Selective Disruption of the Cerebral Neocortex in Alzheimer's Disease

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
PLoS ONE (Impact Factor: 3.23). 09/2010; 5(9):e12853. DOI: 10.1371/journal.pone.0012853
Source: PubMed


Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.
In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aβ levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.
Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.

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    • "While results from the MCI literature are promising, evidence suggests that disease-related neurobiological changes have already taken place prior to the onset of overt symptoms [27]–[29]. A number of studies have been aimed at identifying measures in cognitively normal subjects that are associated with future decline. "
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    ABSTRACT: This study aimed to identify baseline features of normal subjects that are associated with subsequent cognitive decline. Publicly available data from the Alzheimer's Disease Neuroimaging Initiative was used to find differences in baseline clinical assessments (ADAScog, AVLT, FAQ) between cognitively healthy individuals who will suffer cognitive decline within 48 months and those who will remain stable for that period. Linear regression models indicated an individual's conversion status was significantly associated with certain baseline neuroimaging measures, including posterior cingulate glucose metabolism. Linear Discriminant Analysis models built with baseline features derived from MRI and FDG-PET measures were capable of successfully predicting whether an individual will convert to MCI within 48 months or remain cognitively stable. The findings from this study support the idea that there exist informative differences between normal people who will later develop cognitive impairments and those who will remain cognitively stable for up to four years. Further, the feasibility of developing predictive models that can detect early states of cognitive decline in seemingly normal individuals was demonstrated.
    PLoS ONE 09/2013; 8(9):e74062. DOI:10.1371/journal.pone.0074062 · 3.23 Impact Factor
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    • "Three studies found that miR-9 was significantly up-regulated in the hippocampus and temporal lobe neocortex of AD brains compared to normal aging brains, indicating that miR-9 may play a pathological role in AD (Lukiw, 2007; Sethi and Lukiw, 2009; Lukiw et al., 2012). Because these brain regions show extensive pathology during the progression from health to AD (De Leon et al., 1997; Jack et al., 1998; Desikan et al., 2010; Nath et al., 2012; Spulber et al., 2012) up-regulation of miR-9 may play a role in degeneration. However, other studies found miR-9 was down-regulated in the hippocampus, anterior temporal cortex and medial frontal gyrus in AD patients (Cogswell et al., 2008; Hebert et al., 2008). "
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    ABSTRACT: Two of the main research priorities in the United States are cancer and neurodegenerative diseases, which are attributed to abnormal patterns of cellular behavior. MicroRNAs (miRNA) have been implicated as regulators of cellular metabolism, and thus are an active topic of investigation in both disease areas. There is presently a more extensive body of work on the role of miRNAs in cancer compared to neurodegenerative diseases, and therefore it may be useful to examine whether there is any concordance between the functional roles of miRNAs in these diseases. As a case study, the roles of miRNAs in Alzheimer's disease (AD) and their functions in various cancers will be compared. A number of miRNA expression patterns are altered in individuals with AD compared with healthy older adults. Among these, some have also been shown to correlate with neuropathological changes including plaque and tangle accumulation, as well as expression levels of other molecules known to be involved in disease pathology. Importantly, these miRNAs have also been shown to have differential expression and or functional roles in various types of cancer. To examine possible intersections between miRNA functions in cancer and AD, we review the current literature on these miRNAs in cancer and AD, focusing on their roles in known biological pathways. We propose a pathway-driven model in which some molecular processes show an inverse relationship between cancer and neurodegenerative disease (e.g., proliferation and apoptosis) whereas others are more parallel in their activity (e.g., immune activation and inflammation). A critical review of these and other molecular mechanisms in cancer may shed light on the pathophysiology of AD, and highlight key areas for future research. Conclusions from this work may be extended to other neurodegenerative diseases for which some molecular pathways have been identified but which have not yet been extensively researched for miRNA involvement.
    Frontiers in Genetics 11/2012; 3:323. DOI:10.3389/fgene.2012.00323
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    • "Neuropathological, cognitive and epidemiologic data are briefly summarized here (Table 1). The selection of the ITG for our analyses was guided by the following observations: (i) this region of the cerebral cortex shows reduced glucose utilization in AD and in asymptomatic individuals at risk genetically for AD(Small et al., 2000), (ii) ITG gray matter thickness significantly predicts hippocampal volume loss in both amyloid positive and hyperphosphorylated-tau positive individuals amongst MCI and AD individuals(Desikan et al., 2010), (iii) ITG amyloid loads and tangle density matched very well with average total brain amyloid burden (rho = 0.946, p < 0.0001) and tangle density (rho = 0.772, p < 0.0001). "
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    ABSTRACT: Recent evidence has emphasized soluble species of amyloid-β (Aβ) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Aβ, tau, and α-synuclein (αSyn) can promote each other's aggregation, the potential contribution of soluble αSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble αSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble αSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Aβ and tau levels. To examine a putative role for αSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type αSyn. The results revealed that an approximate threefold elevation of αSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble αSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Aβ/APP and human tau seems to be responsible for the abnormal elevation of soluble αSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal αSyn in AD pathophysiology.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2012; 32(30):10253-66. DOI:10.1523/JNEUROSCI.0581-12.2012 · 6.34 Impact Factor
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