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Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 06/2008; 79(6):630-5. DOI: 10.1136/jnnp.2007.124149
Source: PubMed


To use functional MRI (fMRI) to investigate whether hippocampal activation during a memory task can predict cognitive decline in individuals with mild cognitive impairment (MCI).
25 older individuals with MCI performed a visual scene encoding task during fMRI scanning, and were followed clinically for at least 4 years after scanning. A hypothesis driven analysis of fMRI data was performed. First, fMRI data were analysed at the group level to identify the regions of the hippocampal formation that were engaged by this memory task. Parameter estimates of each subject's memory related hippocampal activation (% signal change) were extracted and were analysed with a linear regression model to determine whether hippocampal activation predicted the degree or rate of cognitive decline, as measured by change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB).
Over 5.9 (1.2) years of follow-up after scanning, subjects varied widely in degree and rate of cognitive decline (change in CDR-SB ranged from 0 to 6, and the rate ranged from 0 to 1 CDR-SB unit/year). Greater hippocampal activation predicted greater degree and rate of subsequent cognitive decline (p<0.05). This finding was present even after controlling for baseline degree of impairment (CDR-SB), age, education and hippocampal volume, as well as gender and apolipoprotein E status. In addition, an exploratory whole brain analysis produced convergent results, demonstrating that the hippocampal formation was the only brain region where activation predicted cognitive decline.
In individuals with MCI, greater memory task related hippocampal activation is predictive of a greater degree and rate of cognitive decline subsequent to scanning. fMRI may provide a physiological imaging biomarker useful for identifying the subgroup of MCI individuals at highest risk of cognitive decline for potential inclusion in disease modifying clinical trials.

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Available from: Bradford Dickerson, Dec 13, 2013
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    • "Functional neuroimaging studies found greater activation in the hippocampus and other brain areas in MCI subjects compared to controls (Miller et al. 2008; Clément and Belleville 2010). Greater hippocampal activation correlated with increased brain b-amyloid deposition in PiB-PET scans (Huijbers et al. 2015) and greater rate of cognitive decline (Huijbers et al. 2015; Miller et al. 2008). Drugs with potential disease-modifying properties for AD can modulate neurotrophic systems. "
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    ABSTRACT: There is little information on the dynamics of BDNF in the CSF in the continuum between healthy aging, MCI and AD. We included 128 older adults (77 with amnestic MCI, 26 with AD and 25 healthy controls). CSF BDNF level was measured by ELISA assay, and AD biomarkers (Aβ42, T-Tau and P-Tau181) were measured using a Luminex xMAP assay. CSF BDNF levels were significantly reduced in AD subjects compared to MCI and healthy controls (p = 0.009). Logistic regression models showed that lower CSF BDNF levels (p = 0.008), lower CSF Aβ42 (p = 0.005) and lower MMSE scores (p = 0.007) are significantly associated with progression from MCI to AD. The present study adds strong evidence of the involvement of BDNF in the pathophysiology of neurodegenerative changes in AD. Interventions aiming to restore central neurotrophic support may represent future therapeutic targets to prevent or delay the progression from MCI to AD.
    Neuromolecular medicine 07/2015; 17(3). DOI:10.1007/s12017-015-8361-y · 3.68 Impact Factor
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    • "Based on the STAC-r model, we hypothesized that the cognitively intact APOE ε4 carriers would exhibit greater task-related brain activation than non-carriers at study entry, presumably reflecting a compensatory response that may signal subsequent cognitive decline (Miller et al., 2008). Over time, however, a breakdown of neural scaffolding in the APOE ε4 carrier group is predicted to occur, characterized by the presence of age-inappropriate cognitive impairment. "
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    ABSTRACT: Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer's disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65-85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy. Copyright © 2015 Elsevier Inc. All rights reserved.
    NeuroImage 02/2015; 111. DOI:10.1016/j.neuroimage.2015.02.011 · 6.36 Impact Factor
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    • "Specifically, studies of MCI subjects have shown a non-linear relationship between the BOLD response and cognitive impairment, where lessimpaired MCI subjects show increased activation compared to CN individuals and AD patients, and more impaired MCI subjects show reduced activation similar to patterns observed in mild AD. There is also evidence that increased activation in MCI positively predicts the degree and rate of cognitive decline (Miller et al. 2008), further suggesting that there is an early preclinical epoch, where up-regulation in the BOLD response is indicative of cognitive decline and conversion to AD. However, to date, there is a paucity of longitudinal studies that have explored this preclinical time-frame. "
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    ABSTRACT: Episodic memory decline is one of the earliest preclinical symptoms of AD, and has been associated with an upregulation in the BOLD response in the prodromal stage (e.g. MCI) of AD. In a previous study, we observed upregulation in cognitively normal (CN) subjects with subclinical episodic memory decline compared to non-decliners. In light of this finding, we sought to determine if a separate cohort of Decliners will show increased brain activation compared to Stable subjects during episodic memory processing, and determine whether the BOLD effect was influenced by cerebral blood flow (CBF) or gray matter volume (GMV). Individuals were classified as a "Decliner" if scores on the Rey Auditory Verbal Learning Test (RAVLT) consistently fell ≥ 1.5 SD below expected intra- or inter-individual levels. FMRI was used to compare activation during a facial recognition memory task in 90 Stable (age = 59.1) and 34 Decliner (age = 62.1, SD = 5.9) CN middle-aged adults and 10 MCI patients (age = 72.1, SD = 9.4). Arterial spin labeling and anatomical T1 MRI were used to measure resting CBF and GMV, respectively. Stables and Decliners performed similarly on the episodic recognition memory task and significantly better than MCI patients. Compared to Stables, Decliners showed increased BOLD signal in the left precuneus on the episodic memory task that was not explained by CBF or GMV, familial AD risk factors, or neuropsychological measures. These findings suggest that subtle changes in the BOLD signal reflecting altered neural function may be a relatively early phenomenon associated with memory decline.
    Brain Imaging and Behavior 10/2014; DOI:10.1007/s11682-014-9322-z · 4.60 Impact Factor
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