Non-demented Elderly Subjects Research Articles

Test-Retest of fMRI Activity in Hippocampus and Default Network in Non-demented Elderly Subjects.

Test-Retest of fMRI Activity in Hippocampus and Default Network in Non-demented Elderly Subjects.

Association of White-Matter Lesions with Brain Atrophy Markers: The Three-City Dijon MRI Study

Background: Brain atrophy and white-matter lesions (WML) are common features at cerebral MRI of both normal and demented elderly people. In a population-based study of 1,792 elderly subjects aged 65–80 years, free of dementia, who had a cerebral MRI at entry, we investigated the relationship between WML volume and brain atrophy markers estimated by hippocampal, gray matter (GM) and cerebrospinal fluid (CSF) volumes. Methods: An automated algorithm of detection and quantification of WML was developed, and voxel-based morphometry methods were used to estimate GM, CSF and hippocampal volumes. To evaluate the relation between those volumes and WML load, we used analysis of covariance and multiple linear regression models adjusting for potential confounders and total intracranial volumes. Results: Age was highly correlated with WML load and all brain atrophy markers. Total WML volume was negatively associated with both GM (β = –0.03, p < 0.0001) and hippocampal volumes (β = –0.75, p = 0.0009) and positively with CSF volumes (β = 0.008, p = 0.02) after controlling for sex, age, education level, hypertension and apolipoprotein E genotype. Evidence for a relationship between brain atrophy markers and WML was stronger for periventricular WML. We found that the relationship between WML and hippocampal volumes was independent of other brain tissue volumes. Conclusion: These results suggest that, in the brain of nondemented elderly subjects, degenerative processes and vascular changes co-occur and are related independently of vascular risk factors.

Hypertension and white matter lesions are independently associated with apathetic behavior in healthy elderly subjects: the Sefuri brain MRI study

Apathy is defined as a syndrome of primary loss of motivation not attributable to emotional distress, intellectual impairment or consciousness disturbance. The aim of our study was to investigate the effects of vascular risk factors and silent ischemic brain lesions on apathetic behavior of community-dwelling elderly subjects. Brain MRI and other medical examinations were performed on 222 non-demented community-dwelling elderly subjects (96 men and 126 women, average age 70.1 years). The apathy group was defined as the most apathetic quintile determined by Starkstein's apathy scale. Silent infarction, deep white matter lesions (DWMLs) and periventricular hyperintensities were detected in 12.2, 39.2 and 22.5%, respectively. Linear regression analysis (Pearson) revealed that the scores on the apathy scale correlated slightly but significantly with logarithmically transformed scores of the Modified Stroop Test (r=0.135, P=0.045), but not with the Mini-Mental State Examination. The apathy group tended to have more high blood pressure (141.6/82.6 vs. 136.1/79.6 mm Hg), less prevalent hyperlipidemia (18 vs. 35%) and lower serum albumin. Multivariate analysis (the forward stepwise method of logistic analysis) revealed an independent correlation between the apathy and grade of DWMLs (odds ratio 1.826, 95% confidence interval (CI) 1.129-2.953 per grade) or diastolic blood pressure (DBP) (odds ratio 1.055, 95% CI 1.014-1.098 per mm Hg) after adjusting for possible confounders. The mean apathy scale score in the DBP>or=90 mm Hg group was significantly lower (more apathetic) than that in the DBP<80 group (P=0.011, analysis of covariance). This study showed that hypertension and DWMLs are independently associated with apathy in healthy elderly subjects.

Asymmetric Insular Function Predicts Positional Blood Pressure in Nondemented Elderly

Forty percent of nondemented octogenarians have Braak stages consistent with insular involvement, and may be at risk for "age-related" autonomic dysfunction. The authors examined the association between insular resting cerebral blood flow (rCBF) and cardiovascular functions in 29 nondemented elderly subjects who were highly screened to exclude comorbid cardiovascular disease. Mean insular rCBF was significantly higher on the right than left. However, 35.4% of participants had left dominant rCBF (a high-risk group). Right insular rCBF was significantly lower in the high-risk group. This subset had significantly increased positional drops in systolic blood pressure. While these data cannot address Alzheimer's disease as the specific cause, this possibility is being investigated in other cohorts.

Asymmetric Insular Function Predicts Positional Blood Pressure in Nondemented Elderly

Forty percent of nondemented octogenarians have Braak stages consistent with insular involvement, and may be at risk for "age-related" autonomic dysfunction. The authors examined the association between insular resting cerebral blood flow (rCBF) and cardiovascular functions in 29 nondemented elderly subjects who were highly screened to exclude comorbid cardiovascular disease. Mean insular rCBF was significantly higher on the right than left. However, 35.4% of participants had left dominant rCBF (a high-risk group). Right insular rCBF was significantly lower in the high-risk group. This subset had significantly increased positional drops in systolic blood pressure. While these data cannot address Alzheimer's disease as the specific cause, this possibility is being investigated in other cohorts.

Cerebral blood volume in Alzheimer's disease and correlation with tissue structural integrity

A vascular component is increasingly recognized as important in Alzheimer's disease (AD). We measured cerebral blood volume (CBV) in patients with probable AD or Mild Cognitive Impairment (MCI) and in elderly non-demented subjects using a recently developed Vascular-Space-Occupancy (VASO) MRI technique. While both gray and white matters were examined, significant CBV deficit regions were primarily located in white matter, specifically in frontal and parietal lobes, in which CBV was reduced by 20% in the AD/MCI group. The regions with CBV deficit also showed reduced tissue structural integrity as indicated by increased apparent diffusion coefficients, whereas in regions without CBV deficits no such correlation was found. Subjects with lower CBV tended to have more white matter lesions in FLAIR MRI images and showed slower psychomotor speed. These data suggest that the vascular contribution in AD is primarily localized to frontal/parietal white matter and is associated with brain tissue integrity.

The influence of white matter lesions on neuropsychological functioning in demented and non-demented 85-year-olds.

White matter lesions on computed tomography of the head were studied in relation to neuropsychological functioning in subjects from a representative sample of non-demented (n = 134) and demented (n = 98) 85-year-olds. Non-demented subjects with white matter lesions (n = 46) scored significantly lower in tests of verbal ability (Synonyms), spatial ability (Block Design, Clock Test), perceptual speed (Identical forms), secondary memory (Thurstone Picture Memory), basic arithmetic (Coin Test) and the global cognitive screening test Mini-Mental State Examination than non-demented subjects without white matter lesions (n = 88). Demented subjects with white matter lesions (n = 67) scored significantly lower in tests of spatial ability (Block Design and Clock Test) and secondary memory (free recall in the MIR memory test, Ten-word memory test I and II) and in the Mini-Mental State Examination than demented subjects without white matter lesions (n = 31). It is concluded that white matter lesions contribute to cognitive decline in both non-demented and demented elderly subjects.

Saccadic and smooth pursuit eye movements in memory-impaired elderly people.

The aim of the study was to compare eye movements recorded in 14 non-demented memory impaired elderly subjects with those of 36 sex- and education-matched controls. Eye movements were recorded with the bitemporal electrooculographic technique, and analyzed with a personal computer. Saccades were elicited in accordance with reflexive, predictive and antisaccade paradigms. Smooth pursuit eye movements were elicited with a triangular ramp paradigm. The memory-impaired subjects showed a higher prevalence of increased reflexive saccade latency and a lower smooth pursuit performance index. In addition, we detected a correlation between antisaccade and reflexive saccade latencies. Our results showed very slight differences in eye movement parameters. However, our findings are in keeping with the hypothesis of a subtle involvement of differing cortical areas in memory impaired subjects.

Identification of autoantibody against beta-amyloid peptide in the serum of elderly

Alzheimer's disease (AD) is characterized by two major neurological features: amyloid deposits and neurofibrillary tangles in the brain. According to the amyloid cascade hypothesis, accumulation of amyloid-beta peptide (A-beta) plays a central role in the pathogenesis of AD. Several lines of evidence suggest that antibodies against A-beta play a protective role in the neuropathology of AD. In this study, we describe the purification of an autoantibody against A-beta from human serum using affinity purification method. The purified autoantibody recognized A-beta deposits in the brain of aged Tg2676 mice, an animal model of AD. The serum levels of anti-A-beta autoantibody correlated inversely with age in both AD patients and control non-demented elderly subjects. Furthermore, the levels were significantly lower in AD patients compared with the age-matched control subjects. It is the first time to show the identification of endogenous anti-A-beta autoantibody in human serum and suggesting that serum levels of anti-A-beta autoantibody might be a good biomarker for AD patients.

Interaction between β-amyloid protein and heparan sulfate proteoglycans from the cerebral capillary basement membrane in Alzheimer’s disease

Proteoglycans are important in the pathogenesis of senile dementia of Alzheimer type (SDAT) by participating in amyloidogenesis. Knowledge about specific proteoglycan subtypes in SDAT may be of therapeutic advantage. In this study, we examined proteoglycan constituents of SDAT brains with reference to hyaluronic acid, heparan sulfate (HS), dermatan sulfate and chondroitin sulfate subtypes. Total proteoglycans showed a 1.6-fold increase in the hippocampus and 4.3-fold increase in the gyrus frontalis superior compared to non-demented elderly subjects. The HS subtype showed a 9.3-fold increase in hippocampus and a 6.6-fold increase in gyrus frontalis superior. Immunohistochemical studies of senile plaques revealed the expression of heparan sulfate proteoglycan (HSPG) in a portion of the core of typical plaques. β-amyloid expression was positive in senile plaques and the degenerated neuronal processes and capillary basement membrane, but was negative in endothelial cells. Microglial cells adjacent to senile plaques were positive for HLA-DR expression, and astroglial cells positive for glial fibrillary acidic protein were scattered around the microglial cells. Immunoelectron microscopic examination showed an electron-dense reaction for HSPG in the thickened basement membrane adjacent to the endothelial cells of capillary vessels, but not inside the endothelial cells. These findings suggest that a markedly increased HSPG in SDAT brains is most likely caused by HSPG from the blood capillary basement membrane and that the degenerated processes around senile plaques may arise from microglial or astroglial cells.

Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer's disease

Recently developed positron emission tomography (PET) tracers, such as PIB and FDDNP, help to visualize amyloid plaques and neurofibrillary tangles in living subjects. FDDNP binds to both amyloid plaques and tangles, whereas PIB selectively labels amyloid plaques. Therefore, it will be interesting to see a direct comparison of the regional binding of the two radiotracers for plaques (PIB) and plaques and tangles (FDDNP) using multitracer PET imaging for both PIB and FDDNP in the same subjects with and without Alzheimer's disease. Here we report that multitracer PET images of PIB and FDDNP in the same Alzheimer subjects show negligible PIB but strong FDDNP binding in the medial temporal cortex (hippocampus, amygdala, and parahippocampal gyrus), whereas there are significant quantities of both PIB and FDDNP binding in neocortical areas. These results suggest that tangles rather than amyloid plaques are the dominant pathology in the medial temporal cortex of living Alzheimer patients. In nondemented elderly normal subjects, PIB binding shows a significant increase in the posterior cingulate cortex compared with other brain regions, whereas in the same normal subjects we found significant FDDNP binding in the medial temporal cortex. Interestingly, the medial temporal FDDNP uptake values in normal elderly subjects were inversely correlated with long delay recall scores in the California Verbal Learning Test, a measure of episodic memory performance. We conclude that multitracer PET imaging of amyloid plaques and tangles using FDDNP and PIB in both nondemented and demented subjects provides important insight into these complicated pathological processes in living subjects.

Segmentation of age-related white matter changes in a clinical multi-center study

Age-related white matter changes (WMC) are thought to be a marker of vascular pathology, and have been associated with motor and cognitive deficits. In the present study, an optimized artificial neural network was used as an automatic segmentation method to produce probabilistic maps of WMC in a clinical multi-center study. The neural network uses information from T1- and T2-weighted and fluid attenuation inversion recovery (FLAIR) magnetic resonance (MR) scans, neighboring voxels and spatial location. Generalizability of the neural network was optimized by including the Optimal Brain Damage (OBD) pruning method in the training stage. Six optimized neural networks were produced to investigate the impact of different input information on WMC segmentation. The automatic segmentation method was applied to MR scans of 362 non-demented elderly subjects from 11 centers in the European multi-center study Leukoaraiosis And Disability (LADIS). Semi-manually delineated WMC were used for validating the segmentation produced by the neural networks. The neural network segmentation demonstrated high consistency between subjects and centers, making it a promising technique for large studies. For WMC volumes less than 10 ml, an increasing discrepancy between semi-manual and neural network segmentation was observed using the similarity index (SI) measure. The use of all three image modalities significantly improved cross-center generalizability compared to neural networks using the FLAIR image only. Expert knowledge not available to the neural networks was a minor source of discrepancy, while variation in MR scan quality constituted the largest source of error.

Mutations in exons 2 and 3 of the FOLR1 gene in demented and non-demented elderly subjects

We have previously reported six novel mutations in the 5'-UTR of the gene for folate receptor-alpha (FOLR1). In our search for additional mutations we screened patients, referred for investigation of suspected dementia (DGM subgroup) by SSCP and DNA sequencing from the end of exon 1 to the first bases of intron 3. We found 4 sequence variations, FOLR1 g.1314G>A, g.1816delC, g.1841G>A, and g.1928C>T. Pyrosequencing genotyping assays were developed for all of them, and 389 active seniors (AS subgroup) and the 202 DGM patients were genotyped for these mutations. The frequency q of the mutated allele was, among the AS subjects, 0.068, 0.0026, 0.0026, and 0.024 respectively, and among the DGM subjects, 0.067, 0.0076, 0.0078, and 0.023. The g.1816delC and g.1841G>A mutations thus were more frequent in the DGM than in the AS subgroup, but the difference did not reach statistical significance. The mutated alleles, FOLR1 1816(-) and 1841A, always occurred together in the same subjects, suggestive of a rare double-mutant haplotype. The two common polymorphisms, FOLR1 g. 1314G>A and g.1928C>T seemed not to raise tHcy plasma levels, whereas the double-mutated g.1816(-)-g.1841A haplotype may possibly have a slight tHcy-raising effect. Thus, so far 8 novel rare FOLR1 mutations with a combined prevalence of approximately 1.3% in Whites as well as two common polymorphisms with 5% and 13%, respectively, have been demonstrated. Only a few of the rare mutations may potentially be associated with raised plasma tHcy concentrations. No association with dementia was found.

Memory in the aging brain: Doubly dissociating the contribution of the hippocampus and entorhinal cortex

Since the time of Aristotle it has been thought that memories can be divided into two basic types; conscious recollections and familiarity-based judgments. Neuropsychological studies have provided indirect support for this distinction by suggesting that different regions within the human medial temporal lobe (MTL) are involved in these two forms of memory, but none of these studies have demonstrated that these brain regions can be fully dissociated. In a group of nondemented elderly subjects, we found that performance on recall and recognition tests was predicted preferentially by hippocampal and entorhinal volumes, respectively. Structural equation modeling revealed a double dissociation, whereby age-related reductions in hippocampal volume resulted in decreases in recollection, but not familiarity, whereas entorhinal volume was preferentially related to familiarity. The results demonstrate that the forms of episodic memory supported by the human hippocampus and entorhinal cortex can be fully dissociated, and indicate that recollection and familiarity reflect neuroanatomically distinct memory processes.

An epidemiologic study of mild cognitive impairment in Kolkata, India

To estimate the prevalence of two types of mild cognitive impairment (MCI)-amnestic and multiple domain types-among nondemented and nondepressed elderly subjects aged 50 and older. The study was carried out in Kolkata, the eastern metropolis of India. A cross-sectional community screening was carried out, and 960 subjects were selected by systematic random sampling for the assessment of cognitive function with the help of a validated cognitive questionnaire battery administered through house-to-house survey. A case-control study was also undertaken to identify potential risk factors through univariate analysis. Ultimately, full evaluation of cognitive function was possible in 745 of 960 subjects. An overall prevalence of MCI detected based on neuropsychological testing was 14.89% (95% CI: 12.19 to 17.95). Prevalence of the amnestic type was 6.04% (95% CI: 4.40 to 8.1) and that of the multiple domain type was 8.85% (95% CI: 6.81 to 11.32). Adjusted for age, education. and gender, the amnestic type was more common among men and the multiple domain type among women with advancement of age. Rates differed considerably with educational attainment. Hypertension and diabetes mellitus were the major risk factors for both types of MCI. In this first community-based study of mild cognitive impairment (MCI) from India, prevalence of the amnestic type is comparable with and that of the multiple domain type is less than the prevalence in developed countries. Variations in age, education, and gender specific prevalence of MCI of both types were encountered. The putative risk factors identified merit further study.

Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment (MCI)

MCI is regarded as a precursor of dementia, but not all patients with MCI actually develop dementia. As Alzheimer and vascular dementia (AD and VD, respectively) are thought to share many common etiopathogenetic mechanisms, we investigated whether the vascular risk factor atrial fibrillation affect the risk of conversion to dementia for different MCI subtypes diagnosed according to international criteria. One-hundred-eigthy elderly outpatients with MCI and 431 elderly outpatients with a normal cognition were followed-up for a mean of 3 and 4 years, respectively. The risk of conversion to dementia associated with atrial fibrillation was studied in both samples using a Cox proportional-hazards model adjusted for sociodemographic and medical variables. Overall conversion rate to dementia was 10.5 (8.0–13.8) per 100 person-years in the MCI group and 2.2 (1.5–3.1) per 100 person-years in the normal cognition group. Atrial fibrillation was significantly associated with conversion to dementia (hazard ratio = HR = 4.63, 95% confidence interval = Cl = 1.72–12.46) in the MCI group, but not in the cognitively normal group (HR = 1.10, 95% Cl = 0.40–3.03). Current diagnostic criteria for MCI subtypes define heterogeneous populations, but atrial fibrillation can be useful in identifying people with increased risk of conversion to dementia.

Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle‐only dementia): The Hisayama study

Senile dementia of the neurofibrillary tangle type (SD-NFT) is characterized by numerous neurofibrillary tangles (NFT) in the hippocampal region and the absence or minimal presence of senile plaques throughout the brain. We analyzed 207 demented subjects and 68 non-demented subjects autopsied in the Hisayama study to investigate the clinicopathological aspects of SD-NFF in the general Japanese population. The prevalence of SD-NFT in the consecutive autopsy cases was 8/207 (3.9%), comprising three men and five women. The average age at onset and death was 83.8 +/- 6.8 (mean +/- SD; standard deviation) and 88.1 +/- 7.6 years, respectively. A mild memory disturbance preceded a decrease in the ability to undertake the activities of daily living and the diagnosis of dementia. Focal cerebral symptoms, such as aphasia and paralysis, did not appear during the disease course of any subject. Gross examination of the brains showed moderate to severe diffuse cerebral atrophy with brain weight loss (mean +/- SD; standard deviation: 1118.1 +/- 124.0 g). Histologically, there were abundant NFT and neuropil threads predominantly in or limited to the limbic cortex. The density of NFT in the CA1/subiculum in SD-NFT was much higher than the densities in the other hippocampal regions. The average density of NFT in CA1 in SD-NFT subjects was 115.4 per 100 x field (range 23-247), that in Alzheimer disease (AD) subjects was 80.1 (range 1-227), and that in non-demented elderly subjects was 37.2 (range 0-203). Although many previous papers have reported that the densities of NFT in the limbic system in SD-NFT were significantly higher than those in AD, there was considerable overlap of NFT densities in CA1 among the non-demented elderly, AD subjects and SD-NFT subjects.

Atrial fibrillation and risk of dementia in non-demented elderly subjects with and without mild cognitive impairment

Objectives: Mild cognitive impairment (MCI) is regarded as a precursor to dementia, but not all patients with MCI actually develop dementia. As Alzheimer and vascular dementia are thought to share many common etiopathogenetic mechanisms, we investigated whether the vascular risk factor atrial fibrillation affects the risk of conversion to dementia for different MCI subtypes diagnosed according to international criteria.Methods: One hundred and eighty elderly outpatients with MCI and 431 elderly outpatients with a normal cognition were followed up for a mean of 3 and 4 years, respectively. The risk of conversion to dementia associated with atrial fibrillation was studied in both samples using a Cox proportional hazards model adjusted for socio-demographic and medical variables.Results: Overall conversion rate to dementia was 10.5 (8.0–13.8 per 100 person-years) in the MCI group and 2.2 (1.5–3.1 per 100 person-years) in the normal cognition group. Atrial fibrillation was significantly associated with conversion to dementia [hazard ratio (HR): 4.63; 95% confidence interval: 1.72–12.46] in the MCI group but not in the cognitively normal group (HR: 1.10; 95% confidence interval: 0.40–3.03).Discussion: Current diagnostic criteria for MCI subtypes define heterogeneous populations, but atrial fibrillation can be useful in identifying people with increased risk of conversion to dementia.

Interaction of cardiovascular disease and neurodegeneration: transcranial Doppler ultrasonography and Alzheimer's disease

Objective: Recent post-mortem studies have reported that the severity of atheromatous deposits in the circle of Willis is significantly greater, relative to non-demented (ND) elderly persons, in subjects with neuropathologically diagnosed Alzheimer's disease (AD). Additionally, the severity of intracranial atherosclerosis correlates significantly with the densities of neuritic plaques and neurofibrillary tangles. In this study, we examine the arteries of the circle of Willis by transcranial Doppler (TCD) ultrasonography.Methods: TCD was used to measure, in 25 AD patients and 30 ND elderly subjects, mean flow velocities and pulsatility indices in 16 different segments of the circle of Willis. The data were compared with and without adjustment for age, gender and systolic blood pressure.Results: The AD patients had systematically higher pulsatility indices (p<0.005) than the ND group. Incremental increases of pulsatility indices in these segments had odds ratios ranging from 1.8 to 48 for the presence of AD when adjusted for age, gender and systolic blood pressure. The left internal carotid artery siphon and the left posterior cerebral artery were the two vessels that were strongly associated with AD diagnosis. Mean flow velocities were generally lower in patients with AD but the differences did not reach the significance level.Discussion: The pulsatility indices of the arteries of AD patients were generally greater than those of similarly-aged ND subjects. This difference is most likely due to increased arterial wall rigidity imposed by atherosclerotic changes. Atherosclerotic disease of intracranial arteries may be a risk factor for AD.

Validation of a memory inventory for the assessment of awareness of memory deficits in Alzheimer's disease in Chinese elderly

This paper describes the development and validation of the Memory Inventory for Chinese (MIC), for measuring the awareness of memory deficits in the Chinese population with Alzheimer's disease (AD). A combination of qualitative and quantitative approaches was adopted. The MIC was developed with focus group discussion and pilot testing. It has a patient and a caregiver version. A consecutive series of 79 new out-patients with the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorder Association (NINCDS-ADRDA) criteria of probable and possible AD and 20 non-demented elderly subjects were recruited. A high internal consistency was found, with Cronbach alpha of 0.89 for the patient version and 0.90 for the caregiver version of MIC. The inter-rater reliability was satisfactory. For validity assessment, the caregiver score of the MIC correlated significantly with cognitive score of the subject as assessed by the Mini-Mental State Examination (rp = -0.37; p < 0.01). The Memory Deficit Awareness Score, calculated by subtracting the patient score from the caregiver score, correlated significantly with clinician ratings of awareness of memory impairment (rs = -0.67; p < 0.01). The MIC appears to be a culturally appropriate and valid instrument for the measurement of awareness of memory deficits in Chinese patients with AD. Potential applications of the MIC should be further explored in other subtypes of dementia and in prospective studies.