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

University of Lausanne, Lausanne, Vaud, Switzerland
Journal of the Neurological Sciences (Impact Factor: 2.47). 07/2007; 257(1-2):72-9. DOI: 10.1016/j.jns.2007.01.025
Source: PubMed


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.

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    • "The published literature includes multiple studies of centenarians that came to autopsy. Research subjects in those studies were characterized neuropathologically with regard to the presence and severities of Alzheimer's disease (AD), Lewy body diseases (LBD), hippocampal sclerosis of aging (HS-Aging), cerebrovascular diseases (CVD), and other neuropathologic features (Giannakopoulos, et al., 2008, Giannakopoulos, et al., 1995a, Giannakopoulos, et al., 1993, Giannakopoulos, et al., 1995b, Gold, et al., 2000, Imhof, et al., 2007, Itoh, et al., 1998, Miller, et al., 2010, Mizutani and Shimada, 1992, von Gunten, et al., 2010). In addition to prior case series, there have been excellent reviews of the findings (Hof, et al., 1996, Imhof, et al., 2007, von Gunten, et al., 2010). "
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    ABSTRACT: With an emphasis on evolving concepts in the field, we evaluated neuropathologic data from very old research volunteers whose brain autopsies were performed at the University of Kentucky Alzheimer's Disease Center, incorporating data from the Georgia Centenarian Study (n = 49 cases included), Nun Study (n = 17), and University of Kentucky Alzheimer's Disease Center (n = 11) cohorts. Average age of death was 102.0 (range: 98-107) years overall. Alzheimer's disease pathology was not universal (62% with "moderate" or "frequent" neuritic amyloid plaque densities), whereas frontotemporal lobar degeneration was absent. By contrast, some hippocampal neurofibrillary tangles (including primary age-related tauopathy) were observed in every case. Lewy body pathology was seen in 16.9% of subjects and hippocampal sclerosis of aging in 20.8%. We describe anatomic distributions of pigment-laden macrophages, expanded Virchow-Robin spaces, and arteriolosclerosis among Georgia Centenarians. Moderate or severe arteriolosclerosis pathology, throughout the brain, was associated with both hippocampal sclerosis of aging pathology and an ABCC9 gene variant. These results provide fresh insights into the complex cerebral multimorbidity, and a novel genetic risk factor, at the far end of the human aging spectrum.
    Neurobiology of aging 10/2015; DOI:10.1016/j.neurobiolaging.2015.10.009 · 5.01 Impact Factor
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    • "Post mortem analyses of brains have uncovered many cases in which AD type plaques and tangles are present without the expected deficits in cognitive function (Davis et al., 1999; Price et al., 2009; Balasubramanian et al., 2012). Conversely, in studies of very old adults—individuals 80 to 100+ years old—up to 50% of dementias previously diagnosed as AD were later determined to be of unknown etiology (i.e., postmortem analysis failed to identify brain pathology typical of AD or other dementias; Crystal et al., 2000; Imhof et al., 2007; Middleton et al., 2011). So now, almost three decades after the birth of the amyloid hypothesis, it would seem that deposition of Aβ plaques is neither necessary nor sufficient to produce dementia characteristic of AD. "
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    ABSTRACT: As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia’s annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer’s disease (AD) is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (Aβ), either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD—though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE) genotype is the strongest genetic risk factor for AD: APOE-ε4 is proinflammatory and individuals with this genotype accumulate more Aβ, are at high risk of developing AD, and almost half of all AD patients have at least one ε4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in Aβ clearance, and getting good quality sleep vs. poor quality sleep might reduce the AD risk associated with neuroinflammation and the ε4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: (1) identify individuals at high risk for dementia who may benefit most from sleep interventions; (2) explore the role poor sleep quality plays in exacerbating AD type dementia; (3) examine the science of sleep interventions to date; and (4) provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia.
    Frontiers in Aging Neuroscience 12/2014; 6:325. DOI:10.3389/fnagi.2014.00325 · 4.00 Impact Factor
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    • "Current models of Alzheimer's disease suggest that dementia results when a neuropathological threshold is crossed (Vemuri et al., 2011). Several recent studies have suggested that this threshold between cognitively normal and individuals with Alzheimer's disease narrows with age, especially the oldest-old, those aged 585–90 years (Giannakopoulos et al., 1994; Riley et al., 2002; Imhof et al., 2007; Haroutunian et al., 2008; Savva et al., 2009). As the extensive pathological build up of tau and amyloid-b may precede the emergence of clinical Alzheimer's disease by decades (Braak and Braak, 1997; Sperling et al., 2011), the threshold of neuropathology that defines Alzheimer's disease is challenging to define due to the differential effects of age, individual resilience or plasticity and other unknown factors. "
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    ABSTRACT: The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-β, tau, TDP-43 and α-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n = 66) and without dementia (n = 42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-β, tau, TDP-43 and α-synuclein pathologies as well as hippocampal sclerosis. Amyloid-β and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-β area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while α-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-β continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-β pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-β plaques, more abundant neocortical amyloid-β deposition and hippocampal sclerosis with its attendant TDP-43 pathology.
    Brain 11/2011; 134(Pt 12):3708-15. DOI:10.1093/brain/awr308 · 9.20 Impact Factor
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