Biomedical subjects

Panteleimon Giannakopoulos

Publications and source records attributed to Panteleimon Giannakopoulos.

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

Sustained astrocytic clusterin expression improves remodeling after brain ischemia.

Clusterin is a glycoprotein highly expressed in response to tissue injury. Using clusterin-deficient (Clu-/-) mice, we investigated the role of clusterin after permanent middle cerebral artery occlusion (MCAO). In wild-type (WT) mice, clusterin mRNA displayed a sustained increase in the peri-infarct area from 14 to 30 days post-MCAO. Clusterin transcript was still present up to 90 days post-ischemia in astrocytes surrounding the core infarct. Western blot analysis also revealed an increase of clusterin in the ischemic hemisphere of WT mice, which culminates up to 30 days post-MCAO. Concomitantly, a worse structural restoration and higher number of GFAP-reactive astrocytes in the vicinity of the infarct scar were observed in Clu-/- as compared to WT mice. These findings go beyond previous data supporting a neuroprotective role of clusterin in early ischemic events in that they demonstrate that this glycoprotein plays a central role in the remodeling of ischemic damage.

Animals↗

PubMed2006

Neural substrates of cognitive and behavioral deficits in atypical Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive cognitive decline that typically affects first memory and later executive functions, language, and visuospatial skills. This sequence of cognitive deterioration is thought to reflect the progressive invasion of the cerebral cortex by the two major pathological hallmarks of AD, neurofibrillary tangles (NFT) and senile plaques (SP), as well as degree of neuronal and synaptic loss. In atypical AD, prominent and early deficits are found in language, motor abilities, frontal and executive capacities, or visuospatial skills. These atypical clinical features are associated with an unusual pattern of NFT or SP formation that predominantly involves cortical areas usually spared in the course of the degenerative process. In an attempt to classify this highly heterogeneous subgroup, the present article provides an overview of clinicopathological analyses in patients with atypical progression of AD symptomatology with special reference to the relationship between specific cognitive and behavioral deficits and hierarchical patterns of AD lesion distribution within the cerebral cortex. On the basis of these representative examples of a cortical circuit-based approach to explore the mechanisms giving rise to AD neuropsychological expression, we also critically discuss the possibility to develop a matrix linking clinical presentations to degeneration of forward and backward long corticocortical pathways in this disorder.

Adult↗

PubMed2006

Increased infarct size and lack of hyperphagic response after focal cerebral ischemia in peroxisome proliferator-activated receptor beta-deficient mice.

Peroxisome proliferator-activated receptors (PPARs) are involved in energy expenditure, regulation of inflammatory processes, and cellular protection in peripheral tissues. Among the different types of PPARs, PPARbeta is the only one to be widely expressed in cortical neurons. Using PPARbeta knockout (KO) mice, we report here a detailed investigation of the role of PPARbeta in cerebral ischemic damage, associated inflammatory and antioxidant processes as well as food intake regulation after middle cerebral artery occlusion (MCAO). The PPARbeta KO mice had a two-fold increase in infarct size compared with wild-type (WT) mice. Brain oxidative stress was dramatically enhanced in these KO mice, as documented by an increased content of malondialdehyde, decreased levels of glutathione and manganese superoxide dismutase, and no induction of uncoupling protein 2 (UCP2) mRNA. Unlike WT mice, PPARbeta KO mice showed a marked increase of prooxidant interferon-gamma but no induction of nerve growth factor and tumor necrosis factor alpha after MCAO. In WT mice, MCAO resulted in inflammation-specific transient hyperphagia from day 3 to day 5 after ischemia, which was associated with an increase in neuropeptide Y (NPY) mRNA. This hyperphagic phase and NPY mRNA induction were not observed in PPARbeta KO mice. Furthermore, our study also suggests for the first time that UCP2 is involved in MCAO food intake response. These data indicate that PPARbeta plays an important role in integrating and regulating central inflammation, antioxidant mechanisms, and food intake after MCAO, and suggest that the use of PPARbeta agonists may be of interest for the prevention of central ischemic damage.

Animals↗

PubMed2006

Stereologic analysis of microvascular morphology in the elderly: Alzheimer disease pathology and cognitive status.

The presence of microvascular changes has been documented both in brain aging and Alzheimer disease (AD), although the relationship between the morphometry of brain capillaries and cognitive impairment is still unknown. We performed an analysis of capillary morphometric parameters and AD-related pathology in 19 elderly individuals with variable degrees of cognitive decline. Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale. Total capillary lengths and numbers as well as mean length-weighted diameter, total neurofibrillary tangle (NFT) and neuron numbers, and amyloid volume were estimated in entorhinal cortex and the CA1 field. Total capillary numbers and mean diameters explained almost 40% of the neuron number variability in both the CA1 and entorhinal cortex. Total capillary length and numbers in the CA1 and entorhinal cortex did not predict cognitive status. Mean capillary diameters in the CA1 and entorhinal cortex were significantly related to CDR scores, explaining 18.5% and 31.1% of the cognitive variability, respectively. This relationship persisted after controlling for NFT and neuron numbers in multivariate regression models. Consistent with the growing interest about microvascular pathology in brain aging, the present data indicate that changes in capillary morphometric parameters may represent independent predictors of AD-related neuronal depletion and cognitive decline.

Aged, 80 and over↗

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 and demographic determinants of dementia in depressed patients with subjective memory complaints.

BACKGROUND: Previous studies showed that late-life depression with subjective memory complaints (SMC) may be associated with an increased risk of developing dementia. However, not all such patients have cognitive decline. The aim of this longitudinal study was to identify possible clinical determinants of progressive deterioration in depressed elderly patients with SMC. METHOD: Forty-one consecutive patients referred to a memory clinic because of persistent SMC were investigated and received an ICD-10 diagnosis of mild to moderate depression. Over a mean follow-up period of 15 months, 9 of them (22%) developed dementia. Statistical analysis included Mann-Whitney U and Fisher's exact tests as well as univariate and multivariate logistic regression analyses to assess the relationship between cognitive decline and clinical, demographical and neuropsychological characteristics at baseline. RESULTS: Age at baseline was associated with subsequent dementia, and performance on immediate verbal prose recall and a visual organization test at the initial assessment were worse in those who showed cognitive decline. In a multivariate model, age and immediate recall predicted 32.7% of the cognitive variability, with an additional 2.4% when a visual organization test was added. There was no correlation between cognitive performance and severity of depression at baseline. The study was limited by a small sample size, the nondistinction of depressive subtypes and the absence of a formal neuropsychological assessment on follow-up. CONCLUSION: Impairment of the executive component of working memory as well as limited access to visual knowledge may predict cognitive deterioration in depressed patients with subjective memory complaints.

Aged↗

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

Stereologic analysis of hippocampal Alzheimer's disease pathology in the oldest-old: evidence for sparing of the entorhinal cortex and CA1 field.

Several neuropathologic analyses postulate that Alzheimer disease (AD) in the oldest-old is associated with substantial neurofibrillary tangle (NFT) formation in the CA fields of the hippocampus and neuronal loss confined to the entorhinal cortex. All of these studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathological hallmarks in a global multivariate analysis. We present here a stereologic analysis of AD-related pathology in 12 oldest-old individuals including a complete assessment of total NFT, neuron numbers and amyloid volume in entorhinal cortex, CA fields, and dentate gyrus. The progression of NFT numbers and amyloid volume across the different Clinical Dementia Rating (CDR) groups was significantly slower in these cases compared to previously reported younger cases. Although patients with mild and moderate dementia showed significantly lower mean neuron numbers compared to CDR 0-0.5 cases, there was a marked overlap in individual values among CDR groups. A modest proportion of the variability in CDR scores was explained by NFT numbers in the CA2 field (18.1%) and the dentate gyrus (17.3%). In contrast, neither Nissl-stained neuron numbers nor total amyloid volume in the areas studied significantly predicted cognitive status. These data indicate that the occurrence and progression of AD-related pathologic changes are not an unavoidable consequence of aging. They also suggest that dementia in extreme aging depends more on the damage of hippocampal subdivisions commonly less affected than on severe NFT formation and neuronal loss in the CA1 field and entorhinal cortex.

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

Humoral immunity in brain aging and Alzheimer's disease.

Although the contribution of inflammatory processes in the etiology of late-onset Alzheimer's disease (AD) has been suspected for years, most studies were confined to the analysis of cell-mediated immunological reactions thought to represent an epiphenomenon of AD lesion development. Based on the traditional view of the "immunological privilege" of the brain, which excludes a direct access of human immunoglobulins (Ig) to the central nervous system under normal conditions, little attention has been paid to a possible role of humoral immunity in AD pathogenesis. In the first part of this review, we summarize evidences for a blood-brain barrier (BBB) dysfunction in this disorder and critically comment on earlier observations supporting the presence of anti-brain autoantibodies and immunoglobulins (Ig) in AD brains. Current concepts regarding the Ig turnover in the central nervous system and the mechanisms of glial and neuronal Fc receptors activation are also discussed. In the second part, we present new ex vivo and in vitro data suggesting that human immunoglobulins can interact with tau protein and alter both the dynamics and structural organization of microtubules. Subsequent experiments needed to test this new working hypothesis are addressed at the end of the review.

Aging↗

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↗