Perception and cognition in Parkinson's disease: a neural network perspective

Parkinson’s disease (PD) is a neurodegenerative disorder commonly presenting with perceptual and cognitive dysfunction. Whereas previous work in PD suggests that abnormal basal ganglia activity has profound effects on integrated functioning of widespread cortical networks, the relation of specific network functions to the perceptual and cognitive impairments is still poorly understood. Here, I present a series of fMRI investigations of network-level functioning in non-demented individuals with PD with the aim of elucidating these associations. Study 1 examined the neural correlates of optic flow processing in 23 individuals with PD and 17 age-matched control participants (MC). An optic flow network comprising visual motion areas V6, V3A, MT+ and visuo-vestibular areas PIVC and CSv is known to be important for parsing egomotion depth cues in humans. The hypothesis was that individuals with PD would show less activation in these regions than MC when processing optic flow. While MC participants showed robust activation in this network, PD participants showed diminished activity within MT+ and CSv. Diminished CSv activity also correlated with greater disease severity. Study 2 investigated intrinsic network organization in PD with a focus on the functional coupling among three neurocognitive networks: the default-mode network (DMN), the salience network (SN), and the central executive network (CEN). Twenty-four individuals with PD and 20 MC participants were scanned at rest. The hypothesis was that PD participants would demonstrate dysfunctional SN coupling with the DMN and CEN. Relative to MC, in PD the CEN was less positively coupled with the SN and less anti-correlated with the DMN. Study 3 investigated the association between functional coupling and cognition in the same group that participated in Study 2. As hypothesized, anti-correlated functional coupling between the SN and DMN was related to successful performance on tests of executive function, psychomotor speed, and memory retrieval in MC but not in PD, suggesting that dysfunction within these networks could underlie early cognitive deficits in PD. Together, the results from the three studies suggest that dysfunctional activity in cortical networks important for visual motion processing and neurocognitive efficiency may underlie aspects of perceptual and cognitive impairment in PD.2017-12-06T00:00:00

Altered intrinsic functional coupling between core neurocognitive networks in Parkinson\u27s disease

Parkinson3s 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

Salience and default mode network coupling predicts cognition in aging and Parkinson’s disease

OBJECTIVES: Cognitive impairment is common in Parkinson’s 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 Parkinson’s 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 Parkinson’s disease.Published versio

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.Published versio

Auditory naming is impaired in posterior cortical atrophy and early-onset Alzheimer’s disease

IntroductionVisual naming ability reflects semantic memory retrieval and is a hallmark deficit of Alzheimer’s disease (AD). Naming impairment is most prominently observed in the late-onset amnestic and logopenic variant Primary Progressive Aphasia (lvPPA) syndromes. However, little is known about how other patients across the atypical AD syndromic spectrum perform on tests of auditory naming, particularly those with primary visuospatial deficits (Posterior Cortical Atrophy; PCA) and early onset (EOAD) syndromes. Auditory naming tests may be of particular relevance to more accurately measuring anomia in PCA syndrome and in others with visual perceptual deficits.MethodsForty-six patients with biomarker-confirmed AD (16 PCA, 12 lvPPA, 18 multi-domain EOAD), at the stage of mild cognitive impairment or mild dementia, were administered the Auditory Naming Test (ANT). Performance differences between groups were evaluated using one-way ANOVA and post-hoc t-tests. Correlation analyses were used to examine ANT performance in relation to measures of working memory and word retrieval to elucidate cognitive mechanisms underlying word retrieval deficits. Whole-cortex general linear models were generated to determine the relationship between ANT performance and cortical atrophy.ResultsBased on published cutoffs, out of a total possible score of 50 on the ANT, 56% of PCA patients (mean score = 45.3), 83% of EOAD patients (mean = 39.2), and 83% of lvPPA patients (mean = 29.8) were impaired. Total uncued ANT performance differed across groups, with lvPPA performing most poorly, followed by EOAD, and then PCA. ANT performance was still impaired in lvPPA and EOAD after cuing, while performance in PCA patients improved to the normal range with phonemic cues. ANT performance was also directly correlated with measures of verbal fluency and working memory, and was associated with cortical atrophy in a circumscribed semantic language network.DiscussionAuditory confrontation naming is impaired across the syndromic spectrum of AD including in PCA and EOAD, and is likely related to auditory-verbal working memory and verbal fluency which represent the nexus of language and executive functions. The left-lateralized semantic language network was implicated in ANT performance. Auditory naming, in the absence of a visual perceptual demand, may be particularly sensitive to measuring naming deficits in PCA

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

Alzheimer's 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 ϭ 18; MCI, N ϭ 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 ϭ Ϫ0.66; p Ͻ 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

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 Alzheimer's 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 Alzheimer's 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 Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection

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

Parkinson's 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

Diagnosis and Management of Posterior Cortical Atrophy.

Purpose of reviewThe study aims to provide a summary of recent developments for diagnosing and managing posterior cortical atrophy (PCA). We present current efforts to improve PCA characterisation and recommendations regarding use of clinical, neuropsychological and biomarker methods in PCA diagnosis and management and highlight current knowledge gaps.Recent findingsRecent multi-centre consensus recommendations provide PCA criteria with implications for different management strategies (e.g. targeting clinical features and/or disease). Studies emphasise the preponderance of primary or co-existing Alzheimer's disease (AD) pathology underpinning PCA. Evidence of approaches to manage PCA symptoms is largely derived from small studies.SummaryPCA diagnosis is frequently delayed, and people are likely to receive misdiagnoses of ocular or psychological conditions. Current treatment of PCA is symptomatic - pharmacological and non-pharmacological - and the use of most treatment options is based on small studies or expert opinion. Recommendations for non-pharmacological approaches include interdisciplinary management tailored to the PCA clinical profile - visual-spatial - rather than memory-led, predominantly young onset - and psychosocial implications. Whilst emerging disease-modifying treatments have not been tested in PCA, an accurate and timely diagnosis of PCA and determining underlying pathology is of increasing importance in the advent of disease-modifying therapies for AD and other albeit rare causes of PCA