Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay.
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We have developed an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay for the measurement of Alzheimer's disease (AD) abnormally hyperphosphorylated tau in cerebrospinal fluid (CSF). The assay, which recognizes attomolar amounts of tau, is approximately 400 and approximately 1300 times more sensitive than conventional enzyme-linked immunosorbent assay in determining the hyperphosphorylated tau and total tau, respectively. With this method, we measured both total tau and tau phosphorylated at Ser-396/Ser-404 in lumbar CSFs from AD and control patients. We found that the total tau was 215 +/- 77 pg/ml in cognitively normal control (n = 56), 234 +/- 92 pg/ml in non-AD neurological (n = 37), 304 +/- 126 pg/ml in vascular dementia (n = 46), and 486 +/- 168 pg/ml (n = 52) in AD patients, respectively. However, a remarkably elevated level in phosphorylated tau was only found in AD (187 +/- 84 pg/ml), as compared with normal controls (54 +/- 33 pg/ml), non-AD (63 +/- 34 pg/ml), and vascular dementia (72 +/- 33 pg/ml) groups. If we used the ratio of hyperphosphorylated tau to total tau of > or =0.33 as cutoff for AD diagnosis, we could confirm the diagnosis in 96% of the clinically diagnosed patients with a specificity of 95%, 86%, 100%, and 94% against nonneurological, non-AD neurological, vascular dementia, and all of the three control groups combined, respectively. It is suggested that the CSF level of tau phosphorylated at Ser-396/Ser-404 is a promising diagnostic marker of AD. (+info)
Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss.
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BACKGROUND: Alzheimer's disease (AD) is characterised by functional impairment, cerebral atrophy, and degeneration of specific neuronal populations, especially pyramidal neurones of the cerebral cortex and hippocampal formation. Although patients with subcortical vascular dementia have been shown to have similar metabolic and volumetric deficits to those with AD, the underlying pathogenesis of these changes is poorly understood. OBJECTIVE: To determine whether pyramidal cell loss occurs in small vessel disease (SVD) dementia by quantifying hippocampal volume and CA1 neurone number. METHODS: Fifty four prospectively studied patients with dementia were screened, and four patients fulfilling criteria for SVD with no other significant neuropathological abnormality were identified. These were compared with five patients fulfilling criteria for AD and seven controls matched for age and sex. The hippocampal formation was serially sectioned, and the number of CA1 pyramidal neurones estimated using the optical dissector technique. Analysis of variance was used to evaluate group differences. RESULTS: Patients in both the AD and SVD groups showed a substantial loss of pyramidal neurones from the CA1 region. The pattern of hippocampal atrophy and the degree of CA1 neuronal loss were similar in the two dementia groups. CONCLUSIONS: These findings support recent in vivo studies showing similar metabolic deficits and atrophy in AD and subcortical vascular dementia. In addition, they provide evidence that the underlying cause of these abnormalities is a similar loss of neurones. Whereas the cause of the neuronal loss in AD is related to the deposition of abnormal proteins, the cause in SVD is unknown. In the absence of other pathologies, damage to cerebral microvasculature should be considered a likely candidate. (+info)
Effects of subcortical ischemic vascular dementia and AD on entorhinal cortex and hippocampus.
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OBJECTIVE: To determine the effects of subcortical ischemic vascular dementia (SIVD) and AD on entorhinal cortex (ERC) and hippocampus. METHODS: Thirty-eight cognitively normal subjects, 18 patients with SIVD, and 22 patients with AD were included. Volumes of ERC and hippocampus were manually measured based on MRI. Global cerebral changes of cortical gray matter, subcortical gray matter, white matter, sulcal CSF, ventricular CSF (vCSF), and white matter signal hyperintensities (WMSH) were assessed. RESULTS: Patients with SIVD had 21.7% (p < 0.01) smaller ERC and 18.2% (p < 0.01) smaller hippocampi than cognitively normal subjects and 24.4% (p < 0.01) larger ERC and 11.1% (p < 0.05) larger hippocampi than patients with AD. In addition, patients with SIVD had less cortical gray matter and white matter and more vCSF and WMSH (all p < 0.01) than cognitively normal subjects and more vCSF and WMSH (p < 0.01) than patients with AD. The volumes of ERC and hippocampus were positively correlated to similar extents (p < 0.01) in SIVD and AD. Cortical gray matter loss was positively correlated (p < 0.01) with hippocampal atrophy, but not with ERC atrophy, in SIVD and AD. Hippocampal volume alone could classify 82% of patients with SIVD from cognitively normal subjects and 63% of patients with SIVD from subjects with AD. Adding global cerebral changes to hippocampus substantially improved the classification to 96% between patients with SIVD and cognitively normal subjects and 83% between subjects with SIVD and those with AD, whereas adding ERC change to hippocampus did not significantly improve the discrimination. CONCLUSIONS: The entorhinal cortex and hippocampus are less affected by subcortical ischemic vascular dementia than by AD. (+info)
Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300).
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BACKGROUND AND PURPOSE: Based on the hypothesis of glutamate-induced neurotoxicity (excitotoxicity) in cerebral ischemia, this study examined the efficacy and tolerability of memantine, an uncompetitive N-methyl-D-aspartate antagonist, in the treatment of mild to moderate vascular dementia. METHODS: In this multicenter, 28-week trial carried out in France, 321 patients received 10 mg/d memantine or placebo twice a day; 288 patients were valid for intent-to-treat analysis. Patients had to meet the criteria for probable vascular dementia and have a Mini-Mental State (MMSE) score between 12 and 20 at inclusion. The 2 primary end points were the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog) and the global Clinician's Interview Based Impression of Change (CIBIC-plus). RESULTS: After 28 weeks, the mean ADAS-cog scores were significantly improved relative to placebo. In the intention-to-treat population, the memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score had declined by 1.6 points, ie, a difference of 2.0 points (95% confidence interval, 0.49 to 3.60). The response rate for CIBIC-plus, defined as improved or stable, was 60% with memantine compared with 52% with placebo (P=0.227, intention to treat). Among the secondary efficacy parameters, which were analyzed in the per-protocol subset, MMSE was significantly improved with memantine compared with deterioration with placebo (P=0.003). The Gottfries-Brane-Steen Scale intellectual function subscore and the Nurses' Observation Scale for Geriatric Patients disturbing behavior dimension also showed differences in favor of memantine (P=0.04 and P=0.07, respectively). Memantine was well tolerated with a frequency of adverse events comparable to placebo. CONCLUSIONS: In patients with mild to moderate vascular dementia, memantine 20 mg/d improved cognition consistently across different cognitive scales, with at least no deterioration in global functioning and behavior. It was devoid of concerning side effects. (+info)
Is mild cognitive impairment prodromal for vascular dementia like Alzheimer's disease?
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BACKGROUND AND PURPOSE: Individuals with mild cognitive impairment (MCI) are at increased risk of Alzheimer's disease (AD) and probably other forms of dementia. Some subtypes of vascular dementia (VaD) may possess minor neuropathological changes of AD that may contribute to cognitive impairments. It was posited that MCI, identified by criteria described here, might present as a prodrome for VaD and AD. METHODS: Serial Mini-Mental State Examination was administered at 3- to 6-month intervals, and neuroimaging was performed annually. Subtle cognitive dysfunctions were weighted and measured according to MCI criteria defined here. Subjects identified with MCI were then followed up for an additional 3.88+/-3.01 years. Diagnoses of VaD and AD were made according to established criteria. RESULTS: During 3.72+/-2.94 years of follow-up of the original normative subjects, 73 of 291 (25.1%) developed MCI. Of the 27 subjects who developed VaD, 15 (55.6%) had prodromal MCI. Of these, two thirds were subclassified as having small-vessel dementia. The remaining 12 patients with VaD (44.4%) were diagnosed directly from a cognitively normal status without preceding MCI. These were predominantly multi-infarct or strategic-infarct dementia (66.7%). An additional 35 MCI subjects (47.9%) developed AD. Both VaD and AD diagnosed after MCI prodromes manifested similar spectral domains of cognitive impairments, which included memory, during their MCI stages. CONCLUSIONS: In some VaD subtypes, particularly those caused by subcortical microvascular disease, dementia may be preceded by MCI, which has similar domains of cognitive impairment and a similar progressive course that may mimic AD. (+info)
Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland.
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BACKGROUND AND PURPOSE: Elevated plasma homocysteine level has been associated with increased risk for cardiovascular and cerebrovascular disease. Variation in the levels of this amino acid has been shown to be due to nutritional status and methylenetetrahydrofolate reductase (MTHFR) genotype. METHODS: Under a case-control design we compared fasting levels of homocysteine and MTHFR genotypes in groups of subjects consisting of stroke, vascular dementia (VaD), and Alzheimer disease patients and normal controls from Northern Ireland. RESULTS: A significant increase in plasma homocysteine was observed in all 3 disease groups compared with controls. This remained significant after allowance for confounding factors (age, sex, hypertension, cholesterol, smoking, creatinine, and nutritional measures). MTHFR genotype was not found to influence homocysteine levels, although the T allele was found to increase risk for VaD and perhaps dementia after stroke. CONCLUSIONS: We report that moderately high plasma levels of homocysteine are associated with stroke, VaD, and Alzheimer disease. This is not due to vascular risk factors, nutritional status, or MTHFR genotype. (+info)
Reversible posterior leukoencephalopathy syndrome and silent cerebral infarcts are associated with severe acute chest syndrome in children with sickle cell disease.
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Patients with severe acute chest syndrome (ACS) requiring endotracheal intubation and erythrocytopheresis are at increased risk for neurologic morbidity. This study examines patients with sickle cell disease who developed severe episodes of ACS, leading to endotracheal intubation, ventilatory support for respiratory failure, and erythrocytapheresis. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) studies, a neurologic examination by a pediatric neurologist, and cognitive testing were done in all patients. Five consecutive patients, aged 3 to 9 years, were identified with severe ACS. All patients developed neurologic complications resulting from ACS episodes, including seizures (n = 2), silent cerebral infarcts (n = 3), cerebral hemorrhage (n = 2), and reversible posterior leukoencephalopathy syndrome (n = 3). Children with severe ACS should have a magnetic resonance image of the brain, neurologic examination by a neurologist, and cognitive testing to detect the presence of neurologic morbidity. (+info)
Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community.
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We have observed an unusually high prevalence of dementia of the Alzheimer type (DAT) in Wadi Ara, an inbred Arab community in northern Israel comprising approximately 850 persons over the age of 60 years. Family studies revealed that more than one-third of the DAT cases are members of one hamula (tribal group) within Wadi Ara. To map chromosomal loci contributing to DAT susceptibility, we conducted a 10 cM scan in a series of five cases and five controls selected from this hamula. Markers from 18 chromosomal regions showed significant allelic association with DAT (P<0.05). Locations on chromosomes 2, 9 and 10 remained significant after testing additional affected and non-demented individuals. Significant associations were also observed for markers on chromosome 12 which overlap with a locus implicated in previous genome scans. Analysis of allele frequency distributions for 12 markers spanning 20 cM on chromosome 9 narrowed the possible location of an DAT susceptibility gene to a 13 cM interval between D9S157 and D9S259 (most significant result: P = 2.3 x 10(-7)). Analysis of 14 markers spanning 24 cM on chromosome 12 narrowed the possible location to a 14 cM interval distal to the LRP1 locus (most significant result: P = 1.3 x 10(-6)). Evidence for linkage on chromosome 9 stemmed primarily from excess homozygosity of marker alleles in cases compared with controls, suggesting that the gene at this location behaves in either a recessive or additive fashion. The unique characteristics of this community together with the emergent human genome data should allow for the rapid identification of DAT genes in these candidate regions. (+info)