To investigate the association between midlife systolic blood pressure (SBP) and late-life cognitive decline and brain morphology in a sample of community-dwelling elderly men 68 to 79 years of age.
...Subjects are surviving members from the prospective National Heart, Lung, and Blood Institute Twin Study (intake, 1969 to 1972) who, when examined for a fourth time in 1995 through 1997, underwent brain MRI and repeated assessment of neurobehavioral functioning. Quantification of the MR images determined cerebral volume and total volume of white matter hyperintensities (WMHIs) for 392 subjects. Midlife SBP levels measured in 1970, 1980, and 1985 were used to classify subjects into low, medium, and high midlife SBP categories. A 10-year change in performance on the Mini-Mental State Examination, Digit Symbol Substitution Test, Benton Visual Retention Test, and Verbal Fluency Test was also calculated for these subjects. For all reported analyses, patients were treated as genetically unrelated individuals.
Subjects with high midlife SBP experienced a greater decline in cognitive performance and had larger WMHI volumes at follow-up in late life than did those with low midlife SBP. Decreased brain parenchyma and increased WMHI volumes were associated with decline in neurobehavioral functioning as measured in late life independent of age, education, and baseline levels of cognition.
Midlife SBP is a significant predictor of both decline in cognitive function and MR volumetric measures of brain atrophy in late life. Because decline in neurobehavioral functioning was associated with decreased brain volume and increased WMHI volume, we conclude that the long-term impact of elevated SBP on decline in late-life neurobehavioral functioning is likely to be mediated through its chronic, negative effect on structural characteristics of the brain.
To assess the association of MRI white matter hyperintensities (WMHI) with cognitive performance, cerebral structure, and cerebral metabolism in 51 healthy individuals aged 19 to 91 years without ...cerebrovascular risk factors.
Abnormal white matter signals have been associated with brain atrophy, reduced cerebral blood flow, focal neurologic signs, gait disorder, and poorer neuropsychological test performance. Most studies of WMHI, however, include subjects with hypertension or other identifiable causes of cerebrovascular disease that may have an independent effect on brain structure and function. To assess brain changes associated with WMHI independent of cerebrovascular risk factors, we determined WMHI volume, brain volume, cerebral metabolism, and cognitive performance for a group of subjects free of medical illness. Regional cerebral metabolism and cognitive domains were also assessed to evaluate the possible role of frontal lobe dysfunction in subjects with WMHI.
Cross-sectional study of 51 very healthy subjects aged 19 to 91 years.
WMHI, brain, and CSF volumes were determined by MRI segmentation. Neuropsychological tests were employed to assess multiple cognitive domains. Brain metabolism was determined from 18-fluoro-2-deoxy-D-glucose PET. Multivariate relations were tested with stepwise linear regression. Models included the potential confounders of age and education where appropriate.
The distribution of WMHI volume was bimodal, with five subjects having WMHI volumes beyond three SDs from the normally distributed population. A WMHI volume of greater than 0.5% of intracranial volume was considered abnormal. Within the multivariate models, WMHI volumes were significantly predictive of increased ventricular volume, reduced brain volume, and reduced cognitive scores. Subjects with greater than 0.5% WMHI volume also had significantly lower frontal lobe metabolism, significantly higher systolic blood pressure, significantly larger ventricular volume, and significantly lower scores on frontal lobe-mediated neuropsychological tests than age-matched controls.
WMHI volume is associated with structural and functional brain changes even within a group of very healthy individuals. WMHI is associated with poorer frontal lobe cognitive function and, when severe, is accompanied by significantly reduced frontal lobe metabolism. Subjects with large WMHI volumes have significantly higher systolic blood pressure, brain atrophy, reduced cerebral metabolism, and lower scores on tests of frontal lobe function than age-matched controls. Large amounts of WMHI are, therefore, pathologic and may be related to elevated systolic blood pressure even when it is within the normal age-related range.
To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI).
Previous cross-sectional studies examining the ...relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI.
Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability.
Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline.
Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.
Abstract This study investigated the hypothesis that vascular risk factors are amyloidogenic. Participants were 43 persons, most with normal cognition or mild cognitive impairment. Vascular risk was ...quantified using the Framingham Coronary Risk Profile (FCRP) score. Cerebral amyloid was measured by 11 CPittsburgh compound B (PIB) positron emission tomography (PET) and quantified with a Global PIB index, which is the average of distribution volume ratios in selected cortical regions of interest. In a bivariate model FCRP accounted for 16% of the variance in PIB index ( p < 0.008) and the positive association remained significant controlling for age and sex. The effect of FCRP was independent of apolipoprotein E (APOE) genotype, which was also associated as expected with PIB. Carotid intima-media thickness was not associated with PIB index. Effects of individual FCRP component risk factors, cholesterol, and glycemic status on PIB index were all nonsignificant, suggesting an aggregate effect of risk factors. Although this is a correlational observation it may represent a causal relationship as there are multiple, plausible, amyloidogenic mechanisms of vascular risk factors.
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•Polysaccharide-based thermosensitive hydrogels were developed for cartilage repair.•The hydrogels consisted of methylcellulose, xanthan gum and carboxymethyl chitosan.•Dexamethasone, ...diclofenac sodium and gallic acid were incorporated into them.•The hydrogels showed adequate gelling temperatures and mechanical properties.•The hydrogels were not cytotoxic, being useful for minimally invasive therapies.
In this work, thermosensitive hydrogels formulated with methylcellulose, xanthan gum and/or carboxymethyl chitosan were developed and characterized as a potential treatment for damaged or osteoarthritic joints. The formulations produced experienced a reversible sol–gel transition upon a temperature change from room temperature to 37 °C. Three different drugs were incorporated into the hydrogels: dexamethasone, diclofenac sodium, and gallic acid. The cytotoxicity of the hydrogels was accessed and the hydrogels were also characterized regarding aspect and surface morphology, swelling, and stability, gelling temperature, compressive modulus, FT-IR and drugs release behavior. Sufficiently stable hydrogels with high culture medium absorption capacity were obtained. When freeze-dried, the hydrogels showed a highly interconnected porous structure. The compressive equilibrium and dynamic modulus were higher in the hydrogels with drugs, since gallic acid could crosslink the structures. In summary, the hydrogels produced may be effective candidates for the repair of osteoarthritic joints after minimally invasive surgery.
Cross-sectional studies show that cerebrovascular risk factors are associated with increased brain atrophy, accumulation of abnormal cerebral white matter signals, and clinically silent stroke. We ...extend these findings by examining the relationship between midlife cerebrovascular risk factors and later-life differences in brain atrophy, amount of abnormal white matter, and stroke on MRI.
Subjects were the 414 surviving members of the prospective National Heart, Lung, and Blood Institute Twin Study, who have been examined on 4 separate occasions, spanning the 25 years between 1969-1973 and 1995-1997. Quantitative measures of brain volume, volume of abnormal white matter signal (WMHI), and volume of stroke, when present, were obtained from those participating in the fourth examination.
The mean+/-SD age of the subjects was 47.2+/-3.0 years at initial examination and 72. 5+/-2.9 years at final examination. Average blood pressure (BP) levels were normal, although 32% of the subjects had received or were currently taking antihypertensive medications. As a group, 31% had symptomatic cardiovascular disease, 11% had symptomatic cerebrovascular disease, and 8% had symptomatic peripheral vascular disease. Both systolic and diastolic BP levels at initial examination were inversely related to brain volume and positively related to WMHI volume. Multiple regression analysis identified BP-related measures and vascular risk factors as significant predictors of brain and WMHI volumes. In addition, the magnitude of orthostatic BP change was significantly associated with WMHI volume. Subjects with extensive amounts of WMHI had significantly higher systolic BP at the final examination and a higher prevalence of symptomatic cardiovascular and cerebrovascular disease, without significant differences in the prevalence of hypertension treatment.
Midlife BP measures are significantly associated with later-life brain and WMHI volumes and the prevalence of symptomatic vascular disease. Since WMHI share cerebrovascular risk factors and extensive WMHI are associated with symptomatic vascular disease, extensive WMHI may be a subclinical expression of cerebrovascular disease. Careful treatment of midlife BP elevations may diminish these later-life brain changes.
The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are ...incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
Vascular factors in dementia: an overview DeCarli, Charles
Journal of the neurological sciences,
11/2004, Letnik:
226, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Alzheimer's disease and cerebrovascular disease are two illnesses common to the elderly. Conventional wisdom has sought to separately describe and treat these two diseases. Accumulating evidence, ...however, shows that cerebrovascular risk factors may cause asymptomatic brain injury, share genetic risk with Alzheimer's disease and possibly accelerate the Alzheimer's process. Such evidence suggests that these two diseases may act additively or synergistically to cause clinical dementia. This review focuses on evolving data that support this hypothesis.
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