Fulminant corticobasal degeneration: a distinct variant with predominant neuronal tau aggregates.

Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson's syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.

Comorbidity clusters in generalized osteoarthritis among female patients: A cross-sectional study.

OBJECTIVES: To investigate the prevalence of comorbidities among female patients with generalized osteoarthritis (GOA) in comparison to an age- and sex matched control group. To identify clusters of comorbidities in both groups. METHODS: An observational, cross-sectional study was conducted. Consecutive female patients with hand and knee osteoarthritis according to the American College of Rheumatology (ACR) classification criteria were invited to participate in the study. A control group of participants without musculoskeletal symptoms, history or evidence of osteoarthritis or inflammatory rheumatic disease were also included. Cardiovascular, obstructive pulmonary, gastrointestinal, endocrine, neurological, malignant diseases and depression were recorded in both groups. In both study groups comorbidity cluster and factor analysis was performed. RESULTS: The study population included 200 GOA and 200 control participants. The following comorbidities were observed adjusted to Bonferroni correction with a significantly higher prevalence among individuals with GOA: hypertension, uterine leiomyoma, gastroesophageal reflux disease, diverticulosis, upper gastrointestinal tract ulcers, depression, diseases with vertigo (benign paroxysmal positional vertigo and vertebrobasilar insufficiency) and surgery due to otoclerosis. In the GOA group 5 clusters were identified with different comorbidity patterns. CONCLUSION: We report a high comorbidity rate in GOA. Cluster analysis allowed us to identify different comorbidity subsets for vascular, gastrointestinal and malignant gynaecological disorders. Further research is required to understand the links between GOA and non-musculoskeletal comorbidities.

Association of cortical microinfarcts and cerebral small vessel pathology in the ageing brain.

AIMS: Cortical microinfarcts (CMI) are frequently observed in the ageing brain independent of cognitive decline, but their aetiology is not fully elucidated. To examine the potential role of different vessel pathologies, including cerebral amyloid angiopathy (CAA), arteriolosclerosis-hyalinosis and thromboembolism in the development of CMI, we examined 80 autopsy cases with more than one CMI on routine neuropathological examination. METHODS: Pial and intracortical vessels around CMI were assessed for their integrity with haematoxylin-eosin staining and antibodies against amyloid-ß protein and fibrinogen using a semiquantitative four-level rating scale (absent to severe) in the hippocampus, and the frontal, temporal and occipital cortex. Four histological categories of changes were defined: CAA, vessel pathology other than CAA, thromboembolism and absence of vessel pathology near CMI. RESULTS: A differential distribution of microvascular pathology was observed depending on brain regions. In the occipital cortex, CAA was commonly associated with CMI. In contrast, in the hippocampus and the frontal cortex, cases without any vascular pathology in pial and intracortical vessels were significantly more frequent. CONCLUSIONS: The aetiology of CMI differs depending on brain location. CAA may play a role principally in the occipital cortex. The large number of intact vessels around the CMI (mainly in the frontal cortex and hippocampus) raises the possibility that pathologies other than structural microangiopathy, including hypoperfusion/arterial hypotension or large vessel atherosclerosis, play a role in the development of microvascular lesions. These results are relevant in the context of aetiopathogenesis of vascular changes associated with conditions like vascular dementia.

Imaging of Neurovascular Compression Syndromes: Trigeminal Neuralgia, Hemifacial Spasm, Vestibular Paroxysmia, and Glossopharyngeal Neuralgia.

Neurovascular compression syndromes are usually caused by arteries that directly contact the cisternal portion of a cranial nerve. Not all cases of neurovascular contact are clinically symptomatic. The transition zone between the central and peripheral myelin is the most vulnerable region for symptomatic neurovascular compression syndromes. Trigeminal neuralgia (cranial nerve V) has an incidence of 4-20/100,000, a transition zone of 4 mm, with symptomatic neurovascular compression typically proximal. Hemifacial spasm (cranial nerve VII) has an incidence of 1/100,000, a transition zone of 2.5 mm, with symptomatic neurovascular compression typically proximal. Vestibular paroxysmia (cranial nerve VIII) has an unknown incidence, a transition zone of 11 mm, with symptomatic neurovascular compression typically at the internal auditory canal. Glossopharyngeal neuralgia (cranial nerve IX) has an incidence of 0.5/100,000, a transition zone of 1.5 mm, with symptomatic neurovascular compression typically proximal. The transition zone overlaps the root entry zone close to the brain stem in cranial nerves V, VII, and IX, yet it is more distal and does not overlap the root entry zone in cranial nerve VIII. Although symptomatic neurovascular compression syndromes may also occur if the neurovascular contact is outside the transition zone, symptomatic neurovascular compression syndromes are more common if the neurovascular contact occurs at the transition zone or central myelin section, in particular when associated with nerve displacement and atrophy.

The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease.

AIMS: Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid ß protein (Aß) in the meningeal and intracerebral vessels. It is often observed as an accompanying lesion of Alzheimer's disease (AD) or in the brain of elderly individuals even in the absence of dementia. CAA is largely age-dependent. In subjects with severe CAA a higher frequency of vascular lesions has been reported. The goal of our study was to define the frequency and distribution of CAA in a 1-year autopsy population (91 cases) from the Department of Internal Medicine, Rehabilitation, and Geriatrics, Geneva. MATERIALS AND METHODS: Five brain regions were examined, including the hippocampus, and the inferior temporal, frontal, parietal and occipital cortex, using an antibody against Aß, and simultaneously assessing the severity of AD-type pathology with Braak stages for neurofibrillary tangles identified with an anti-tau antibody. In parallel, the relationships of CAA with vascular brain lesions were established. RESULTS: CAA was present in 53.8% of the studied population, even in cases without AD (50.6%). The strongest correlation was seen between CAA and age, followed by the severity of amyloid plaques deposition. Microinfarcts were more frequent in cases with CAA; however, our results did not confirm a correlation between these parameters. CONCLUSION: The present data show that CAA plays a role in the development of microvascular lesions in the ageing brain, but cannot be considered as the most important factor in this vascular pathology, suggesting that other mechanisms also contribute importantly to the pathogenesis of microvascular changes.

[Alzheimer disease: from pathogenetic issues to clinical perspectives]. / Maladie d'Alzheimer: de la pathogénie aux perspectives cliniques.

The aim of this article is a critical review of the main pathogenetic issues debated in Alzheimer disease, with a focus on the clinical perspectives that could derive from. The pertinence of the amyloid cascade hypothesis as a unique and causal explanation of cognitive deterioration is challenged in the light of recent therapeutic failures of clinical trials and increasing role of tau protein in clinical expression. The detection of very early and possibly preclinical stages of the disease emerges as a necessary condition for the efficacy of future amyloid or tau-oriented curative strategies. In this respect, the possibility of finding individual vulnerability markers--in the group of patients with "mild cognitive impairment" or even in cognitively intact subjects--represents a major challenge of the clinical research in this field.

Microvascular changes in late-life schizophrenia and mood disorders: stereological assessment of capillary diameters in anterior cingulate cortex.

AIMS: Previous neuroimaging reports described morphological and functional abnormalities in anterior cingulate cortex (ACC) in schizophrenia and mood disorders. In earlier neuropathological studies, microvascular changes that could affect brain perfusion in these disorders have rarely been studied. Here, we analysed morphological parameters of capillaries in this area in elderly cases affected by these psychiatric disorders. METHODS: We analysed microvessel diameters in the dorsal and subgenual parts of the ACC in eight patients with schizophrenia, 10 patients with sporadic bipolar disorder, eight patients with sporadic major depression, and seven age- and gender-matched control cases on sections stained with modified Gallyas silver impregnation using a stereological counting approach. All individuals were drug-naïve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Statistical analysis included Kruskal-Wallis group comparisons with Bonferroni correction as well as multivariate regression models. RESULTS: Mean capillary diameter was significantly decreased in the dorsal and subgenual parts of areas 24 in bipolar and unipolar depression cases, both in layers III and V, whereas schizophrenia patients were comparable with controls. These differences persisted when controlling for age, local neuronal densities, and cortical thickness. In addition, cortical thickness was significantly smaller in both layers in schizophrenia patients. CONCLUSIONS: Our findings indicate that capillary diameters in bipolar and unipolar depression but not in schizophrenia are reduced in ACC. The significance of these findings is discussed in the light of the cytoarchitecture, brain metabolism and perfusion changes observed in ACC in mood disorders.

[Vascular dementia: big effects of small lesions]. / Démence vasculaire: les grands effets des petites lésions.

Vascular dementia due to multiple large strokes (multi-infarct dementia) is a well known entity. However, new clinicopathologic and neuroimaging data have highlighted the common occurrence of small vessel and microscopic vascular pathology in aging brains and recognized that vascular dementia due to small lesions is probably the most common form. In such cases, cortical microinfarcts are the strongest correlate of global cognitive function followed by basal ganglia and thalamic lacunes. Demyelination is only weekly associated with cognition and this relation is no longer significant after adjustement for the presence of lacunes. Awareness of the importance of small vascular lesions in brain aging, can improve diagnostic accuracy and help identify new targets, that could lead to novel therapeutic approaches in old age dementia.

Brain aging in the oldest-old.

Nonagenarians and centenarians represent a quickly growing age group worldwide. In parallel, the prevalence of dementia increases substantially, but how to define dementia in this oldest-old age segment remains unclear. Although the idea that the risk of Alzheimer's disease (AD) decreases after age 90 has now been questioned, the oldest-old still represent a population relatively resistant to degenerative brain processes. Brain aging is characterised by the formation of neurofibrillary tangles (NFTs) and senile plaques (SPs) as well as neuronal and synaptic loss in both cognitively intact individuals and patients with AD. In nondemented cases NFTs are usually restricted to the hippocampal formation, whereas the progressive involvement of the association areas in the temporal neocortex parallels the development of overt clinical signs of dementia. In contrast, there is little correlation between the quantitative distribution of SP and AD severity. The pattern of lesion distribution and neuronal loss changes in extreme aging relative to the younger-old. In contrast to younger cases where dementia is mainly related to severe NFT formation within adjacent components of the medial and inferior aspects of the temporal cortex, oldest-old individuals display a preferential involvement of the anterior part of the CA1 field of the hippocampus whereas the inferior temporal and frontal association areas are relatively spared. This pattern suggests that both the extent of NFT development in the hippocampus as well as a displacement of subregional NFT distribution within the Cornu ammonis (CA) fields may be key determinants of dementia in the very old. Cortical association areas are relatively preserved. The progression of NFT formation across increasing cognitive impairment was significantly slower in nonagenarians and centenarians compared to younger cases in the CA1 field and entorhinal cortex. The total amount of amyloid and the neuronal loss in these regions were also significantly lower than those reported in younger AD cases. Overall, there is evidence that pathological substrates of cognitive deterioration in the oldest-old are different from those observed in the younger-old. Microvascular parameters such as mean capillary diameters may be key factors to consider for the prediction of cognitive decline in the oldest-old. Neuropathological particularities of the oldest-old may be related to "longevity-enabling" genes although little or nothing is known in this promising field of future research.

Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.

AIMS: Previous neuropathological studies documented that small vascular and microvascular pathology is associated with cognitive decline. More recently, we showed that thalamic and basal ganglia lacunes are associated with post-stroke depression and may affect emotional regulation. The present study examines whether this is also the case for late-onset depression. METHODS: We performed a detailed analysis of small macrovascular and microvascular pathology in the post mortem brains of 38 patients with late-onset major depression (LOD) and 29 healthy elderly controls. A clinical diagnosis of LOD was established while the subjects were alive using the DSM-IV criteria. Additionally, we retrospectively reviewed all charts for the presence of clinical criteria of vascular depression. Neuropathological evaluation included bilateral semi-quantitative assessment of lacunes, deep white matter and periventricular demyelination, cortical microinfarcts and both focal and diffuse gliosis. The association between vascular burden and LOD was investigated using Fisher's exact test and univariate and multivariate logistic regression models. RESULTS: Neither the existence of lacunes nor the presence of microvascular ischaemic lesions was related to occurrence of LOD. Similarly, there was no relationship between vascular lesion scores and LOD. This was also the case within the subgroup of LOD patients fulfilling the clinical criteria for vascular depression. CONCLUSIONS: Our results challenge the vascular depression hypothesis by showing that neither deep white matter nor periventricular demyelination is associated with LOD. In conjunction with our previous observations in stroke patients, they also imply that the impact of lacunes on mood may be significant solely in the presence of acute brain compromise.

Clusterin expression during fetal and postnatal CNS development in mouse.

Clusterin (or apolipoprotein J) is a widely distributed multifunctional glycoprotein involved in CNS plasticity and post-traumatic remodeling. Using biochemical and morphological approaches, we investigated the clusterin ontogeny in the CNS of wild-type (WT) mice and explored developmental consequences of clusterin gene knock-out in clusterin null (Clu-/-) mice. A punctiform expression of clusterin mRNA was detected through the hypothalamic region, neocortex and hippocampus at embryonic stages E14/E15. From embryonic stage E16 to the first week of the postnatal life, the vast majority of CNS neurons expressed low levels of clusterin mRNA. In contrast, a very strong hybridizing signal mainly localized in pontobulbar and spinal cord motor nuclei was observed from the end of the first postnatal week to adulthood. Astrocytes expressing clusterin mRNA were often detected through the hippocampus and neocortex in neonatal mice. Real-time polymerase chain amplification and clusterin-immunoreactivity dot-blot analyses indicated that clusterin levels paralleled mRNA expression. Comparative analyses between WT and Clu-/- mice during postnatal development showed no significant differences in brain weight, neuronal, synaptic and astrocyte markers as well myelin basic protein expression. However, quantitative estimation of large motor neuron populations in the facial nucleus revealed a significant deficit in motor cells (-16%) in Clu-/- compared with WT mice. Our data suggest that clusterin expression is already present in fetal life mainly in subcortical structures. Although the lack of this protein does not significantly alter basic aspects of the CNS development, it may have a negative impact on neuronal development in certain motor nuclei.

Stereological analysis of neuropil threads in the hippocampal formation: relationships with Alzheimer's disease neuronal pathology and cognition.

Although neuropil threads are thought to account for 85-90% of cortical tau pathology in brain ageing, their clinical significance remains controversial. Previous studies have measured densities, rather than absolute numbers, and most did not take into account possible interactions among the pathological hallmarks of Alzheimer's disease (AD). We report here stereological estimates of total neurofibrillary tangle (NFT) and neuron numbers as well as total amyloid volume and neuropil thread (NT) length, in the hippocampus and entorhinal cortex of 19 very old individuals (age range: 83-101 years) with various degrees of cognitive decline. Total NT length in all areas studied increased in mildly demented cases but showed a marked decrease in Clinical Dementia Rating (CDR) scale 3 cases. Both total NFT and neuron numbers were related to NT length in the CA1 field and entorhinal cortex. A strong positive relationship was also present between the total NFT numbers in the entorhinal cortex and NT length in the CA1 field and dentate gyrus. Total NT length in the CA1 field was related to both CDR scores and presence or absence of dementia explaining 7% and 37% of their variability respectively. In multivariate models, this relationship was highly dependent on the severity of NFT formation in this area. Our data reveal that NT formation in hippocampal subdivisions and entorhinal cortex accompanies AD neuronal pathology in early stages of the degenerative process, yet its rate may decrease in severe dementia. In terms of clinicopathological correlations, NT length in the hippocampal formation does not represent an independent marker of dementia severity.

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 beta-protein (Abeta) 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%. Abeta 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, Abeta 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.

Neuropathological analysis of an asymptomatic adult case with Dandy-Walker variant.

The Dandy-Walker (DW) complex is a rare posterior fossa malformation, usually observed during the prenatal period or the early infancy. Clinically, it is characterized by mental retardation, seizures, cerebellar ataxia as well as symptoms of hydrocephalus. Structural imaging reveal a hypoplasia or agenesis of the cerebellar vermis, enlargement of the fourth ventricle with a posterior fossa cyst. Additional neurodevelopmental changes such as agenesis of the corpus callosum, lissencephaly and cortical dysplasia are also present. We report the first neuropathological analysis of an adult asymptomatic DW case. Brain computerized tomography showed a massive posterior fossa cyst and hypoplasia of the cerebellum. An Ehlers-Danlos syndrome type IV characterized by repetitive intestinal perforations and a saccular aneurysm on the left posterior communicating artery was also present. Macroscopic brain examination revealed hypoplasia of both cerebellar hemispheres and posterior part of the vermis, as well as dilatation of the fourth ventricle without hydrocephalus. The posterior fossa cyst wall was formed by an external arachnoid layer, middle layer with loose connective tissue and an internal layer of ependymal cells. There were two foci of cerebellar cortical dysplasia but no ectopic neurons, neuronal loss or gliosis in both cerebellum and cerebral cortex. No vascular or significant neurodegenerative lesions were observed. In comparison with previous reports in DW infants, this adult case displayed milder brain abnormalities compatible with a diagnosis of DW variant. The preservation of the cortical cytoarchitecture as well as the paucity of additional neurodevelopmental changes may explain the absence of clinical expression.

Expression of NOX1, a superoxide-generating NADPH oxidase, in colon cancer and inflammatory bowel disease.

Reactive oxygen species (ROS) are at the centre of many physiological and pathological processes. NOX1, a ROS-producing NADPH oxidase, is highly expressed in the colon but its function in colonic physiology or pathology is still poorly understood. It has been suggested to play a role in host defence, but also in cell growth and possibly malignant transformation. In this study we characterized NOX1 expression in human colon samples derived from healthy control subjects and patients with colon cancer or inflammatory bowel disease (IBD). NOX1 mRNA expression was assessed by dot-blot hybridization, real-time PCR and in situ hybridization, using samples derived from surgical specimens from patients undergoing colon resection. In normal tissues, NOX1 expression was low in the ileum, intermediate in the right colon, and high in the left colon (p = 0.0056 right vs. left colon). NOX1 mRNA levels were not influenced by factors linked to colon tumourigenesis, such as age or sex. Moreover, there was no statistical difference in NOX1 expression between samples derived from adenomas, well differentiated or poorly differentiated colon adenocarcinomas. At a cellular level, NOX1 was highly expressed in colon epithelial cells, both within the crypts and on the luminal surface. In addition, a population of lymphocytes, particularly in the appendix, showed NOX1 expression. Lymphocytes in lesions of Crohn's disease and ulcerative colitis were also strongly positive for NOX1. In conclusion, NOX1 is an enzyme that is constitutively expressed in colon epithelium and is not associated with tumourigenesis. Its distribution in crypts and on the luminal surface, as well as its left-to-right gradient in the colon, suggests a role in host defence function. In addition to the known epithelial localization, we define lymphocytes as a novel site of NOX1 expression, where it may potentially be involved in the pathogenesis of inflammatory bowel diseases.

Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia.

Ischemia-induced neuronal damage has been linked to elevated production of reactive oxygen species (ROS) both in animal models and in humans. NADPH oxidase enzymes (NOX-es) are a major enzymatic source of ROS, but their role in brain ischemia has not yet been investigated. The present study was carried out to examine the expression of NOX4, one of the new NADPH oxidase isoforms in a mouse model of focal permanent brain ischemia. We demonstrate that NOX4 is expressed in neurons using in situ hybridization and immunohistochemistry. Ischemia, induced by middle cerebral artery occlusion resulted in a dramatic increase in cortical NOX4 expression. Elevated NOX4 mRNA levels were detectable as early as 24 h after the onset of ischemia and persisted throughout the 30 days of follow-up period, reaching a maximum between days 7 and 15. The early onset suggests neuronal reaction, while the peak period corresponds to the time of neoangiogenesis occurring mainly in the peri-infarct region. The occurrence of NOX4 in the new capillaries was confirmed by immunohistochemical staining. In summary, our paper reports the presence of the ROS producing NADPH oxidase NOX4 in neurons and demonstrates an upregulation of its expression under ischemic conditions. Moreover, a role for NOX4 in ischemia/hypoxia-induced angiogenesis is suggested by its prominent expression in newly formed capillaries.

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.