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.

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.

Amnesia in frontotemporal dementia: shedding light on the Geneva historical data.

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.

A neuronal aging pattern unique to humans and common chimpanzees.

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.

No neuropathological evidence for a direct topographical relation between microbleeds and cerebral amyloid angiopathy.

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.

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.

Neuropathology of parkinsonism in patients with pure Alzheimer's disease.

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.

Comparison of frailty of primary neurons, embryonic, and aging mouse cortical layers.

Superficial layers I to III of the human cerebral cortex are more vulnerable toward Aß 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 Aß(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 Aß 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 Aß 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.

Amyloid deposition is decreasing in aging brains: an autopsy study of 1,599 older people.

OBJECTIVE: To explore cohort effects on age- and Alzheimer disease (AD)-related neuropathologic changes. METHODS: We compared amyloid deposition in autopsied cases aged 65 years and older who died between 1972 and 2006. We included consecutive cases for 1972-1975, 1980, 1985, 1990, 1995, and 2000-2006. We used linear regression models to assess period effects after adjustment for age, cognitive status, and neurofibrillary tangle (NFT) staging. We calculated amyloid/NFT stage ratios to account for possible changes in AD prevalence/severity over time. RESULTS: Mean amyloid stage was significantly related to year of death (p = 0.001) in the total population (1,599 cases, mean age 82 ± 8 years) and decreased 24%, from 1.88 ± 0.89 to 1.57 ± 0.81 (p < 0.0001), in 1,265 individuals without dementia. This decrease was particularly marked in the oldest age groups; people 85 years and older in 2006 had less amyloid deposition compared with those aged 75 to 84 years in 1972. Recent cohorts had lower amyloid deposition. The amyloid/NFT stage ratio decreased from 1.51 ± 0.74 to 0.99 ± 0.56 (p < 0.0001) in cases without dementia and from 0.74 ± 0.13 to 0.56 ± 0.21 (p = 0.0019) in individuals with dementia, confirming that more recent cases had less amyloid despite higher NFT densities. Cohort effects were highly significant (p < 0.0001). CONCLUSION: The strong cohort effect we describe may influence the performance of early amyloid-based AD markers. It also provides preclinical evidence supporting recently described decreases in AD incidence. This trend, if confirmed in community-based studies, may lead to new insights in our understanding of both normal and pathologic brain aging.

Do brain T2/FLAIR white matter hyperintensities correspond to myelin loss in normal aging? A radiologic-neuropathologic correlation study.

BACKGROUND: White matter hyperintensities (WMH) lesions on T2/FLAIR brain MRI are frequently seen in healthy elderly people. Whether these radiological lesions correspond to irreversible histological changes is still a matter of debate. We report the radiologic-histopathologic concordance between T2/FLAIR WMHs and neuropathologically confirmed demyelination in the periventricular, perivascular and deep white matter (WM) areas. RESULTS: Inter-rater reliability was substantial-almost perfect between neuropathologists (kappa 0.71 - 0.79) and fair-moderate between radiologists (kappa 0.34 - 0.42). Discriminating low versus high lesion scores, radiologic compared to neuropathologic evaluation had sensitivity / specificity of 0.83 / 0.47 for periventricular and 0.44 / 0.88 for deep white matter lesions. T2/FLAIR WMHs overestimate neuropathologically confirmed demyelination in the periventricular (p < 0.001) areas but underestimates it in the deep WM (0 < 0.05). In a subset of 14 cases with prominent perivascular WMH, no corresponding demyelination was found in 12 cases. CONCLUSIONS: MRI T2/FLAIR overestimates periventricular and perivascular lesions compared to histopathologically confirmed demyelination. The relatively high concentration of interstitial water in the periventricular / perivascular regions due to increasing blood-brain-barrier permeability and plasma leakage in brain aging may evoke T2/FLAIR WMH despite relatively mild demyelination.

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.

Neuropathology of dementia in a large cohort of patients with Parkinson's disease.

The aim of our study was to establish the contribution of distinct pathological aggregates (cortical Lewy bodies (LB), neuronal tau-inclusions and ß-amyloid plaque (Aß) deposition) in dementia related to Parkinson's disease (PD) in a large autopsy cohort. We studied the brains of 155 PD patients, 109 of whom were clinically demented. The total LB score, the Braak stages for neurofibrillary tangles (NFT) and the Thal phases for Aß deposition were assessed in each case, according to previously published guidelines. All the three lesion types were more abundant in the demented PD group, compared to the non-demented PD group, but neocortical LB pathology was the most important substrate of dementia. A significant correlation was found between the severity of Aß phases, NFT stages and cortical LB scores. In a subgroup of severely demented PD patients, cortical tau burden was much higher than in the rest of the group. Extensive cortical NFTs associate unavoidably with dementia. Some patients remain cognitively intact despite high cortical LB score. In conclusion, our data strongly support a combining, yet distinct role of neocortical LBs and tau deposits.

Etiologies of Parkinsonism in a century-long autopsy-based cohort.

We investigated the distribution of different etiologies underlying Parkinsonism in a hospital-based autopsy collection, studied the demographic data and evaluated diagnostic accuracy using histopathological examination as the gold standard. Out of a total of 9359 consecutive autopsy cases collected between 1914 and 2010, we identified 261 individuals who carried a clinical diagnosis of a Parkinsonian syndrome at death. A detailed neuropathological examination revealed idiopathic Parkinson's disease (PD) in 62.2%, progressive supranuclear palsy (PSP) in 4.2%, multiple system atrophy (MSA) in 2.3%, corticobasal degeneration (CBD) in 1.2%, postencephalitic Parkinsonism (PEP) in 2.7%, vascular Parkinsonism (VaP) in 8.8% and Alzheimer-type pathology (ATP) of the substantia nigra in 8%. The diagnostic accuracy of PD in our cohort was lower (71.2%) than those reported in previous studies, although it tended to increase during the last decades up to 85.7%. Of particular interest, we found that PD, while being the most frequent cause of Parkinsonism, was greatly overdiagnosed, with VaP and ATP being the most frequent confounding conditions.

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'.

Microvascular burden and Alzheimer-type lesions across the age spectrum.

The occurrence of microvascular and small macrovascular lesions and Alzheimer's disease (AD)-related pathology in the aging human brain is a well-described phenomenon. Although there is a wide consensus about the relationship between macroscopic vascular lesions and incident dementia, the cognitive consequences of the progressive accumulation of these small vascular lesions in the human brain are still a matter of debate. Among the vast group of small vessel-related forms of ischemic brain injuries, the present review discusses the cognitive impact of cortical microinfarcts, subcortical gray matter and deep white matter lacunes, periventricular and diffuse white matter demyelinations, and focal or diffuse gliosis in old age. A special focus will be on the sub-types of microvascular lesions not detected by currently available neuroimaging studies in routine clinical settings. After providing a critical overview of in vivo data on white matter demyelinations and lacunes, we summarize the clinicopathological studies performed by our center in large cohorts of individuals with microvascular lesions and concomitant AD-related pathology across two age ranges (the younger old, 65-85 years old, versus the oldest old, nonagenarians and centenarians). In conjunction with other autopsy datasets, these observations fully support the idea that cortical microinfarcts are the only consistent determinant of cognitive decline across the entire spectrum from pure vascular cases to cases with combined vascular and AD lesion burden.

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.