Deepti Putcha

Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden

Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimers disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimers disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimers-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Amyloid-β Associated Cortical Thinning in Clinically Normal Elderly

Both amyloid‐β (Aβ) deposition and brain atrophy are associated with Alzheimers disease (AD) and the disease process likely begins many years before symptoms appear. We sought to determine whether clinically normal (CN) older individuals with Aβ deposition revealed by positron emission tomography (PET) imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD.

Intrinsic connectivity between the hippocampus and posteromedial cortex predicts memory performance in cognitively intact older individuals.

Coherent fluctuations of spontaneous brain activity are present in distinct functional-anatomic brain systems during undirected wakefulness. However, the behavioral significance of this spontaneous activity has only begun to be investigated. Our previous studies have demonstrated that successful memory formation requires coordinated neural activity in a distributed memory network including the hippocampus and posteromedial cortices, specifically the precuneus and posterior cingulate (PPC), thought to be integral nodes of the default network. In this study, we examined whether intrinsic connectivity during the resting state between the hippocampus and PPC can predict individual differences in the performance of an associative memory task among cognitively intact older individuals. The intrinsic connectivity, between regions within the hippocampus and PPC that were maximally engaged during a subsequent memory fMRI task, was measured during a period of rest prior to the performance of the memory paradigm. Stronger connectivity between the hippocampal and posteromedial regions during rest predicted better performance on the memory task. Furthermore, hippocampal-PPC intrinsic connectivity was also significantly correlated with episodic memory measures on neuropsychological tests, but not with performance in non-memory domains. Whole-brain exploratory analyses further confirmed the spatial specificity of the relationship between hippocampal-default network posteromedial cortical connectivity and memory performance in older subjects. Our findings provide support for the hypothesis that one of the functions of this large-scale brain network is to subserve episodic memory processes. Research is ongoing to determine if impaired connectivity between these regions may serve as a predictor of memory decline related to early Alzheimers disease.

Hippocampal Hyperactivation Associated with Cortical Thinning in Alzheimer's Disease Signature Regions in Non-Demented Elderly Adults

Alzheimers disease (AD) is associated with functional and structural alterations in a distributed network of brain regions supporting memory and other cognitive domains. Functional abnormalities are present in mild cognitive impairment (MCI) with evidence of early hyperactivity in medial temporal lobe regions, followed by failure of hippocampal activation as dementia develops. Atrophy in a consistent set of cortical regions, the “cortical signature of AD,” has been reported at the stage of dementia, MCI, and even in clinically normal (CN) older individuals predicted to develop AD. Despite multiple lines of evidence for each of these findings, the relationship between this structural marker of AD-related neurodegeneration and this functional marker of the integrity of the episodic memory system has not yet been elucidated. We investigated this relationship in 34 nondemented older humans (CN, N = 18; MCI, N = 16). Consistent with previous studies, we found evidence of hippocampal hyperactivation in MCI compared with CN. Additionally, within this MCI group, increased hippocampal activation correlated with cortical thinning in AD-signature regions. Even within the CN group, increased hippocampal activity was negatively correlated with cortical thinning in a subset of regions, including the superior parietal lobule (r = −0.66; p < 0.01). These findings, across a continuum of nondemented and mildly impaired older adults, support the hypothesis that paradoxically increased hippocampal activity may be an early indicator of AD-related neurodegeneration in a distributed network.

Age and amyloid-related alterations in default network habituation to stimulus repetition.

The neural networks supporting encoding of new information are thought to decline with age, although mnemonic techniques such as repetition may enhance performance in older individuals. Accumulation of amyloid-β, one hallmark pathology of Alzheimers disease (AD), may contribute to functional alterations in memory networks measured with functional magnetic resonance imaging (fMRI) prior to onset of cognitive impairment. We investigated the effects of age and amyloid burden on fMRI activity in the default network and hippocampus during repetitive encoding. Older individuals, particularly those with high amyloid burden, demonstrated decreased task-induced deactivation in the posteromedial cortices during initial stimulus presentation and failed to modulate fMRI activity in response to repeated trials, whereas young subjects demonstrated a stepwise decrease in deactivation with repetition. The hippocampus demonstrated similar patterns across the groups, showing task-induced activity that decreased in response to repetition. These findings demonstrate that age and amyloid have dissociable functional effects on specific nodes within a distributed memory network, and suggest that functional brain changes may begin far in advance of symptomatic Alzheimers disease.

Altered intrinsic functional coupling between core neurocognitive networks in Parkinson's disease

Parkinsons disease (PD) is largely attributed to disruptions in the nigrostriatal dopamine system. These neurodegenerative changes may also have a more global effect on intrinsic brain organization at the cortical level. Functional brain connectivity between neurocognitive systems related to cognitive processing is critical for effective neural communication, and is disrupted across neurological disorders. Three core neurocognitive networks have been established as playing a critical role in the pathophysiology of many neurological disorders: the default-mode network (DMN), the salience network (SN), and the central executive network (CEN). In healthy adults, DMN–CEN interactions are anti-correlated while SN–CEN interactions are strongly positively correlated even at rest, when individuals are not engaging in any task. These intrinsic between-network interactions at rest are necessary for efficient suppression of the DMN and activation of the CEN during a range of cognitive tasks. To identify whether these network interactions are disrupted in individuals with PD, we used resting state functional magnetic resonance imaging (rsfMRI) to compare between-network connectivity between 24 PD participants and 20 age-matched controls (MC). In comparison to the MC, individuals with PD showed significantly less SN–CEN coupling and greater DMN–CEN coupling during rest. Disease severity, an index of striatal dysfunction, was related to reduced functional coupling between the striatum and SN. These results demonstrate that individuals with PD have a dysfunctional pattern of interaction between core neurocognitive networks compared to what is found in healthy individuals, and that interaction between the SN and the striatum is even more profoundly disrupted in those with greater disease severity.

Reliability of functional magnetic resonance imaging associative encoding memory paradigms in non-demented elderly adults.

Functional magnetic resonance imaging (fMRI) holds significant potential to aid in the development of early interventions to improve memory function, and to assess longitudinal change in memory systems in aging and early Alzheimers disease (AD). However, the test–retest reliability of hippocampal activation and of “beneficial” deactivation in the precuneus has yet to be fully established during memory encoding tasks in older subjects. Using a mixed block and event‐related face‐name associative encoding paradigm, we assessed the reliability of hippocampal activation and default network deactivation over a 4‐ to 6‐week interscan interval in 27 older individuals who were cognitively normal [Clinical Dementia Rating (CDR) Scale = 0; n = 18] or mildly impaired (CDR = 0.5; n = 9). Reliability was assessed in whole brain maps and regions of interest using both a full‐task paradigm of six functional runs as well as an abbreviated paradigm of the first two functional runs, which would be advantageous for use in clinical trials. We found reliable hippocampal signal response across both block‐ and event‐related designs in the right hippocampus. Comparable reliability in hippocampal activation was found in the full and the abbreviated paradigm. Similar reliability in hippocampal activation was observed across both CDR groups overall, but the CDR 0.5 group was more variable in left hippocampal activity. Task‐related deactivation in the precuneus demonstrated much greater variability than hippocampal activation in all analyses. Overall, these results are encouraging for the utility of fMRI in “Proof of Concept” clinical trials investigating the efficacy of potentially therapeutic agents for treatment of age‐related memory changes, cognitive impairment, and early AD. Hum Brain Mapp, 2011.

Functional correlates of optic flow motion processing in Parkinson's disease.

The visual input created by the relative motion between an individual and the environment, also called optic flow, influences the sense of self-motion, postural orientation, veering of gait, and visuospatial cognition. An optic flow network comprising visual motion areas V6, V3A, and MT+, as well as visuo-vestibular areas including posterior insula vestibular cortex (PIVC) and cingulate sulcus visual area (CSv), has been described as uniquely selective for parsing egomotion depth cues in humans. Individuals with Parkinson’s disease (PD) have known behavioral deficits in optic flow perception and visuospatial cognition compared to age- and education-matched control adults (MC). The present study used functional magnetic resonance imaging (fMRI) to investigate neural correlates related to impaired optic flow perception in PD. We conducted fMRI on 40 non-demented participants (23 PD and 17 MC) during passive viewing of simulated optic flow motion and random motion. We hypothesized that compared to the MC group, PD participants would show abnormal neural activity in regions comprising this optic flow network. MC participants showed robust activation across all regions in the optic flow network, consistent with studies in young adults, suggesting intact optic flow perception at the neural level in healthy aging. PD participants showed diminished activity compared to MC particularly within visual motion area MT+ and the visuo-vestibular region CSv. Further, activation in visuo-vestibular region CSv was associated with disease severity. These findings suggest that behavioral reports of impaired optic flow perception and visuospatial performance may be a result of impaired neural processing within visual motion and visuo-vestibular regions in PD.

Salience and Default Mode Network Coupling Predicts Cognition in Aging and Parkinson’s Disease

OBJECTIVES Cognitive impairment is common in Parkinsons disease (PD). Three neurocognitive networks support efficient cognition: the salience network, the default mode network, and the central executive network. The salience network is thought to switch between activating and deactivating the default mode and central executive networks. Anti-correlated interactions between the salience and default mode networks in particular are necessary for efficient cognition. Our previous work demonstrated altered functional coupling between the neurocognitive networks in non-demented individuals with PD compared to age-matched control participants. Here, we aim to identify associations between cognition and functional coupling between these neurocognitive networks in the same group of participants. METHODS We investigated the extent to which intrinsic functional coupling among these neurocognitive networks is related to cognitive performance across three neuropsychological domains: executive functioning, psychomotor speed, and verbal memory. Twenty-four non-demented individuals with mild to moderate PD and 20 control participants were scanned at rest and evaluated on three neuropsychological domains. RESULTS PD participants were impaired on tests from all three domains compared to control participants. Our imaging results demonstrated that successful cognition across healthy aging and Parkinsons disease participants was related to anti-correlated coupling between the salience and default mode networks. Individuals with poorer performance scores across groups demonstrated more positive salience network/default-mode network coupling. CONCLUSIONS Successful cognition relies on healthy coupling between the salience and default mode networks, which may become dysfunctional in PD. These results can help inform non-pharmacological interventions (repetitive transcranial magnetic stimulation) targeting these specific networks before they become vulnerable in early stages of Parkinsons disease.

Predictors of independence in instrumental activities of daily living: Amnestic versus nonamnestic MCI

ABSTRACT Introduction: Individuals with mild cognitive impairment (MCI) demonstrate deficits in instrumental activities of daily living (IADL) that place them at high risk for progression to dementia. The cognitive profiles, IADL deficits, and risk of progression differ between MCI subgroups of amnestic (aMCI) and nonamnestic MCI (naMCI), though many studies of functional impairment have not examined these subgroups separately. This study aims to determine whether common neuropsychological measures, as well as the related concept of patient anosognosia, are associated with IADL functioning differently in aMCI compared to naMCI. Method: Seventy-one individuals were identified as naMCI, and 99 individuals were identified as aMCI based on neuropsychological evaluation. Controlling for age, gender, and education, we examined whether performance on neuropsychological tests predicted informant-rated IADL dysfunction. We also investigated the ability of patient awareness, as rated by clinicians and informants, to predict informant-rated IADL dysfunction within MCI subgroups. Results: Better performance in cognitive domains of attention/processing speed and executive functioning predicted IADL independence in aMCI, but not in naMCI. Exploratory analysis with a subset of these individuals revealed that after accounting for an estimate of cerebrovascular burden, better performance in Delayed Memory predicted IADL independence in the naMCI group, but not in the aMCI group. Lastly, informant, but not clinician, ratings of patient awareness predicted IADL independence within the aMCI group only. Conclusion: Neuropsychological performance on tests of attention/processing speed and executive functioning may be better able to predict cognitive contributions to IADL dysfunction specifically in aMCI. After controlling for vascular burden, memory deficits may be the earliest cognitive indication of IADL dysfunction in naMCI. These results suggest that executive functions and memory, in addition to patient’s awareness of deficits, differentially predict early IADL dysfunction in subgroups of MCI and can be used to formulate patient prognosis and recommendations on a more individualized basis.