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.

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.

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.

Detailed analyses of the neuropathologic changes in the cerebral cortex of elderly individuals and Alzheimer's disease patients have demonstrated that certain components of the neocortical and hippocampal circuits are likely to be selectively vulnerable. Based on the distribution of neurofibrillary tangles (NFTs) and senile plaques, it has been proposed that a global cortico-cortical disconnection leads to the loss of integrated functions observed in Alzheimer's disease. In order to investigate the distribution of lesions associated with aging as well as with the earliest symptoms of senile dementia, we performed a quantitative neuropathologic avaluation of a large series of elderly patients representing the entire autopsy population for the year 1989 from a geriatric hospital. Among the 145 cases quantitatively assessed, there were 102 nondemented patients, 33 patients presenting clinically with globally intact intellectual function but early signs of impairment of specific cognitive functions, and 10 cases with senile dementia of the Alzheimer type. All of the cases had NFTs in layer II of the entorhinal cortex, regardless of their clinical diagnosis, and most cases had some NFTs in the CA1 field of the hippocampus. Severe pathologic changes within the inferior temporal neocortex were observed only in the demented cases. The extent of amyloid deposition was not correlated with the clinical diagnosis and seemed to be present in the neocortical areas earlier than in the hippocampal formation. Also, several cases contained NFTs without amyloid deposition, but amyloid never occurred without NFTs. These results suggests that involvement of certain structures within the hippocampal formation is a consistent feature of aging. Thus, involvement of the hippocampal formation may be a necessary, but not sufficient, condition for the clinical expression of dementia, which is likely to be more closely related to the progressive degeneration of select neuronal populations in the neocortex.

The objective of this study was to determine the sensitivity and specificity of clinical criteria for possible vascular dementia (VaD) recently developed independently by two groups: the State of California Alzheimer9s Disease Diagnostic and Treatment Centers (ADDTC) and the National Institute for Neurological Disorders and Stroke with the Association Internationale pour la Recherche et l9Ehseignement en Neurosciences(NINDS-AIREN). We also wished to compare the performance of the new criteria to that of the Hachinski Ischemic Score (HIS). The study was comprised of a retrospective chart review and clinicopathologic correlation, and took place in 304-bed acute-care geriatric hospital. The subjects were 113 autopsied elderly patients with dementia, who were assessed to determine sensitivity and specificity of the ADDTC and NINDS-AIRENS criteria for possible VaD. Sensitivity and specificity were calculated using the neuropathologic diagnosis as a gold standard. Sensitivity was 0.63, and specificity was 0.64 for the ADDTC, 0.58 sensitivity and 0.80 specificity for the NINDS, and 0.43 sensitivity and 0.88 specificity for the HIS. Test combinations did not lead to substantial gains in sensitivity or specificity. The majority of patients with Alzheimer9s disease were successfully excluded by the ADDTC (87%), the NINDS-AIREN (91%), and the HIS (97%). The proportion of mixed dementia cases clinically misclassified as VaD was 54% for the ADDTC, 29% for the NINDS-AIREN, and 18% for the HIS. Low sensitivity is the main weakness of the above clinical criteria for possible VaD. Mixed dementia is better excluded by the NINDS-AIREN than the ADDTC. Data from this validation study provide valuable information to clinicians and researchers who wish to apply these criteria to the diagnosis of VaD.