Panteleimon Giannakopoulos

Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease

Objective: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. Background: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. Methods: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. Results: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. Conclusions: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.

Evidence-based guidelines for mental, neurological, and substance use disorders in low- and middle-income countries: summary of WHO recommendations.

Shekhar Saxena and colleagues summarize the recent WHO Mental Health Gap Action Programme (mhGAP) intervention guide that provides evidence-based management recommendations for mental, neurological, and substance use (MNS) disorders.

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 A&bgr;-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 A&bgr;-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.

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 (48 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 (1525 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.

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 Aβ-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.

Cerebral cortex pathology in aging and Alzheimer's disease: a quantitative survey of large hospital-based geriatric and psychiatric cohorts

In order to explore the relationships between the involvement of specific neuronal populations and cognitive deterioration, and to compare the hierarchical patterns of cortical involvement in normal brain aging and Alzheimers disease, over 1200 brains from elderly subjects without cognitive deficits, as well as from patients with age-associated memory impairment and Alzheimers disease, were examined. Our results suggest that the neuropathological changes associated with normal brain aging and Alzheimers disease affect select cortical circuits at different points in time. Extensive hippocampal alterations are correlated with age-associated memory impairment, whereas substantial neurofibrillary tangle formation in neocortical association areas of the temporal lobe is a prerequisite for the development of Alzheimers disease. Despite several lines of evidence involving amyloid deposit in the pathogenesis of Alzheimers disease and Downs syndrome, our observations indicate that there is no correlation between senile plaque densities and degree of dementia in both disorders. In contrast to younger elderly cases, in the ninth and tenth decades of life, there is a differential cortical involvement in that parietal and cingulate areas are early affected in the course of Alzheimers disease, and neocortical senile plaques densities are strongly correlated with the severity of dementia. Moreover, Alzheimers disease symptomatology is characterized in these very old patients by high neurofibrillary tangle densities in the anterior CA1 field, but not in the entorhinal cortex and inferior temporal cortex. These observations are discussed in the light of the hypothesis of global corticocortical disconnection and with respect to the notion of selective neuronal vulnerability in Alzheimers disease.

Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: Stereologic analysis of prefrontal cortex area 9

We performed a stereologic analysis of a subset of pyramidal neurons known to be vulnerable in Alzheimers disease (AD) and characterized by particularly high somatodendritic levels of nonphosphorylated neurofilament protein. In the neocortex, these large pyramidal neurons reside in the deep part of layer III (layer IIIc) and the superficial part of layer V (layer Va). We focused on prefrontal cortex area 9 in elderly control cases in comparison to cases with different degrees of cognitive dysfunction. The results confirmed that these neurons are preferentially vulnerable in AD, as their numbers decrease dramatically in cases with definite dementia, correlating strongly with the severity of the disease, to a nearly complete loss (>90%) in the endstages of AD. Furthermore, a triple‐labeling experimental paradigm revealed that these particular neurons are far more likely to develop neurofibrillary tangles (NFT) and do so at a faster rate than other pyramidal cells. Nonphosphorylated neurofilament protein‐rich neurons also shrink considerably during formation of NFT and the largest among them are preferentially affected. Laminar differences in the severity of these effects were observed, layer Va being more severely affected, possibly correlating with the involvement of specific cortical projections. These data reveal that different populations of neurons prone to NFT formation are lost at different rates in AD, and that nonphosphorylated neurofilament protein‐enriched neurons emerge as a strikingly vulnerable subpopulation of neurons. Their preferential involvement suggests that neurons providing specific corticocortical connections between association areas are at high risk for degeneration in AD. J. Comp. Neurol. 463:281–302, 2003.

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.

Clinicometabolic dissociation of cognitive functions and social behavior in frontal lobe lesions.

Objective/background: Case studies suggest a dissociation between cognitive functions that have been impaired after damage to the dorsolateral prefrontal cortex and social skills disturbed when the ventromedial prefrontal areas are affected. Because this dissociation had not been confirmed in a clinical setting, clinicometabolic correlations were sought in 13 patients with various lesions of the prefrontal cortex. Design/methods: The clinical assessment included extensive testing of executive functions and evaluation of behavioral abnormalities based on an informant questionnaire. Regional cerebral glucose metabolism (rCMRGlu) was measured with [18F] fluorodeoxyglucose ([18F] FDG) and 31-slide high-resolution PET. Results: Executive-function test performance was significantly correlated with rCMRGlu in the dorsolateral prefrontal cortex (Brodmanns areas 8, 9, 45, 46, and 47) and anterior cingulate cortex (Brodmanns areas 24 and 32). Behavioral scores were significantly correlated with rCMRGlu in the frontopolar (Brodmanns area 10) and orbitofrontal cortex (Brodmanns areas 11, 12, 13, and 14). Conclusion: These results show that impaired executive functions and serial skill deficits are associated with distinct metabolic patterns in patients with frontal lobe pathology. In agreement with activation studies in normal subjects, our data suggest the existence of a modular organization of the frontal cortex in humans, as previously reported in nonhuman primates.

Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia

Objective: To investigate the possible synergistic effect of microvascular lesions with mild Alzheimer disease (AD) pathology in mixed cases. Methods: We assessed the cognitive impact of cortical microinfarcts, deep white matter and periventricular demyelination, as well as diffuse and focal gliosis in a large series of 43 prospectively evaluated autopsy cases scored Braak neurofibrillary tangle stage III, but without macroscopic vascular pathology or substantial non-AD, nonvascular microscopic lesions. We included bilateral assessment of all types of microvascular lesions and used multivariate models that control for the possible confounding effect of age and amyloid β-protein (Aβ) deposits. Results: Only cortical microinfarcts and periventricular demyelination were significantly associated with the Clinical Dementia Rating Scale (CDR) score. In a univariate model, the cortical microinfarct score explained 9% of the variability in CDR scores and periventricular demyelination score 7.3%. Aβ deposition explained only 3.5% of the CDR variability. In a logistic regression model, both variables were strongly associated with the presence of dementia (R = 0.45; p < 0.05). When the CDR sum of the boxes was used, Aβ staging explained 8.9% of cognitive variability, the addition of cortical microinfarct predicted an extra 15.5%, and that of periventricular demyelination an extra 9%. Conclusions: Cortical microinfarcts and, to a lesser degree, periventricular demyelination contribute to the cognitive decline in individuals at high risk for dementia. Both should be taken into account when defining the neuropathologic criteria for mixed dementia.