AIMS: Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid beta protein (Abeta) 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 one-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 Abeta, 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 [...] KOVARI, Eniko Veronika, et al. The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease. Neuropathology and Applied Neurobiology, 2013, vol. 39, no. 5, p. 498-509 DOI : 10.1111/nan.12003

Recent findings in the XXIst century have revealed a high frequency of microscopic cerebral lesions including microinfarcts (MI) and microbleeds (MB). In order to determine their clinical impact on cognition, we have studied more than 300 cases that were evaluated cognitively and autopsied within 1 year. We explored the correlation between global cognitive function rated according to the clinical dementia rating scale (CDR) and the presence of MI on post-mortem brain neuropathological examination of older individuals. We also assessed potential associations between MI, MB and cerebral amyloid angiopathy (CAA). MI were a strong correlate of cognitive function explaining up to 36% of CDR variablility. In mixed cases MI neuropathological scores and Braak neurofibrillary tangle stages predicted the presence of dementia with more than 80% accuracy. MB were extremely frequent (up to 93% of the cases) but less clearly related to cognition. MI were not related to CAA and many cases of MB, including lobar MB occurred in the absence of CAA. Microscopic ischemic lesions, particularly MI are powerful determinants of cognition. They represent new and highly promising therapeutic targets and should lead us to review our understanding and current paradigms in vascular and mixed dementia.

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 beta 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. (C) 2017 Elsevier Inc. All rights reserved.

Recent accumulated evidence indicates that episodic memory impairments could be part of the initial clinical expression of frontotemporal dementia (FTD). An early study on this issue was carried out by Constantinidis and colleagues in 1974, but it was subsequently overlooked for a long period of time. The scope of the present research was: (a) to explore the presence of early episodic memory impairments in the entire population of neuropathologically confirmed FTD patients from the Geneva brain collection; and (b) to expand the present insight on the association between the initial symptomatology and various characteristics, namely gender, age at onset, disease duration, and presence of Pick body neuropathology. A careful review of the records of 50 FTD patients hospitalized at the Department of Psychiatry of the Bel-Air Hospital, Geneva, Switzerland, from 1929 to 1999, was conducted. Further in-depth neuropathological analysis with novel immunohistological methods was carried out in 37 of the cases. The data showed that memory impairments were the first clinical symptom in several of the patients. In addition, this specific phenotypic expression of FTD was associated with the female gender, advanced age, and positive Pick body neuropathology. The current findings give the opportunity to historically vindicate the early work of Constantinidis and colleagues. In addition, the novel observations about the association of episodic memory impairments with the female gender and positive Pick body neuropathology add to the existing knowledge about this phenotypic expression of FTD.

BACKGROUND/AIMS:Investigations of Aβ oligomers in neuropathologically confirmed Alzheimer's disease (AD) are still scarce. We report neurohistopathological and biochemical analyses using antibodies against tau and amyloid β (Aβ) 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 Aβ oligomer densities in the mesial temporal cortex (TC).RESULTS:NFT, fibrillar amyloid and Aβ oligomeric deposit densities were significantly higher in AD patients than in controls. There was no relationship between oligomeric Aβ densities and Braak NFT staging scores. Furthermore, Aβ oligomer expression was closely correlated with Aβ plaques in the TC. By Western blot, Aβ 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.

Lipofuscin pigment accumulation is among the most prominent markers of cellular aging in postmitotic cells. The formation of lipofuscin is related to oxidative enzymatic activity and free radical-induced lipid peroxidation. In various mammals such as rat, dog, macaque as well as in cheirogaleid primates, most of the large neurons, such as cerebellar Purkinje cells and neocortical pyramidal cells, show heavy lipofuscin accumulation in adulthood. In contrast, a well-known yet poorly studied feature of the aging human brain is that although lipofuscin accumulation is most marked in large neurons of the cerebral cortex, the large neurons of the cerebellar cortex—the Purkinje cells—appear to remain free of lipofuscin accumulation. It is however, not known whether this characteristic of human Purkinje cells is shared with other primates or other mammals. This study reports results from histological observation of Purkinje cells in humans, non-human primates, and other mammals. Procedures include histochemistry, immunocytochemistry, and fluorescence microscopy. Abundant lipofuscin deposition was observed in Purkinje cells of all the species we examined except Homo sapiens (including Alzheimer’s disease cases) and Pan troglodytes . In contrast, lipofuscin deposition was observed in neurons of the dentate nucleus. Our findings suggest that when compared with other primates, Purkinje cells in chimpanzees and humans might share a common aging pattern that involves mechanisms for neuroprotection. This observation is important when considering animal models of aging.

BACKGROUND:Alzheimer disease is characterized by cognitive decline, senile plaques of β-amyloid (Aβ) peptides, neurofibrillary tangles composed of hyperphosphorylated τ proteins and neuronal loss. Aβ 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 Aβ, 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 Aβ42 levels. Confocal microscopy revealed that JNK3 was associated with Aβ 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 hallmarks of Alzheimer's disease (AD) include tangles (NFT) and beta amyloid (Aβ) plaques. Despite numerous neuropathological studies that assessed the relationship of cognitive decline with neuropathologic lesions, their correlation still remains unclear. NFTs and Aβ 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.

Introduction Cerebral microbleeds correspond to blood breakdown products, including hemosiderin-containing macrophages around small vessels on histological examination. Superficial lobar cerebral microbleeds are increasingly recognized on MRI as a biomarker of cerebral amyloid angiopathy but the direct association between amyloid-laden vessels burden and cerebral microbleeds has yet to be validated neuropathologically. To address this issue, we examined the frequency of histopathologically-defined cerebral microbleeds in different brain regions and their relationship with cerebral amyloid angiopathy in a large autopsy population. Results The frontal, parietal and occipital cortex as well as the adjacent white matter and basal ganglia of 113 consecutive autopsies were examined. Cerebral microbleedss were identified on haematoxylin-eosin-stained histological slides, cerebral amyloid angiopathy using anti-amyloid antibody. Cerebral microbleeds were present in 92.9 % of the cases and cerebral amyloid angiopathy in 44.3 % of them. Cerebral microbleeds were more frequent in parietal and frontal lobes followed by the occipital region and basal ganglia. In contrast, cerebral amyloid angiopathy was most frequent in the occipital lobe. There was no significant topographical association between cerebral amyloid angiopathy presence or severity and cerebral microbleeds in any brain region. In lobar areas, cerebral amyloid angiopathy was found in the cortex, predominantly affecting pial arteries and their superficial cortical branches, in contrast to microbleeds which were mainly in the white matter and occurred around deeper arteries and arterioles, including the subcortical segment of long penetrating branches of pial vessels. Conclusions Our study does not support a direct relation between cerebral microbleeds and cerebral amyloid angiopathy burden at the neuropathological level, raising intriguing questions on the potential pathophysiological mechanisms of cerebral microbleeds in the context of cerebral amyloid angiopathy or other small vessel disease pathology.

In cognitively intact individuals and patients with Alzheimer’s disease (AD) the formation of neurofibrillary tangles (NFTs), senile plaques (SPs), and the synaptic loss characterizes the neuropathology of brain aging. There is a differential cortical vulnerability to the degenerative process in extreme brain aging. In the oldest-old population the distribution and the severity of NFTs and SPs could be different compared to younger persons.

About one third of Alzheimer's disease (AD) patients develop some parkinsonian features, yet half of them do not have Lewy body pathology at autopsy. The neuropathological substrate of parkinsonism in AD is still unclear. In the present study, we measured neuronal and neurofibrillary tangles (NFTs) densities in the substantia nigra pars compacta (SN) and in the putamen of 22 AD patients, 11 with and 11 without parkinsonism, here defined as the presence of bradykinesia and at least one of resting tremor, rigidity, or gait disorders. Our study showed that parkinsonism associated with AD was related to a significant loss of neurons both in the SN and in the putamen, suggesting pre-and postsynaptic alterations of the nigrostriatal pathway. Neuronal tau deposition was a less important factor as density of NFTs correlated with parkinsonism only in the SN but not in the putamen. We propose that a subgroup of pure AD patients develop parkinsonian symptoms as a result of neuronal loss in the basal ganglia, indicating a prominent subcortical involvement, which appears unrelated to the Braak stage of AD.

Physical exercise has frequently been the target of research studies related to the treatment of Alzheimer's disease. The level and routine of physical exercise can influence the progression of the disease, as well as influence the intensity of the deleterious effects from Alzheimer's disease. The objective of this article is to introduce the reader to this subject and point out the main findings in scientific literature related to physical exercise and its effects on Alzheimer's disease. This article will identify the general characteristics of the disease, the exercise programs currently used, and the main effects for each of these topics. It will also address a very current topic related to this issue, blood markers, and other techniques for future studies with this population.

Superficial layers I to III of the human cerebral cortex are more vulnerable toward Aβ peptides than deep layers V to VI in aging. Three models of layers were used to investigate this pattern of frailty. First, primary neurons from E14 and E17 embryonic murine cortices, corresponding respectively to future deep and superficial layers, were treated either with Aβ(1-42), okadaic acid, or kainic acid. Second, whole E14 and E17 embryonic cortices, and third, in vitro separated deep and superficial layers of young and old C57BL/6J mice, were treated identically. We observed that E14 and E17 neurons in culture were prone to death after the Aβ and particularly the kainic acid treatment. This was also the case for the superficial layers of the aged cortex, but not for the embryonic, the young cortex, and the deep layers of the aged cortex. Thus, the aged superficial layers appeared to be preferentially vulnerable against Aβ and kainic acid. This pattern of vulnerability corresponds to enhanced accumulation of senile plaques in the superficial cortical layers with aging and Alzheimer's disease.

Alzheimer's disease (AD) is characterized by senile plaques made of β-amyloid (Aβ) peptides, neurofibrillary tangles formed by hyperphosphorylated tau proteins, and neuronal loss. Aβ and tau are useful markers in the cerebrospinal fluid (CSF). C-Jun N-terminal kinases (JNKs) are serine-threonine protein kinases activated by phosphorylation. JNK3 is mainly expressed in the brain and JNKs can be involved in neuronal death. In this study, the levels of brain JNK isoforms and CSF JNK3 was evaluated in AD and control patients. In 10 AD and 10 control brains, JNKs levels were assessed by western blots and Aβ42 was evaluated by ELISA. In 8 AD and 9 control brains JNKs immunostainings were also carried out. CSF analysis included Aβ42, tau and ptau by ELISA and JNK3 by immunoblot in 30 AD patients and 26 neurological disease controls. AD patients were followed from two to three years using MMSE scores. Biochemical and histological results revealed significant increased JNK3 and phosphorylated JNK levels in AD brains and JNK3 levels correlated with Aβ42 levels. Confocal microscopy showed that JNK3 was associated with Aβ in senile plaques. CSF JNK3 levels were significantly enhanced in AD patients and were statistically correlated with the rate of cognitive decline. A mild enhancement of CSF JNK3 level was linked to a more accentuated slope of cognitive impairment. All together, brain and CSF JNK3 levels are increased in AD and CSF levels could reflect the rate of cognitive in AD patients.

About 30 % of Alzheimer’s disease (AD) patients develop parkinsonian features, but Lewy body pathology is not always present at autopsy. So the neuropathological substrate of extrapyramidal signs in AD remains unclear. In the present study neuronal and neurofibrillary tangle (NFT) densities were counted in the substantia nigra pars compacta (SN) and in the putamen of 22 AD patients, 11 with and 11 without parkinsonism. Parkinsonism was defined as the presence of bradykinesia and at least one of resting tremor, rigidity, or gait disorders. Our results showed that parkinsonism in AD is related to a significant neuronal loss both in the SN and in the putamen, suggesting pre- and postsynaptic alterations of the nigrostriatal pathway.

During the last century a worldwide population aging was observed, thanks to improved living and medical conditions. It is not known whether these progresses have had any effect on cerebral aging.

The XXth century has seen worldwide population aging thanks to improved living conditions and medical progress. It is not known whether these improvements have had any effect on cerebral aging. We compared amyloid deposition in autopsied cases aged 65 and over, between 1972 and 2006 in one hospital. Consecutive cases were included in 1972 to 1975, 1980, 1985, 1990, 1995, and 2000 to 2006. Multiple linear regression models were used to assess period effects adjusting for age and cognitive status. The amyloid/NFT stage ratio was calculated to account for possible changes in AD prevalence or severity over time. Yearly mean amyloid stage was significantly related to cohort year (p=0•001) in the total 1599 cases. In 1265 non-demented individuals, it decreased 24%, from 1•88 ± 0•89 to 1•57 ± 0•81 (p<0•0001). This was particularly marked in oldest age groups: people over 85 years in 2006 had lower average amyloid deposition than those 75 to 84 years old in 1972. The amyloid/NFT stage ratio decreased from 1•51 ± 0•74 to 0•99 ± 0•56 (p<0.0001) in non-demented cases and from 0•74 ± 0•13 to 0•56 ± 0•21 (p=0•0019) in individuals with dementia. These results are consistent with a strong period effect suggesting that the oldest-old were ten years younger (from an amyloid point of view) in the XXIst century compared to cohorts examined 30 years earlier. If this trend is confirmed in community-based studies it may lead to new insights in our understanding of both normal and pathological brain aging.