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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    • "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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    • "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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