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Biomedical subjects

Gabriel Gold

Publications and source records attributed to Gabriel Gold.

At least 19 recordsLinked to original sources
PubMed2007

Distinction between perceptual and attentional processing in working memory tasks: a study of phase-locked and induced oscillatory brain dynamics.

Working memory involves the short-term storage and manipulation of information necessary for cognitive performance, including comprehension, learning, reasoning and planning. Although electroencephalogram (EEG) rhythms are modulated during working memory, the temporal relationship of EEG oscillations with the eliciting event has not been well studied. In particular, the dynamics of the neural network supporting memory processes may be best captured in induced oscillations, characterized by a loose temporal link with the stimulus. In order to differentiate induced from evoked functional processes, the present study proposes a time-frequency analysis of the 3 to 30 Hz EEG oscillatory activity in a verbal n-back working memory paradigm. Control tasks were designed to identify oscillatory activity related to stimulus presentation (passive task) and focused attention to the stimulus (detection task). Evoked theta activity (4-8 Hz) phase-locked to the visual stimulus was evidenced in the parieto-occipital region for all tasks. In parallel, induced theta activity was recorded in the frontal region for detection and n-back memory tasks, but not for the passive task, suggesting its dependency on focused attention to the stimulus. Sustained induced oscillatory activity was identified in relation to working memory in the theta and beta (15-25 Hz) frequency bands, larger for the highest memory load. Its late occurrence limited to nonmatched items suggests that it could be related to item retention and active maintenance for further task requirements. Induced theta and beta activities displayed respectively a frontal and parietal topographical distribution, providing further functional information on the fronto-posterior network supporting working memory.

Adult↗
PubMed2006

Assessing the cognitive impact of Alzheimer disease pathology and vascular burden in the aging brain: the Geneva experience.

The progressive development of Alzheimer disease (AD)-related lesions, such as neurofibrillary tangles (NFT), amyloid deposits and synaptic loss, and the occurrence of microvascular and small macrovascular pathology within the cerebral cortex are conspicuous neuropathologic features of brain aging. Recent neuropathologic studies strongly suggested that the clinical diagnosis of dementia depends more on the severity and topography of pathological changes than on the presence of a qualitative marker. However, several methodological problems, such as selection biases, case-control design, density-based measures and masking effects, of concomitant pathologies persisted. In recent years, we performed several clinicopathologic studies using stereological counting of AD lesions. In order to define the cognitive impact of lacunes and microvascular lesions, we also analyzed pure vascular cases without substantial AD pathology. Our data revealed that total NFT numbers in the CA1 field, cortical microinfarcts and subcortical gray matter lacunes were the stronger determinants of dementia. In contrast, the contribution of periventricular and subcortical white matter demyelinations had a modest cognitive effect even in rare cases with isolated microvascular pathology. Importantly, in cases with pure AD pathology, more than 50% of Clinical Dementia Rating scale variability was not explained by NFT, amyloid deposits and neuronal loss in the hippocampal formation. In cases with microvascular pathology or lacunes, this percentage was even lower. The present review summarizes our data in this field and discusses their relevance within the theoretical framework of the functional neuropathology of brain aging and with particular reference to the current efforts to develop standardized neuropathological criteria for mixed dementia.

Aging↗
PubMed2006

Decreased theta event-related synchronization during working memory activation is associated with progressive mild cognitive impairment.

BACKGROUND: Among the different quantitative electroencephalographic markers, theta activity is known to reflect neural resources involved in memory processes and directed attention. Previous studies suggested that synchronization likelihood analysis in theta-band frequency might be a sensitive method to identify early alterations of neuronal networks in mild cognitive impairment (MCI). METHODS: We report here a longitudinal study of 24 MCI patients with theta event-related synchronization (ERS) analysis during the n-back working memory task and neuropsychological follow-up after 1 year. Statistical analysis included analysis of variance and logistic regression to assess the relationship between cognitive decline and theta ERS. RESULTS: Upon follow-up, 13 MCI patients showed progressive MCI and 11 remained stable. In both groups, the phasic increase in theta amplitude after stimulus presentation did not depend on working memory load and electrode sites. Progressive MCI cases displayed significantly lower theta ERS power over all electrode sites compared to stable MCI cases. Theta ERS was significantly related to the cognitive outcome explaining 15.5% of its variability. In terms of MCI classification, the best combination of sensitivity and specificity was 0.87 and 0.60, respectively, with an area under the corresponding receiver operating characteristic curve reaching 76%. CONCLUSIONS: The present data indicate that a decrease in the early phasic theta ERS power during working memory activation may predict cognitive decline in MCI. This phenomenon is not related to working memory load but may reflect the presence of early deficits in directed attention-related neural circuits in MCI.

Aged↗
PubMed2006

Validation of clinical criteria for possible vascular dementia in the oldest-old.

Although vascular dementia (VaD) is a main pathology in nonagenarians and centenarians, the validity of clinical criteria for this diagnosis is unknown. We analyzed 110 autopsy cases and reported sensitivities and specificities of the State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) and National Institute for Neurological Disorders and Stroke (NINDS-AIREN) criteria for possible VaD as well as Hachinski ischemic score (HIS). Among them, there were 36 neuropathologically confirmed VaD cases. All criteria displayed comparable sensitivities (0.56-0.58). Specificities values were 0.74, 0.73 and 0.66, respectively. There was an age-related decrease on ADDTC criteria sensitivity due to the fact that 42% of pure VaD cases did not present with stroke. Thirty percent of mixed dementia (MD) cases were diagnosed as VaD by both NINDS-AIREN and ADDTC criteria. This proportion reached 45.9% for the HIS. These data demonstrate that the new diagnostic criteria for possible VaD do not provide a substantial gain of sensitivity compared to the HIS. Although their specificity was significantly lower in this age group compared to younger cohorts, all of them successfully exclude AD cases.

Age Factors↗
PubMed2006

Pain in severe dementia: self-assessment or observational scales?

OBJECTIVES: To assess the performance of self-assessment scales in severely demented hospitalized patients and to compare it with observational data. DESIGN: Prospective clinical study. SETTING: Geriatrics hospital and a geriatric psychiatry service. PARTICIPANTS: All patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for dementia, with a Mini-Mental State Examination score less than 11 and a Clinical Dementia Rating score of 3. MEASUREMENTS: Three self-assessment tools--the verbal, horizontal visual, and faces pain scales--were administered in randomized order. A nursing team independently completed an observational pain rating scale. Main outcomes were comprehension (ability to explain scale use and correctly indicate positions for no pain and extreme pain, on two separate occasions), inter- and intrarater reliability, and comparison of pain intensities measured by the different scales. RESULTS: Sixty-one percent of 129 severely demented patients (mean age 83.7, 69% women) demonstrated comprehension of at least one scale. Comprehension rates were significantly better for the verbal and the faces pain scales. For patients who demonstrated good comprehension, the inter- and intrarater reliability of the three self-assessment scales was high (intraclass correlation coefficient=0.88-0.98). Correlation between the three self-assessment scales was moderate to strong (Spearman correlation coefficient (r)=0.45-0.94; P<.001). Observational rating correlated at least moderately with self-assessment (r=0.25-0.63), although for patients reporting pain, the observational rating scale underestimated severity compared with all three self-assessment scales. CONCLUSION: Clinicians should not apply observational scales routinely in severely demented patients, because many are capable of reliably reporting their own pain.

Aged, 80 and over↗
PubMed2005

Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia.

BACKGROUND AND PURPOSE: Most previous studies addressed the cognitive impact of lacunar infarcts using radiologic correlations that are known to correlate poorly with neuropathological data. Moreover, absence of systematic bilateral assessment of vascular lesions and masking effects of Alzheimer disease pathology and macrovascular lesions may explain discrepancies among previous reports. To define the relative contribution of silent lacunes to cognitive decline, we performed a detailed analysis of lacunar and microvascular pathology in both cortical and subcortical areas of 72 elderly individuals without significant neurofibrillary tangle pathology or macrovascular lesions. METHODS: Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included Abeta-protein deposition staging and bilateral assessment of microvascular ischemic pathology and lacunes; statistical analysis included multivariate models controlling for age, amyloid deposits, and microvascular pathology. RESULTS: Thalamic and basal ganglia lacunes were negatively associated with CDR scores; cortical microinfarcts, periventricular and diffuse white matter demyelination also significantly affected cognition. In a multivariate model, cortical microinfarcts and thalamic and basal ganglia lacunes explained 22% of CDR variability; amyloid deposits and microvascular pathology explained 12%, and the assessment of thalamic and basal ganglia lacunes added an extra 17%. Deep white matter lacunes were not related to cognitive status in univariate and multivariate models. CONCLUSIONS: In agreement with the recently proposed concept of subcortical ischemic vascular dementia, our autopsy series provides important evidence that gray matter lacunes are independent predictors of cognitive decline in elderly individuals without concomitant dementing processes such as Alzheimer disease.

Aged↗
PubMed2005

Cognitive impact of neuronal pathology in the entorhinal cortex and CA1 field in Alzheimer's disease.

The relative contribution of Alzheimer's disease (AD) hippocampal neuronal pathology in cognitive decline is still a matter of debate. To address this issue, we performed a stereological analysis of layer II of the entorhinal cortex and the CA1 field of the hippocampus in 34 autopsy cases covering the whole spectrum of old age and Clinical Dementia Rating (CDR) scores. In both areas, the proportion of neurofibrillary tangle (NFT)-containing neurons increased steadily as a function of the CDR score. Questionable dementia was associated with a 1.9% neuronal loss in the entorhinal cortex and 26% in the CA1 field. NFT numbers predicted only 38% of the neuron number variability in the entorhinal cortex and 55% in the CA1 field. Neuron counts in the entorhinal cortex and both neuron and NFT counts in the CA1 field were significantly associated with cognitive status explaining 25% and 44% of the CDR variability, respectively. Our data reveal a dissociation between the patterns of progression of NFT and neuronal loss in the entorhinal cortex and CA1 field. Moreover, they show that less than 50% of the cognitive variability may be attributable to AD neuronal pathology in these areas.

Age Factors↗
PubMed2005

[The economical impact of dementia].

An epidemiology closely linked with the increase in life span. In most countries, the prevalence of dementia varies between 6 and 8% for individuals aged 65 years or more. It then dramatically increases with each subsequent decade, reaching around 30% of the population aged over 85. The costs associated with dementia are correlated with the increase in age and are of increasing concern for politicians, healthcare professionals and family members of demented patients. Current estimations are approximate, but dementia appears to be the most costly disease for society after the age of 65 years in France, the Netherlands, Sweden, or the United States. Detailed cost analyses have distinguished the direct medical,direct non-medical and intangible costs. The most important contribution in costs for society is the long-term care by health care professionals (institutionalization corresponding to 2/3 of the total costs for society!), but the care provided by the helpers and the families is even greater, even though difficult to quantify. The current question is to know whether present and future medical treatments will be able to reduce the tremendous financial costs of this chronic disease.

Activities of Daily Living↗
PubMed2005

Feasibility and reliability of four pain self-assessment scales and correlation with an observational rating scale in hospitalized elderly demented patients.

BACKGROUND: Acute and chronic pain is common in hospitalized demented elderly people, yet there are limited data about the performance of pain assessment tools in this population. The aim of this study was to evaluate the feasibility and reliability of four pain self-assessment scales in this population and compare their performance to an observational pain rating scale. METHODS: Our prospective clinical study was conducted in an acute-care and intermediate-care geriatric hospital on 160 consecutive inpatient referrals to the dementia consultation who met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for dementia. Exclusion criteria were delirium, terminal care, and severe sensory impairment. Four unidimensional self-assessment tools--the verbal, horizontal visual, vertical visual, and faces pain scales--were administered in randomized order to mild, moderate, and severely demented patients. An observational pain rating scale was independently completed by the nursing team. RESULTS: Only 12% of the 160 patients (mean age 85 years, 71% women) understood no scale. Respectively, 97%, 90%, and 40% of patients with mild, moderate, and severe dementia understood at least one scale (p <.05). There was a nonsignificant trend toward poorer comprehension of the faces scale. Test-retest reliability was high for all four self-assessment scales, and the correlation between these scales was very strong (Spearman's r(s) = 0.81-0.95; p <.001). Observational rating correlated moderately with self-assessment and tended to underestimate pain intensity (r(s) = 0.31-0.40; p <.05). CONCLUSIONS: Self-assessment pain scales can be used reliably in the vast majority of older hospitalized patients with mild to moderate dementia and in nearly half of those with severe dementia. Observational pain rating scales correlate only moderately with self-assessment and should be reserved for those few patients who have demonstrated that they cannot complete a self-assessment.

Aged↗
PubMed2005

Early event-related potential changes during working memory activation predict rapid decline in mild cognitive impairment.

BACKGROUND: The conversion of mild cognitive impairment (MCI) to Alzheimer's disease is associated with substantial compromise of neocortical circuits subserving rapid cognitive functions such as working memory. Event-related potential (ERP) analysis is a powerful tool to identify early impairment of these circuits, yet research for an electrophysiological marker of cognitive deterioration in MCI is scarce. Using a "2-back" activation paradigm, we recently described an electrophysiological correlate of working memory activation (positive-negative working memory [PN(wm)] component) over parietal electrodes. METHODS: Ours was a longitudinal study of 24 MCI patients with ERP analysis at inclusion and neuropsychological follow-up after 1 year. We used ERP waveform subtraction analysis between the n-back and control tasks. Analysis of variance (ANOVA) was used to compare electroencephalograph latencies between progressive MCI (PMCI) and stable MCI (SMCI), and univariate regression was used to assess the relationship between neuropsychological measures at baseline and clinical outcome. RESULTS: Thirteen (54%) MCI patients showed PMCI, and 11 (46%) remained stable (SMCI). In SMCI, a PN(wm) component with significantly larger density compared to baseline was identified when subtracting the detection task for both the 1- and 2-back tasks. In contrast, in PMCI, the PN(wm) component was absent in both 1-back and 2-back conditions. Neuropsychological variables and n-back test performance at inclusion did not predict cognitive deterioration 1 year later. CONCLUSIONS: In conjunction with recent functional imaging data, the present results support the notion of an early dysfunction of neural generators within the parietal cortex in MCI. They also reveal that the absence of the PN(wm) component may provide an easily applicable qualitative predictive marker of rapid cognitive deterioration in MCI.

Aged↗
PubMed2005

Pathological correlates of poststroke depression in elderly patients.

OBJECTIVE: The authors examined the relationship between poststroke depression and location of stroke. METHODS: They performed a clinicopathological analysis of 95 consecutively autopsied elderly initial-stroke survivors. RESULTS: The severity of brain vessel arteriosclerosis and frequency of brain vascular lesions were not significantly different between 21 cases with poststroke depression and 74 cases without. Earlier death was the only variable significantly associated with poststroke depression. No lesion pattern characterized the depression group. CONCLUSIONS: Neuropathological data confirm that depression is associated with worse prognosis in elderly stroke patients and lend support to the hypothesis that psychological rather than neurological factors are the main determinants of poststroke depression.

Aged↗
PubMed2004

Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study.

Ubiquitin-positive tau-negative inclusions were initially described in the rare form of frontotemporal dementia (FTD) associated with motor neuron disease. However, recent studies have indicated that these inclusions are also present in typical FTD, which is usually characterized by nonspecific histological changes. To examine the contribution of these inclusions to neuronal loss and to explore their relationship with disease duration, we performed a quantitative immunocytochemical analysis of 38 typical FTD cases. Relationships between neuron and ubiquitin inclusion densities as well as between duration of illness and neuropathological parameters was studied using linear regression in both univariate and multivariate models. Ubiquitin-positive tau-negative intracytoplasmic inclusions were present in 65.8% of cases in the dentate gyrus, 57.9% in temporal cortex and 31.6% in frontal cortex. The highest densities of ubiquitin-positive inclusions were consistently observed in the dentate gyrus, followed by the temporal and frontal cortex. There was no statistically significant relationship between neuron and ubiquitin-positive inclusion densities in any of the areas studied. In contrast, ubiquitin-positive inclusion densities in the dentate gyrus were negatively related to the duration of illness. Our data suggest that the development of ubiquitin-related pathology is the rule and not the exception in typical FTD, yet is not causally related to neuronal loss. They also reveal that the development of ubiquitin-positive inclusion densities in the dentate gyrus may be associated with a more aggressive form of the disease.

Adult↗
PubMed2004

Cortical microinfarcts and demyelination significantly affect cognition in brain aging.

BACKGROUND AND PURPOSE: Microvascular lesions are common in brain aging, but their clinical impact is debated. Methodological problems such as the masking effect of concomitant pathologies may explain discrepancies among previous studies. To evaluate the cognitive consequences of such lesions, we prospectively investigated elderly individuals with various degrees of cognitive impairment but without significant neurofibrillary tangle pathology or macrovascular lesions. METHODS: This was a clinicopathological study of 45 elderly individuals. Cognitive status was assessed prospectively with the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included Abeta-protein deposition staging and bilateral semiquantitative assessment of cortical microinfarcts, focal cortical and white matter glioses, and diffuse white matter and periventricular demyelination. RESULTS: In a univariate logistic regression model, cortical microinfarcts explained 36.1% of the variability in CDR; periventricular demyelination, 10.6%; and diffuse white matter demyelination, 4.6%. After controlling for age and Abeta-protein deposition, cortical microinfarcts were the best predictor of cognitive status (19.9% of CDR variability), whereas periventricular and diffuse white matter demyelination accounted for 9.7% and 5.4% of CDR variability, respectively. Altogether, these 3 types of microvascular lesions explained 27.9% of the clinical variability. Focal cortical and white matter glioses were not related to clinical outcome. CONCLUSIONS: Our data imply that cortical microinfarcts and both periventricular and deep white matter demyelination contribute significantly to the progression of cognitive deficits in brain aging. In contrast, the neuropathological evaluation of focal cortical and white matter gliosis has no clinical validity.

Aged↗
PubMed2003

A new electrophysiological index for working memory load in humans.

Working memory, the ability to store and simultaneously manipulate information, is affected in several neuropsychiatric disorders which lead to severe cognitive and functional deficits. An electrophysiological marker for this process could help identify early cerebral function abnormalities. In subjects performing working memory-specific n-back tasks, event-related potential analysis revealed a positive-negative waveform (PNwm) component modulated in amplitude by working memory load. It occurs in the expected time range for this process, 140-280 ms after stimulus onset, superimposed on the classical P200 and N200 components. Independent Component Analysis extracted two functional components with latencies and topographical scalp distributions similar to the PNwm. Our results imply that the PNwm represents a new electrophysiological index for working memory load in humans.

Adult↗
PubMed2003

Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers.

Alzheimer disease (AD) is characterized neuropathologically by neurofibrillary tangles and senile plaques. A key component of plaques is A beta, a polypeptide derived from A beta-precursor protein (APP) through proteolytic cleavage catalyzed by beta and gamma-secretase. We hypothesized that sequence variation in genes BACE1 (on chromosome 11q23.3) and BACE2 (on chromosome 21q22.3), which encode two closely related proteases that seem to act as the APP beta-secretase, may represent a genetic risk factor for AD. We analyzed the frequencies of single nucleotide polymorphisms (SNPs) in BACE1 and BACE2 genes in a community-based sample of 96 individuals with late-onset AD and 170 controls selected randomly among residents of the same community. The genotype data in both study groups did not demonstrate any association between AD and BACE1 or BACE2. After stratification for APOE status, however, an association between a BACE1 polymorphism located within codon V262 and AD in APOE epsilon 4 carriers was observed (P = 0.03). We conclude that sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; however, a combination of a specific BACE1 allele and APOE epsilon 4 may increase the risk for Alzheimer disease over and above that attributed to APOE epsilon 4 alone.

Alzheimer Disease↗
PubMed2003

Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson's disease.

Previous studies reported an association between cortical Lewy body (LB) formation and dementia in Parkinson's disease (PD). However, it is unclear whether cognitive decline in this disorder is related to specific patterns of LB distribution within the cerebral cortex. Moreover, the prediction of cognitive status based on concomitant assessment of LB and Alzheimer's disease lesions has led to conflicting results. We performed a clinicopathological study in 22 elderly PD patients in whom parkinsonism preceded cognitive decline by at least 3 years. Cognitive status was assessed prospectively using the clinical dementia rating scale (CDR); quantitative assessment of LB, neurofibrillary tangles (NFT), and senile plaques (SP) was performed in Brodmann areas 9, 21, 24, 40 and the entorhinal cortex. Statistical analysis was performed using both correlation coefficients and logistic regression models. There was a highly significant correlation between CDR scores and regional LB scores in the entorhinal cortex and area 24. LB and SP densities in the entorhinal cortex accounted for 36.2% and 19.3% of the variability in CDR scores. LB densities in area 24 could explain 25.2% of this variability. NFT densities did not predict cognitive status. In multivariate models only LB densities in the entorhinal cortex and anterior cingulate cortex were significantly associated with CDR scores. These results imply that an assessment of LB pathology limited to the entorhinal cortex and area 24 may be sufficient to predict cognition in PD. They also suggest that LB formation in limbic areas may be crucial for the development of PD dementia.

Age Distribution↗