A Study of Aß Oligomers in the Temporal Cortex and Cerebellum of Patients with Neuropathologically Confirmed Alzheimer's Disease Compared to Aged Controls.

BACKGROUND/AIMS: Investigations of Aß oligomers in neuropathologically confirmed Alzheimer's disease (AD) are still scarce. We report neurohistopathological and biochemical analyses using antibodies against tau and amyloid ß (Aß) pathology. METHODS: Thirty elderly AD patients and 43 age-matched controls with or without deposition of amyloid plaques (AP) were analyzed by immunohistochemistry. In 21 cases with available fresh tissue, Western blots were also performed. Neuropathological analysis included quantitative assessment of neurofibrillary tangles (NFT), AP and Aß oligomer densities in the mesial temporal cortex (TC). RESULTS: NFT, fibrillar amyloid and Aß oligomeric deposit densities were significantly higher in AD patients than in controls. There was no relationship between oligomeric Aß densities and Braak NFT staging scores. Furthermore, Aß oligomer expression was closely correlated with Aß plaques in the TC. By Western blot, Aß oligomers were observed in AD patients, in plaque-free controls, in 1 'tangle-only AD' case, as well as in the cerebellum. A band near 55 kDa was the only Western blot signal that was significantly increased in the TC of AD patients compared to controls as well as less expressed in the cerebellum. CONCLUSION: These results suggest that a putative dodecamer, near 55 kDa, may contribute to AD vulnerability of the TC.

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline.

BACKGROUND: Alzheimer disease is characterized by cognitive decline, senile plaques of ß-amyloid (Aß) peptides, neurofibrillary tangles composed of hyperphosphorylated τ proteins and neuronal loss. Aß and τ are useful markers in the cerebrospinal fluid (CSF). C-Jun N-terminal kinases (JNKs) are serine-threonine protein kinases activated by phosphorylation and involved in neuronal death. METHODS: In this study, Western blots, enzyme-linked immunosorbent assay and histological approaches were used to assess the concentrations of Aß, τ and JNK isoforms in postmortem brain tissue samples (10 Alzheimer disease and 10 control) and in CSF samples from 30 living patients with Alzheimer disease and 27 controls with neurologic disease excluding Alzheimer disease. Patients with Alzheimer disease were followed for 1-3 years and assessed using Mini-Mental State Examination scores. RESULTS: The biochemical and morphological results showed a significant increase of JNK3 and phosphorylated JNK levels in patients with Alzheimer disease, and JNK3 levels correlated with Aß42 levels. Confocal microscopy revealed that JNK3 was associated with Aß in senile plaques. The JNK3 levels in the CSF were significantly elevated in patients with Alzheimer disease and correlated statistically with the rate of cognitive decline in a mixed linear model. LIMITATIONS: The study involved different samples grouped into 3 small cohorts. Evaluation of JNK3 in CSF was possible only with immunoblot analysis. CONCLUSION: We found that JNK3 levels are increased in brain tissue and CSF from patients with Alzheimer disease. The finding that increased JNK3 levels in CSF could reflect the rate of cognitive decline is new and merits further investigation.

Neuropathological changes in aging brain.

Neuropathological hallmarks of Alzheimer's disease (AD) include tangles (NFT) and beta amyloid (Aß) plaques. Despite numerous neuropathological studies that assessed the relationship of cognitive decline with neuropathologic lesions, their correlation still remains unclear. NFTs and Aß plaques have been widely implicated and described in normal aging. The number of NFTs in the CA1 and the entorhinal cortex seems to be more closely related to cognitive status, compared to the amyloid load whose role still remains controversial in the AD. In this review, we refer to our main studies performed in Geneva during the past two decades attempting to assess the correlation of pathology with clinical expression. The theory of cognitive reserve has been proposed for further understanding of interindividual differences in terms of compensation despite the presence of pathological lesions. The increasing prevalence of the AD, the limitations of actual treatments, as well as the high public cost reflect the imperative need for better therapeutic and early diagnosis strategies in the future.

Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway.

Beta-site APP cleaving enzyme 1 (BACE1) is the rate limiting enzyme for accumulation of amyloid ß (Aß)-peptide in the brain in Alzheimer's disease (AD). Oxidative stress (OS) that leads to metabolic dysfunction and apoptosis of neurons in AD enhances BACE1 expression and activity. The activation of c-jun N-terminal kinase (JNK) pathway was proposed to explain the BACE1 mRNA increase under OS. However, little is known about the translational control of BACE1 in OS. Recently, a post-transcriptional increase of BACE1 level controlled by phosphorylation of eIF2α (eukaryotic translation initiation factor-2α) have been described after energy deprivation. PKR (double-stranded RNA dependant protein kinase) is a pro-apoptotic kinase that phosphorylates eIF2α and modulates JNK activation in various cellular stresses. We investigated the relations between PKR, eIF2α and BACE1 in AD brains in APP/PS1 knock-in mice and in hydrogen peroxide-induced OS in human neuroblastoma (SH-SY5Y) cell cultures. Immunoblotting results showed that activated PKR (pPKR) and activated eIF2α (peIF2α) and BACE1 levels are increased in AD cortices and BACE1 correlate with phosphorylated eIF2α levels. BACE1 protein levels are increased in response to OS in SH-SY5Y cells and specific inhibitions of PKR-eIF2α attenuate BACE1 protein levels in this model. Our findings provide a new translational regulation of BACE1, under the control of PKR in OS, where eIF2α phosphorylation regulates BACE1 protein expression.

Neuroimaging of dementia in 2013: what radiologists need to know.

The structural and functional neuroimaging of dementia have substantially evolved over the last few years. The most common forms of dementia, Alzheimer disease (AD), Lewy body dementia (LBD) and fronto-temporal lobar degeneration (FTLD), have distinct patterns of cortical atrophy and hypometabolism that evolve over time, as reviewed in the first part of this article. The second part discusses unspecific white matter alterations on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images as well as cerebral microbleeds, which often occur during normal aging and may affect cognition. The third part summarises molecular neuroimaging biomarkers recently developed to visualise amyloid deposits, tau protein deposits and neurotransmitter systems. The fourth section reviews the utility of advanced image analysis techniques as predictive biomarkers of cognitive decline in individuals with early symptoms compatible with mild cognitive impairment (MCI). As only about half of MCI cases will progress to clinically overt dementia, whereas the other half remain stable or might even improve, the discrimination of stable versus progressive MCI is of paramount importance for both individual patient treatment and patient selection for clinical trials. The fifth and final part discusses the inter-individual variation in the neurocognitive reserve, which is a potential constraint for all proposed methods.

Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals.

Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'.

Neuropathological substrates and structural changes in late-life depression: the impact of vascular burden.

A first episode of depression after 65 years of age has long been associated with both severe macrovascular and small microvascular pathology. Among the three more frequent forms of depression in old age, post-stroke depression has been associated with an abrupt damage of cortical circuits involved in monoamine production and mood regulation. Late-onset depression (LOD) in the absence of stroke has been related to lacunes and white matter lesions that invade both the neocortex and subcortical nuclei. Recurrent late-life depression is thought to induce neuronal loss in the hippocampal formation and white matter lesions that affect limbic pathways. Despite an impressive number of magnetic resonance imaging (MRI) studies in this field, the presence of a causal relationship between structural changes in the human brain and LOD is still controversial. The present article provides a critical overview of the contribution of neuropathology in post-stroke, late-onset, and late-life recurrent depression. Recent autopsy findings challenge the role of stroke location in the occurrence of post-stroke depression by pointing to the deleterious effect of subcortical lacunes. Despite the lines of evidences supporting the association between MRI-assessed white matter changes and mood dysregulation, lacunes, periventricular and deep white matter demyelination are all unrelated to the occurrence of LOD. In the same line, neuropathological data show that early-onset depression is not associated with an acceleration of aging-related neurodegenerative changes in the human brain. However, they also provide data in favor of the neurotoxic theory of depression by showing that neuronal loss occurs in the hippocampus of chronically depressed patients. These three paradigms are discussed in the light of the complex relationships between psychosocial determinants and biological vulnerability in affective disorders.

Interhemispheric distribution of Alzheimer disease and vascular pathology in brain aging.

BACKGROUND AND PURPOSE: Most of the neuropathological studies in brain aging were based on the assumption of a symmetrical right-left hemisphere distribution of both Alzheimer disease and vascular pathology. To explore the impact of asymmetrical lesion formation on cognition, we performed a clinicopathological analysis of 153 cases with mixed pathology except macroinfarcts. METHODS: Cognitive status was assessed prospectively using the Clinical Dementia Rating scale; neuropathological evaluation included assessment of Braak neurofibrillary tangle and Ass deposition staging, microvascular pathology, and lacunes. The right-left hemisphere differences in neuropathological scores were evaluated using the Wilcoxon signed rank test. The relationship between the interhemispheric distribution of lesions and Clinical Dementia Rating scores was assessed using ordered logistic regression. RESULTS: Unlike Braak neurofibrillary tangle and Ass deposition staging, vascular scores were significantly higher in the left hemisphere for all Clinical Dementia Rating scores. A negative relationship was found between Braak neurofibrillary tangle, but not Ass staging, and vascular scores in cases with moderate to severe dementia. In both hemispheres, Braak neurofibrillary tangle staging was the main determinant of cognitive decline followed by vascular scores and Ass deposition staging. The concomitant predominance of Alzheimer disease and vascular pathology in the right hemisphere was associated with significantly higher Clinical Dementia Rating scores. CONCLUSIONS: Our data show that the cognitive impact of Alzheimer disease and vascular lesions in mixed cases may be assessed unilaterally without major information loss. However, interhemispheric differences and, in particular, increased vascular and Alzheimer disease burden in the right hemisphere may increase the risk for dementia in this group.

Differential impact of lacunes and microvascular lesions on poststroke depression.

BACKGROUND AND PURPOSE: Previous studies have postulated that poststroke depression (PSD) might be related to cumulative vascular brain pathology rather than to the location and severity of a single macroinfarct. We performed a detailed analysis of all types of microvascular lesions and lacunes in 41 prospectively documented and consecutively autopsied stroke cases. METHODS: Only cases with first-onset depression <2 years after stroke were considered as PSD in the present series. Diagnosis of depression was established prospectively using DSM-IV criteria for major depression. Neuropathological evaluation included bilateral semiquantitative assessment of microvascular ischemic pathology and lacunes; statistical analysis included Fisher exact test, Mann-Whitney U test, and regression models. RESULTS: Macroinfarct site was not related to the occurrence of PSD for any of the locations studied. Thalamic and basal ganglia lacunes occurred significantly more often in PSD cases. Higher lacune scores in basal ganglia, thalamus, and deep white matter were associated with an increased PSD risk. In contrast, microinfarct and diffuse or periventricular demyelination scores were not increased in PSD. The combined lacune score (thalamic plus basal ganglia plus deep white matter) explained 25% of the variability of PSD occurrence. CONCLUSIONS: The cumulative vascular burden resulting from chronic accumulation of lacunar infarcts within the thalamus, basal ganglia, and deep white matter may be more important than single infarcts in the prediction of PSD.

Assessing the role of cingulate cortex in bipolar disorder: neuropathological, structural and functional imaging data.

OBJECTIVES: Most of the neuroanatomical models of bipolar disorder (BD) propose a key role for the anterior cingulate cortex (ACC). We provide here a review of currently available data regarding the CC neuroimaging and neuropathological alterations in BD. MATERIALS AND METHODS: After an exploratory search of the MEDLINE, we first identified all English-written articles that provide separate data for BD patients and report original experimental data on cingulate gyrus. Subsequently, we selected those including neuroimaging or neuropathological data. Among the 161 articles updated through June 2007, 81 articles were retained using this procedure. RESULTS: The review of in vivo volumetric imaging data, as well as ex vivo morphometric and histological studies indicates that BD patients show volume changes of the subgenual ACC (sgACC-BA 25 and part of 24) during the early stages of the disease. Whether this phenomenon is due to neuronal and glial depletion or damage of corticocortical connections is still a matter of debate. The resting state activity in the left BA 25 appears to be state dependent showing significant increase during mania and decrease during depressive phases. The presence of a deficient GABAergic activity in ACC is also documented. Pharmacological treatment partly restores BD-related functional imaging changes. CONCLUSION: The present review reveals the striking discrepancies of the experimental results present both for functional and structural imaging studies but also for neuropathological analyses. Methodological and conceptual limitations are addressed with particular reference to the heterogeneity of BD clinical patterns. We also critically discuss the validity of CC changes as possible trait- or state-markers of the disease.

Clusterin increases post-ischemic damages in organotypic hippocampal slice cultures.

Clusterin or apolipoprotein J is a heterodimeric glycoprotein which is known to be increased during tissue involution in response to hormonal changes or injury and under circumstances leading to apoptosis. Previous studies in wild-type (WT) and clusterin-null (Clu-/-) mice indicated a protective role of clusterin over-expression in astrocytes lasting up to 90 days post-ischemia. However, in in vitro and in vivo models of neonatal hypoxia-ischemia, clusterin exacerbates necrotic cell death. We developed recombinant forms of clusterin and examined their effect on propidium iodide uptake, neuronal and synaptic markers as well as electrophysiological recordings in hippocampal slice cultures from Clu-/- and WT mice subjected to oxygen-glucose deprivation (OGD). WT mice displayed a marked up-regulation of clusterin associated with electrophysiological deficits and dramatic increase of propidium iodide uptake 5 days post-OGD. Immunocytochemical and western blot analyses revealed a substantial decrease of neuronal nuclei and synaptophysin immunoreactivity that predominated in WT mice. These findings contrasted with the relative post-OGD resistance of Clu-/- mice. The addition of biologically active recombinant forms of human clusterin for 24 h post-OGD led to the abolishment of the ischemic tolerance in Clu-/- slices. This deleterious effect of clusterin was reverted by the concomitant administration of the NMDA receptor antagonist, d-2-amino-5-phosphonopentanoate. The present data indicate that in an in vitro model of ischemia characterized by the predominance of NMDA-mediated cell death, clusterin exerts a negative effect on the structural integrity and functionality of hippocampal neurons.

Postsynaptic density protein PSD-95 expression in Alzheimer's disease and okadaic acid induced neuritic retraction.

In order to understand how plasticity is related to neurodegeneration, we studied synaptic proteins with quantitative immunohistochemistry in the entorhinal cortex from Alzheimer patients and age-matched controls. We observed a significant decrease in presynaptic synaptophysin and an increase in postsynaptic density protein PSD-95, positively correlated with beta amyloid and phosphorylated Tau proteins in Alzheimer cases. Furthermore, Alzheimer-like neuritic retraction was generated in okadaic acid (OA) treated SH-SY5Y neuroblastoma cells with no decrease in PSD-95 expression. However, in a SH-SY5Y clone with decreased expression of transcription regulator LMO4 (as observed in Alzheimer's disease) and increased neuritic length, PSD-95 expression was enhanced but did not change with OA treatment. Therefore, increased PSD-95 immunoreactivity in the entorhinal cortex might result from compensatory mechanisms, as in the SH-SY5Y clone, whereas increased Alzheimer-like Tau phosphorylation is not related to PSD-95 expression, as suggested by the OA-treated cell models.

Identification of Alzheimer and vascular lesion thresholds for mixed dementia.

To explore the pathological substrates of mixed dementia, we performed a detailed analysis of lacunar and microvascular pathology in 156 autopsied, elderly individuals with various degrees of Alzheimer's disease (AD) pathology. Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included Braak neurofibrillary tangle (NFT) and Ass-protein deposition staging and bilateral semi-quantitative assessment of microvascular ischaemic pathology and lacunes; statistics included univariate and multiple regression models controlling for age, and receiver-operating characteristic analysis. Sensitivity analysis was performed in a randomized derivation sub-sample and tested in a validation sub-sample. White matter lacunes, periventricular and diffuse white matter demyelination and focal and diffuse cortical gliosis were not associated with cognition. Braak NFT, Ass deposition, cortical microinfarcts (CMI) and thalamic and basal ganglia lacunes (TBGL) predicted 27% of CDR variability and 49% of the presence of dementia. Braak NFT, CMI and TBGL thresholds determined in a derivation sample yielded 0.88 sensitivity, 0.79 specificity and 0.85 correct classification rate for dementia in a validation sample. The same thresholds distinguished three groups of demented cases consistent with mixed dementia, pure vascular dementia and AD. These findings indicate that the clinical expression of the vascular component in mixed cases is highly dependent on lesion type and location as well as severity of concomitant AD-related pathology. Proposed thresholds for vascular and degenerative lesions predict the presence of dementia with great accuracy and provide a basis for distinguishing pure vascular dementia or AD from mixed cases.

Early Alzheimer-type lesions in cognitively normal subjects.

Amyloid deposits and tau-immunoreactive neurofibrillary tangles, together with neuronal and synaptic loss, are the neuropathological hallmarks of Alzheimer's disease (AD). Both proteins are present in the normal brain during aging. However, the temporal sequence of their involvement in the onset of AD pathology remains controversial. To define whether amyloid ß protein deposits or tau protein lesions appear first during normal brain aging, we performed an immunohistological study on serial sections from 105 autopsy brains (age range: 40-104 years) from patients free of clinical signs of cognitive decline, using anti-tau (AT8) and anti-amyloid (4G8) antibodies in the hippocampus, entorhinal cortex, inferior temporal cortex (Brodmann area 20), prefrontal cortex (Brodmann area 9), occipital cortex (Brodmann areas 17 and 18), and in the brainstem. All cases older than 48 years displayed at least a few neurofibrillary tangles, which appeared more frequently in the entorhinal than in the transentorhinal cortex. Tau pathology in these areas preceded tau inclusions in the brainstem. Furthermore, the first site of the apparition of tau pathology is inconsistent, being the entorhinal cortex in most cases, and in fewer cases, the transentorhinal region. There was no case presenting with amyloid deposition in the absence of neurofibrillary tangles, lending evidence to the fact that neurofibrillary tangles appear earlier than amyloid plaques during normal brain aging. However, the role of amyloid in promoting tau deposition cannot be excluded in some cases but may not represent the sole mechanism of disease induction and progression.

Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of lactate dehydrogenase 5 and pyruvate dehydrogenase.

BACKGROUND: For a long time now, glucose has been thought to be the main, if not the sole substrate for brain energy metabolism. Recent data nevertheless suggest that other molecules, such as monocarboxylates (lactate and pyruvate mainly) could be suitable substrates. Although monocarboxylates poorly cross the blood brain barrier (BBB), such substrates could replace glucose if produced locally. The two key enzymatiques systems required for the production of these monocarboxylates are lactate dehydrogenase (LDH; EC1.1.1.27) that catalyses the interconversion of lactate and pyruvate and the pyruvate dehydrogenase complex that irreversibly funnels pyruvate towards the mitochondrial TCA and oxydative phosphorylation. RESULTS: In this article, we show, with monoclonal antibodies applied to post-mortem human brain tissues, that the typically glycolytic isoenzyme of lactate dehydrogenase (LDH-5; also called LDHA or LDHM) is selectively present in astrocytes, and not in neurons, whereas pyruvate dehydrogenase (PDH) is mainly detected in neurons and barely in astrocytes. At the regional level, the distribution of the LDH-5 immunoreactive astrocytes is laminar and corresponds to regions of maximal 2-deoxyglucose uptake in the occipital cortex and hippocampus. In hippocampus, we observed that the distribution of the oxidative enzyme PDH was enriched in the neurons of the stratum pyramidale and stratum granulosum of CA1 through CA4, whereas the glycolytic enzyme LDH-5 was enriched in astrocytes of the stratum moleculare, the alveus and the white matter, revealing not only cellular, but also regional, selective distributions. The fact that LDH-5 immunoreactivity was high in astrocytes and occurred in regions where the highest uptake of 2-deoxyglucose was observed suggests that glucose uptake followed by lactate production may principally occur in these regions. CONCLUSION: These observations reveal a metabolic segregation, not only at the cellular but also at the regional level, that support the notion of metabolic compartmentalization between astrocytes and neurons, whereby lactate produced by astrocytes could be oxidized by neurons.

Sorting out the clinical consequences of ischemic lesions in brain aging: a clinicopathological approach.

BACKGROUND: Vascular lesions are particularly common in the aged brain. However, it is still unclear whether all such lesions affect cognition. OBJECTIVES: To better explore relationships between specific characteristics of vascular lesions (type, size and location) and cognitive status. METHODS: We performed a review of currently available neuroimaging and post-mortem studies taking into account several recent clinicopathological reports in elderly individuals with varying levels of cognitive impairment. RESULTS: New data reveals the significant impact of cortical microinfarcts on intellectual function, in contrast to focal cortical and white matter gliosis which are not significantly associated with cognitive status. Structural neuroimaging studies show inconsistent data regarding the cognitive consequences of WML. Neuropathological analyses reveal that both periventricular and subcortical demyelination are associated with cognitive status in the absence of macrovascular pathology. When lacunes are present, these microvascular lesions have no independent effect on intellectual impairment. The relationship between lacunes and cognition is highly dependent on localization. Basal ganglia and thalamic lacunes correlate with cognitive decline but not lacunes in the frontal, temporal and parietal deep white matter. CONCLUSION: Recent studies suggest that some cases of dementia might be misclassified: 1. Cases with typical Alzheimer course and moderate lacunes in subcortical white matter should probably be considered pure Alzheimer's disease. 2. The presence of microscopic infarcts can markedly impact cognition but is not detectable by currently available neuroimaging techniques and the vascular component of such mixed cases may go undiagnosed. The development of urgently needed new criteria for vascular dementia should take into account the relative contribution of various types of vascular lesions that can impact cognitive function.

Morphological substrates of cognitive decline in nonagenarians and centenarians: a new paradigm?

Brain aging is characterized by the formation of neurofibrillary tangles (NFT) and senile plaques (SP) in both cognitively intact individuals and patients with Alzheimer's disease (AD). The ubiquitous presence of these lesions and the steady increase of the prevalence of dementia up to 85 years have strongly supported a continuum between normal brain aging and AD. In this context, the study of nonagenarians and centenarians could provide key informations about the characteristics of extreme aging. We provide here a detailed review of currently available neuropathological data in very old individuals and critically discuss the patterns of NFT, SP and neuronal loss distribution as a function of age. In younger cohorts, NFTs are usually restricted to hippocampal formation, whereas clinical signs of dementia appear when temporal neocortex is involved. SPs would not be a specific marker of cognitive impairment as no correlation was found between their quantitative distribution and AD severity. The low rate of AD lesions even in severe AD as well as the weakness of clinicopathological correlations reported in the oldest-old indicate that AD pathology is not a mandatory phenomenon of increasing chronological age. Our recent stereological observations of hippocampal microvasculature in oldest-old cases challenge the traditional lesional model by revealing that mean capillary diameters is an important structural determinant of cognition in this age group.