0.51-0.61). There was little overlap between the distributions of measurements in cases and controls. A cut-off (< 0.79 MoM) selected to yield a 5% false-positive rate gave an expected detection rate of 92%. A cut-off selected to yield a false-positive rate of 1% (< 0.70 MoM) yielded a 79% detection rate. 20 of the 44 patients with histopathologically diagnosed AD had been scanned more than once before death, and the test (cut-off < 0.79 MoM) was positive in all 20 more than a year before and in 9/10 more than 2 years before death. In 10 subjects with dementia but with histopathology excluding AD, the mean minimum width of the medial temporal lobe was significantly greater than that in the cases with AD, but was not significantly different from that in controls. Medial temporal lobe CT is a non-invasive, rapid, simple and effective test for AD which could have immediate application firstly in improving the accuracy of prevalence and incidence studies and, secondly, for the identification of groups of high-risk patients in the evaluation of novel treatments for AD. In the future, it could be applied as a screening test.

Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer’s disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions

Abstract Recent studies, showing that cell cycle-related nuclear proteins p105 and Ki-67 are associated with Alzheimer’s disease (AD)-related cytoskeletal pathology, suggested that these proteins, in addition to their functions in regulating the cell cycle, may have more specialised functions in the adult nervous system. In order to test this hypothesis we studied the expression of the cell cycle-related proteins Ki-67, pCNA and p53 in the hippocampi of 33 subjects, including some with AD or other neurodegenerative disorders and some with no neurological disease. By immunohistochemistry we found nuclear expression of Ki-67 in all subregions of the hippocampus, with the highest levels in the dentate gyrus. Both neurons and glial cells expressed this protein. The proportion of cells positive for Ki-67 and the distribution pattern varied considerably depending on the pathological diagnosis. Neuronal nuclear expression of Ki-67 was increased in AD but was also elevated in young Down’s syndrome subjects and in those with Pick’s disease. Expression of this protein was therefore not AD-specific. We did not find nuclear pCNA or p53 expressed in our patient groups. Contrary to previous studies AD-type neurofibrillary tangles were not labelled with any of the cell cycle markers used. The presence of nuclear Ki-67 expression indicates that some hippocampal neurons are not in the quiescent G0 phase but have re-entered the cell cycle. The absence of nuclear pCNA or p53 suggests that the cycle is arrested in G1. The significance of our findings and their relationship to the production of neurodegenerative cell death via an apoptotic mechanism are discussed.

Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease

The effect of the apolipoprotein E genotype on the development of late onset Alzheimers disease is still debated. Neuropathological studies of Alzheimers disease have found a great extent of amyloid deposition in cortex and blood vessel walls in association with the apolipoprotein E epsilon 4 genotype [Rebeck G. W. et al. (1993) Neuron 11, 575-580; Schmechel et al. (1993) Proc. natn. Acad. Sci. U.S.A. 90, 9649-9653]. In contrast, the relationship of apolipoprotein E genotype to neurofibrillary pathology in Alzheimers disease has been less clear. In this study we present evidence on the influence of the apolipoprotein E genotype on Alzheimers disease related pathology in a series of 76 autopsy cases that had pathology that fulfilled the CERAD criteria for Alzheimers disease. We found that the presence of the apolipoprotein E epsilon 4 allele is correlated with increased amounts of both amyloid and neuritic pathology in the neocortex as determined using an image analysis system. Comparison of plaque and tangle densities with the allele doses of epsilon 2 and epsilon 4 revealed a striking parallelism, suggesting that the alleles exert their effects very early in the pathological process before deposition of plaques and tangles. Although the apolipoprotein E epsilon 2 allele had a protective effect against both amyloid deposition and neurofibrillary tangle formation, in the presence of the epsilon 4 allele this protective effect against neuritic pathology was less marked than against amyloid deposition. This differential effect on amyloid deposition and the accumulation of neuritic pathology suggests that different molecular mechanisms are involved in the effect of apolipoprotein E on amyloid deposition and on tau phosphorylation.

SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study.

Objective: Numerous studies have suggested that temporoparietal hypoperfusion seen on brain imaging with SPECT may be useful in diagnosing AD during life. However, these studies have often been limited by lack of pathologic validation and unrepresentative samples. The authors performed this study to determine whether SPECT imaging provides diagnostically useful information in addition to that obtained from a clinical examination. Methods: Clinical data and SPECT images were collected prospectively, and patients were followed to autopsy. Clinical history, pathologic findings, and SPECT images were each evaluated by raters blind to other features, and clinical and SPECT diagnoses were compared with pathologic diagnoses. The study population consisted of 70 patients with dementia, followed to autopsy; 14 controls followed to autopsy; and 71 controls (no autopsy performed). The primary outcome was the likelihood of a pathologic diagnosis of AD given a positive clinical diagnosis, a positive SPECT diagnosis, and both. Results: When all participants (patients and controls) were included in the analysis, the clinical diagnosis of “probable” AD was associated with an 84% likelihood of pathologic AD. A positive SPECT scan raised the likelihood of AD to 92%, whereas a negative SPECT scan lowered the likelihood to 70%. SPECT was more useful when the clinical diagnosis was “possible” AD, with the likelihood of 67% without SPECT, 84% with a positive SPECT, and 52% with a negative SPECT. Similar results were found when only patients with dementia were included in the analysis. Conclusions: In the evaluation of dementia, SPECT imaging can provide clinically useful information indicating the presence of AD in addition to the information that is obtained from clinical evaluation.

Rapidly progressing atrophy of medial temporal lobe in Alzheimer's disease

The symptoms of Alzheimers disease are associated with pathological change and loss of neurons in the medial temporal lobe. By yearly temporal-lobe-oriented computed tomograms the average rate of atrophy of the medial temporal lobe was 15.1% per year (95% CI 10.0, 20.2) in 20 patients with histopathologically, confirmed Alzheimers disease and 1.5% (0.2, 2.8) in 47 healthy ageing controls. Such excessive atrophy presumably reflects the vulnerability of the medial temporal lobe to a catastrophic event, probably a pathological cascade process. Thus, Alzheimers disease may not be due simply to an acceleration of normal ageing but, rather, is the consequence of a true disease process.

Intake of Flavonoid-Rich Wine, Tea, and Chocolate by Elderly Men and Women Is Associated with Better Cognitive Test Performance

In a cross-sectional study, we examined the relation between intake of 3 common foodstuffs that contain flavonoids (chocolate, wine, and tea) and cognitive performance. 2031 participants (70-74 y, 55% women) recruited from the population-based Hordaland Health Study in Norway underwent cognitive testing. A cognitive test battery included the Kendrick Object Learning Test, Trail Making Test, part A (TMT-A), modified versions of the Digit Symbol Test, Block Design, Mini-Mental State Examination, and Controlled Oral Word Association Test. Poor cognitive performance was defined as a score in the highest decile for the TMT-A and in the lowest decile for all other tests. A self-reported FFQ was used to assess habitual food intake. Participants who consumed chocolate, wine, or tea had significantly better mean test scores and lower prevalence of poor cognitive performance than those who did not. Participants who consumed all 3 studied items had the best test scores and the lowest risks for poor test performance. The associations between intake of these foodstuffs and cognition were dose dependent, with maximum effect at intakes of approximately 10 g/d for chocolate and approximately 75-100 mL/d for wine, but approximately linear for tea. Most cognitive functions tested were influenced by intake of these 3 foodstuffs. The effect was most pronounced for wine and modestly weaker for chocolate intake. Thus, in the elderly, a diet high in some flavonoid-rich foods is associated with better performance in several cognitive abilities in a dose-dependent manner.