Biology subjects

Dagher, A.

Publications and source records attributed to Dagher, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2019

Disrupted neural synchrony mediates the relationship between white matter integrity and cognitive performance in older adults.

Our main goal was to determine the influence of white matter integrity on the dynamic coupling between brain regions and the individual variability of cognitive performance in older adults. EEG was recorded while participants performed a task specifically designed to engage working memory and inhibitory processes, and the associations among functional activity, structural integrity, and cognitive performance were assessed. We found that the association between white matter microstructural integrity and cognitive functioning with aging is mediated by time-varying alpha and gamma phase-locking value (PLV). Specifically, older individuals with better preservation of the inferior fronto-occipital fasciculus showed greater task-related modulations of alpha and gamma long-range PLV between the inferior frontal gyrus and occipital lobe, lower local phase-amplitude coupling in occipital lobes, and better cognitive control performance. Our results help delineate the role of individual variability of white matter microstructure in dynamic synchrony and cognitive performance during normal aging, and show that even small reductions in white matter integrity can lead to altered communications between brain regions, which in turn can result in reduced efficiency of cognitive functioning. Significance statementCognitive aging is associated with large individual differences, as some individuals maintain cognitive performance similar to that of young adults while others are significantly impaired. We hypothesized that individual differences in white matter integrity would influence the functional synchrony between frontal and posterior brain regions, and cognitive performance in older adults. We found that the association between reduced tract integrity and worse cognitive performance in older adults was mediated by task-related modulations of coupling synchrony in the alpha and gamma bands. Results offer a mechanistic explanation for the neural basis of the variability of cognitive performance in older adults who do not have any clinically diagnosable neuropathology, and for the association between structural network integrity and cognition in older adults.

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bioRxiv2019

Neural correlates of evidence and urgency during human perceptual decision-making in dynamically changing conditions

Current models of decision-making assume that the brain gradually accumulates evidence and drifts towards a threshold which, once crossed, results in a choice selection. These models have been especially successful in primate research, however transposing them to human fMRI paradigms has proved challenging. Here, we exploit the face-selective visual system and test whether decoded emotional facial features from multivariate fMRI signals during a dynamic perceptual decision-making task are related to the parameters of computational models of decision-making. We show that trial-by-trial variations in the pattern of neural activity in the fusiform gyrus reflect facial emotional information and modulate drift rates during deliberation. We also observed an inverse-urgency signal based in the caudate nucleus that was independent of sensory information but appeared to slow decisions, particularly when information in the task was ambiguous. Taken together, our results characterize how decision parameters from a computational model (i.e., drift rate and urgency signal) are involved in perceptual decision-making and reflected in the activity of the human brain.

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bioRxiv2019

Nucleus accumbens volume is related to obesity measures in an age-dependent fashion

Motivation theories of obesity suggest that one of the brain mechanisms underlying pathological eating and weight gain is the dysregulation of dopaminergic circuits. While these dysregulations occur likely at the microscopic level, studies on gray matter volume reported macroscopic differences associated with obesity. One region suggested to play a key role in the pathophysiology of obesity is the nucleus accumbens (NAcc). We performed a meta-analysis of findings regarding NAcc volume and overweight/obesity. We additionally examined whether gray matter volume in the NAcc and other mesolimbic areas depends on the longitudinal trajectory of obesity, using the UK Biobank dataset. To this end, we analysed the data using a latent growth model, which identifies whether certain variables of interest (e.g. NAcc volume) is related to another variables (BMI) initial values or longitudinal trajectories. Our meta-analysis showed that, overall, NAcc volume is positively related to BMI. However, further analyses revealed that the relationship between NAcc volume and BMI is dependent on age. For younger individuals such relationship is positive, while for older adults it is negative. This was corroborated by our analysis in the UK Biobank dataset, which includes older adults, where we found that higher BMI was associated with lower NAcc and thalamus volume. Overall, our study suggests that increased NAcc volume in young age might be a vulnerability factor for obesity, while in the older age decreased NAcc volume with increased BMI might be an effect of prolonged influences of neuroinflammation on the brain.

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bioRxiv2019

Activity in the left amygdala in response to foods differs depending on the emotional context

Emotions can influence our eating behaviors. Facing an acute stressor or being in a positive mood are examples of situations that tend to modify appetite. However, the question of how the brain integrates these emotion-related changes in food processing remains elusive. Here we designed an emotional priming fMRI task to test if amygdala activity during food pictures differs depending on the emotional context. Fifty-eight female participants completed a novel emotional priming task, in which emotional images of negative, neutral or positive situations were followed by pictures of either foods or objects. After priming in each trial, participants rated how much they liked the shown foods or objects. We analyzed how brain activity during the contrast \"foods > objects\" changed according to the emotional context - in the whole brain and in the amygdala. We also examined the potential effect of adiposity (i.e., waist circumference). We observed a higher difference between liking scores for foods and objects after positive priming than after neutral priming. In the left amygdala, activity in the contrast \"foods > objects\" was higher after neutral priming relative to negative priming. Waist circumference was not significantly related to this emotional priming effect on food processing. Our results suggest that emotional context alters food and non-food perception, both in terms of liking scores and with regards to engagement of the left amygdala. Moreover, our findings indicate that emotional context has an impact on the salience advantage of food, possibly affecting eating behavior.

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bioRxiv2019

Obesity and brain topological organization differences throughout the lifespan

Life expectancy and obesity rates have drastically increased in recent years. An unhealthy weight is related to long-lasting biological deregulations that might compromise the normal course of aging. The aim of the current study was to test whether the network composition of young adults with obesity would show signs of premature aging. To this end, subjects with obesity (N = 30, mean age 32.8 {+/-} 5.68), healthy-weight controls (N = 33, mean age 30.9 {+/-} 6.24) as well as non-demented seniors (N = 30, mean age 67.1 {+/-} 6.65) all underwent a resting-state MRI acquisition. Functional connectivity was studied by means of graph-theory measurements (i.e., small-world index, clustering coefficient, characteristic path length, and mean degree). Contrary to what expected, obesity in adults was related to disruptions in small-world properties driven by increases in network segregation (i.e., clustering coefficient) as compared to elders. Also, this group showed alterations in global and regional centrality metrics (i.e., degree) relative to controls and seniors. Despite not mimicking what was here shown by seniors, the topological organization linked to an obesity status may represent a flaw for cognitive functions depending on the rapid combination between different modular communities.

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bioRxiv2019

Neuroanatomical Changes in White and Grey Matter after Sleeve Gastrectomy

BackgroundMRI studies show that obese adults have reduced grey (GM) and white matter (WM) tissue density as well as altered WM integrity. It remains to be examined if bariatric surgery induces structural brain changes. The aim of this study is to characterize GM and WM density changes in a longitudinal setting, comparing pre- and post-operation and to determine whether these changes are related to inflammation and cardiometabolic markers.\n\nMethods29 severely obese participants (age: 45.9{+/-}7.8 years) scheduled to undergo sleeve gastrectomy (SG) were recruited. High-resolution T1-weighted anatomical images were acquired 1 month prior to as well as 4 and 12 months after surgery. GM and WM densities were quantified using voxel-based morphometry (VBM). Circulating lipid profile, glucose, insulin and inflammatory markers (interleukin (IL)-6, C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) were measured at each time point. A linear mixed effect model was used to compare brain changes before and after SG, controlling for age, gender, initial BMI and diabetic status. To assess the associations between changes in adiposity, metabolism and inflammation and changes in GM or WM density, the mean GM and WM densities were extracted across all the participants using atlas, and linear mixed-effect models were used.\n\nResultsAs expected, weight, BMI, waist circumference and neck circumference significantly decreased after SG compared with baseline (p<0.001 for all). A widespread increase in WM density was observed after surgery, particularly in the cerebellum, brain stem, cerebellar peduncle, cingulum, corpus callosum and corona radiata (p<0.05, after FDR correction). Significant increases in GM density were observed 4 months after SG compared to baseline in several brain regions such as the bilateral occipital cortex, temporal cortex, precentral gyrus and cerebellum as well as right fusiform gyrus, right hippocampus and right insula. These GM and WM increases were more pronounced and widespread after 12 months and were significantly associated with post-operative weight loss and the improvement of metabolic alterations. Our linear mixed-effect models also showed strong associations between post-operative reductions in LBP, a marker of inflammation, and increased WM density. To confirm our results, we tested whether the peak of each significant region showed BMI-related differences in an independent dataset (Human Connectome Project). We matched a group of severely obese individuals with a group of lean individuals for age, gender and ethnicity. Severe obesity was associated with reduced WM density in the brain stem and cerebellar peduncle as well as reduced GM density in cerebellum, regions that significantly changed after surgery (p<0.01 for all clusters).\n\nConclusionsBariatric surgery-induced weight loss and improvement in metabolic alterations is associated with widespread increases in WM and GM densities. These post-operative changes overlapped with baseline brain differences between severely obese and normal-weight individuals, which may suggest a recovery of WM and GM alterations after bariatric surgery.

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bioRxiv2019

Spatial patterning of tissue volume deformation in schizophrenia reflects brain network architecture

BackgroundThere is growing recognition that connectome architecture shapes cortical and sub-cortical grey matter atrophy across a spectrum of neurological and psychiatric diseases. Whether connectivity contributes to tissue volume loss in schizophrenia in the same manner remains unknown.\n\nMethodsHere we relate tissue volume loss in patients with schizophrenia to patterns of structural and functional connectivity. Grey matter deformation was estimated in a sample of N = 133 individuals with chronic schizophrenia (48 female, 34.7 {+/-} 12.9 years) and N = 113 controls (64 female, 23.5 {+/-} 8.4 years). Deformation-based morphometry (DBM) was used to estimate cortical and subcortical grey matter deformation from T1-weighted MR images. Structural and functional connectivity patterns were derived from an independent sample of N = 70 healthy participants using diffusion spectrum imaging and resting-state functional MRI.\n\nResultsWe find that regional deformation is correlated with the deformation of structurally- and functionally-connected neighbours. Distributed deformation patterns are circumscribed by specific functional systems (the ventral attention network) and cytoarchitectonic classes (limbic class), with an epicenter in the anterior cingulate cortex.\n\nConclusionsAltogether, the present study demonstrates that brain tissue volume loss in schizophrenia is conditioned by structural and functional connectivity, accounting for 25-35% of regional variance in deformation.

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bioRxiv2019

An MRI Atrophy Biomarker Predicts Global Prognosis in Early De Novo Parkinson's Disease

BackgroundCommonly used neuroimaging biomarkers in Parkinsons disease (PD) are useful for diagnosis but poor at predicting outcomes. We explored whether an atrophy pattern from whole-brain structural MRI, measured in the drug-naive early stage, could predict PD prognosis. Methods362 de novo PD patients with T1-weighted MRI (n=222 for the main analysis, 140 for the validation analysis) were recruited from the Parkinsons Progression Markers Initiative (PPMI). We investigated a previously identified PD-specific network atrophy pattern as a potential biomarker of disease severity and prognosis. Progression trajectories of motor function (MDS-UPDRS-part III), cognition (Montreal Cognitive Assessment (MoCA)), and a global composite outcome measure were compared between atrophy tertiles using mixed effect models. The prognostic value of the MRI atrophy measure was compared with 123I ioflupane single photon emission computed tomography, the postural-instability-gait-disturbance score, and cerebrospinal fluid markers. FindingsAfter 4.5 years follow-up, PD-specific atrophy network score at baseline significantly predicted change in UPDRS-part III (r=-0.197, p=0.003), MoCA (r=0.253, p=0.0002) and global composite outcome (r=-0.249, p=0.0002). Compared with the 3rd tertile (i.e. least atrophy), the tertile with the highest baseline atrophy (i.e. the 1st tertile) had a 3-point annual faster progression in UPDRS-part III (p=0.012), faster worsening of posture-instability gait scores (+0.21 further annual increase, p<0.0001), faster decline in MoCA (-0.74 further annual decline in MoCA, p=0.0372) and a +0.38 (p=0.0029) faster annual increase in the global composite z-score. All findings were replicated in a validation analysis using 1.5T MRI. By comparison, the other biomarkers were limited in their ability to predict prognosis either in the main or validation analysis. InterpretationA PD-specific network atrophy pattern predicts progression of motor, cognitive, and global outcome in PD, and is a stronger predictor of prognosis than any of the other tested biomarkers. Therefore, it has considerable potential as a prognostic biomarker for clinical trials of early PD.

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bioRxiv2018

Connectome architecture, gene expression and functional co-activation shape the propagation of misfolded proteins in neurodegenerative disease

It is becoming increasingly clear that brain network organization shapes the course and expression of neurodegenerative diseases. Parkinsons disease (PD) is marked by progressive spread of atrophy from the midbrain to subcortical structures and eventually, to the cerebral cortex. Recent discoveries suggest that the neurodegenerative process involves the misfolding and prion-like propagation of endogenous -synuclein via axonal projections. However, the mechanisms that translate local \"synucleinopathy\" to large-scale network dysfunction and atrophy remain unknown. Here we use an agent-based epidemic spreading model to integrate structural connectivity, functional connectivity and gene expression, and to predict sequential volume loss due to neurodegeneration. The dynamic model replicates the spatial and temporal patterning of empirical atrophy in PD and implicates the substantia nigra as the disease epicenter. We reveal a significant role for both connectome topology and geometry in shaping the distribution of atrophy. The model also demonstrates that SNCA and GBA transcription influence -synuclein concentration and local regional vulnerability. Functional co-activation further amplifies the course set by connectome architecture and gene expression. Altogether, these results support the theory that the progression of PD is a multifactorial process that depends on both cell-to-cell spreading of misfolded proteins and regional vulnerability.

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bioRxiv2018

Neural and behavioral endophenotypes of obesity

BackgroundImpulsivity increases the risk for obesity and weight gain. However, the precise role of impulsivity in the aetiology of overeating behavior and obesity is currently unknown. Here we examined the relationships between personality-related measures of impulsivity, Uncontrolled Eating, BMI, and longitudinal weight changes. Additionally, we analyzed the associations between general impulsivity domains and brain cortical thickness to elucidate brain vulnerability factors related to weight gain. MethodsStudents in their first year of university - a risky period for weight gain - completed questionnaire measures of impulsivity and eating behavior at the beginning (N = 2318) of the school year. We also collected their weight at the end of the term (N = 1197). Impulsivity was divided into factors stress reactivity, reward sensitivity and lack of self-control. Using structural equation models, we tested the plausibility of a hierarchical relationship, in which impulsivity traits were associated with Uncontrolled Eating, which in turn predicted BMI and weight change. 71 participants underwent T1-weighted MRI to investigate the correlation between impulsivity and cortical thickness. ResultsImpulsivity traits showed positive correlations with Uncontrolled Eating. Higher scores in Uncontrolled Eating were in turn associated with higher BMI. None of the impulsivity-related measurements nor Uncontrolled Eating were correlated with longitudinal weight gain. Higher stress sensitivity was associated with increased cortical thickness in the superior temporal gyrus. Lack of self-control was positively associated with increased thickness in the superior medial frontal gyrus. Finally, higher reward sensitivity was associated with lower thickness in the inferior frontal gyrus. ConclusionThe present study provides a comprehensive characterization of the relationships between different facets of impulsivity and obesity. We show that differences in impulsivity domains might be associated with BMI via Uncontrolled Eating. Our results might inform future clinical strategies aimed at fostering self-control abilities to prevent and/or treat unhealthy weight gain.

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bioRxiv2018

Ghrelin enhances food odor conditioning in healthy humans: an fMRI study

Vulnerability to obesity includes eating in response to food cues, which acquire incentive value through conditioning. The conditioning process is largely subserved by dopamine, theorized to encode the discrepancy between expected and actual rewards, known as the reward prediction error (RPE). Ghrelin is a gut-derived homeostatic hormone that triggers hunger and eating. Despite extensive evidence that ghrelin stimulates dopamine, it remains unknown in humans if ghrelin modulates food cue learning. Here we show using functional magnetic resonance imaging that intravenously administered ghrelin increased RPE-related activity in dopamine-responsive areas during food odor conditioning in healthy volunteers. Participants responded faster to food odor-associated cues and perceived them to be more pleasant following ghrelin injection. Ghrelin also increased functional connectivity between hippocampus and ventral striatum. Our work demonstrates that ghrelin promotes the ability of cues to acquire incentive salience, and has implications for the development of vulnerability to obesity.

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bioRxiv2018

Dopamine signaling modulates the stability and integration of intrinsic brain networks

Dopaminergic projections are hypothesized to stabilize neural signaling and neural representations, but how they shape regional information processing and large-scale network interactions remains unclear. Here we investigated effects of lowered dopamine levels on within-region temporal signal variability (measured by sample entropy) and between-region functional connectivity (measured by pairwise temporal correlations) in the healthy brain at rest. The acute phenylalanine and tyrosine depletion (APTD) method was used to decrease dopamine synthesis in 51 healthy participants who underwent resting-state functional MRI (fMRI) scanning. Functional connectivity and regional signal variability were estimated for each participant. Multivariate partial least squares (PLS) analysis was used to statistically assess changes in signal variability following APTD as compared to the balanced control treatment. The analysis captured a pattern of increased regional signal variability following dopamine depletion. Changes in hemodynamic signal variability were concomitant with changes in functional connectivity, such that nodes with greatest increase in signal variability following dopamine depletion also experienced greatest decrease in functional connectivity. Our results suggest that dopamine may act to stabilize neural signaling, particularly in networks related to motor function and orienting attention towards behaviorally-relevant stimuli. Moreover, dopaminedependent signal variability is critically associated with functional embedding of individual areas in large-scale networks.

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bioRxiv2017

Central Role of Cognitive Control Networks in Weight Loss During Voluntary Calorie Restriction

Insufficient responses to hypocaloric diets have been attributed to hormonal adaptations that override self-control of food intake. We tested this hypothesis by measuring brain fMRI reactivity to food cues and circulating energy-balance hormones in 24 overweight/obese participants before, and 1 and 3 months after starting a calorie restriction diet. Increased activity in prefrontal regions at month 1 correlated with weight loss at months 1 and 3. Weight loss was also correlated with increased plasma ghrelin and decreased leptin at month 1, and these changes were associated with greater food cue reactivity in reward-related brain regions. However, the reduction in leptin did not counteract weight loss; indeed, it was correlated with further weight loss at month 3. Activation in a network of prefrontal regions associated with self-control could contribute to individual differences in weight loss and maintenance, whereas we failed to find that the hormonal adaptations play a major role.

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bioRxiv2017

White Matter Hyperintensities and Cognitive Decline in de Novo Parkinson’s Disease Patients

ObjectiveWhite Matter Hyperintensities (WMHs) are associated with cognitive decline in normative aging and Alzheimers disease. However, the pathogenesis of cognitive decline in Parkinsons disease (PD) is not directly related to vascular causes, and therefore the role of WMHs in PD remains unclear. If WMH has a higher impact on cognitive decline in PD, vascular pathology should be assessed and treated with a higher priority in this population. Here we investigate whether WMH leads to increased cognitive decline in PD, and if these effects relate to cortical thinning\n\nMethodsTo investigate the role of WMHs in PD, it is essential to study recently-diagnosed/non-treated patients. De novo PD patients and age-matched controls (NPD=365,NControl=174) with FLAIR/T2-weighted scans at baseline were selected from Parkinsons Progression Markers Initiative (PPMI). WMHs and cortical thickness were measured to analyse the relationship between baseline WMHs and future cognitive decline (follow-up:4.09{+/-}1.14 years) and cortical thinning (follow-up:1.05{+/-}0.10 years).\n\nResultsHigh WMH load (WMHL) at baseline in PD was associated with increased cognitive decline, significantly more than i) PDs with low WMHL and ii) controls with high WMHL. Furthermore, PD patients with higher baseline WMHL showed more cortical thinning in right frontal lobe than subjects with low WMHL. Cortical thinning of this region also predicted decline in performance on a cognitive test.\n\nInterpretationPresence of WMHs in de novo PD patients predicts greater future cognitive decline and cortical thinning than in normal aging. Recognizing WMHs as a potential predictor of cognitive deficit in PD provides an opportunity for timely interventions.

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bioRxiv2017

Neurobehavioural Correlates of Obesity are Largely Heritable

Recent molecular genetic studies have shown that the majority of genes associated with obesity are expressed in the central nervous system. Obesity has also been associated with neurobehavioural factors such as brain morphology, cognitive performance, and personality. Here, we tested whether these neurobehavioural factors were associated with the heritable variance in obesity measured by body mass index (BMI) in the Human Connectome Project (N=895 siblings). Phenotypically, cortical thickness findings supported the \"right brain hypothesis\" for obesity. Namely, increased BMI associated with decreased cortical thickness in right frontal lobe and increased thickness in the left frontal lobe, notably in lateral prefrontal cortex. In addition, lower thickness and volume in entorhinal-parahippocampal structures, and increased thickness in parietal-occipital structures in obese participants supported the role of visuospatial function in obesity. Brain morphometry results were supported by cognitive tests, which outlined obesitys negative association with visuospatial function, verbal episodic memory, impulsivity, and cognitive flexibility. Personality-obesity correlations were inconsistent. We then aggregated the effects for each neurobehavioural factor for a behavioural genetics analysis and demonstrated the factors genetic overlap with obesity. Namely, cognitive test scores and brain morphometry had 0.25 - 0.45 genetic correlations with obesity, and the phenotypic correlations with obesity were 77-89% explained by genetic factors. Neurobehavioural factors also had some genetic overlap with each other. In summary, obesity has considerable genetic overlap with brain and cognitive measures. This supports the theory that obesity is inherited via brain function, and may inform intervention strategies.\n\nSignificance StatementObesity is a widespread heritable health condition. Evidence from psychology, cognitive neuroscience, and genetics has proposed links between obesity and the brain. The current study tested whether the heritable variance in obesity is explained by brain and behavioural factors in a large brain imaging cohort that included multiple related individuals. We found that the heritable variance in obesity had genetic correlations 0.25 - 0.45 with cognitive tests, cortical thickness, and regional brain volume. In particular, obesity was associated with frontal lobe asymmetry and differences in temporal-parietal perceptual systems. Further, we found genetic overlap between certain brain and behavioural factors. In summary, the genetic vulnerability to obesity is expressed in the brain. This may inform intervention strategies.

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bioRxiv2017

Subtypes of functional brain connectivity as early markers of neurodegeneration in Alzheimer’s disease

HighlightsO_LIReliable functional brain network subtypes accompany cognitive impairment in AD\nC_LIO_LISymptom-related subtypes exist in the default-mode, limbic and salience networks\nC_LIO_LIA limbic subtype is associated with a familial risk of AD in healthy older adults\nC_LIO_LILimbic subtypes also associate with beta amyloid deposition and ApoE4\nC_LI\n\nIn BriefWe found reliable subtypes of functional brain connectivity networks in older adults, associated with AD-related clinical symptoms in patients as well as several AD risk factors/biomarkers in asymptomatic individuals.\n\nSummaryThe heterogeneity of brain degeneration has not been investigated yet for functional brain network connectivity, a promising biomarker of Alzheimers disease. We coupled cluster analysis with resting-state functional magnetic resonance imaging to discover connectivity subtypes in healthy older adults and patients with cognitive disorders related to Alzheimers disease, noting associations between subtypes and cognitive symptoms in the default-mode, limbic and salience networks. In an independent asymptomatic cohort with a family history of Alzheimers dementia, the connectivity subtypes had good test-retest reliability across all tested networks. We found that a limbic subtype was overrepresented in these individuals, which was previously associated with symptoms. Other limbic subtypes showed associations with cerebrospinal fluid A{beta}1-42 levels and ApoE4 genotype. Our results demonstrate the existence of reliable subtypes of functional brain networks in older adults and support future investigations in limbic connectivity subtypes as early biomarkers of Alzheimers degeneration.

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bioRxiv2017

A clinical-anatomical signature of Parkinson’s Disease identified with partial least squares and magnetic resonance imaging

Parkinsons disease (PD) is a neurodegenerative disorder characterized by a wide array of motor and non-motor symptoms. It remains unclear whether neurodegeneration in discrete loci gives rise to discrete symptoms, or whether network-wide atrophy gives rise to the unique behavioural and clinical profile associated with PD. Here we apply a data-driven strategy to isolate large-scale, multivariate associations between distributed atrophy patterns and clinical phenotypes in PD. In a sample of N = 229 de novo PD patients, we estimate disease-related atrophy using deformation based morphometry (DBM) of T1 weighted MR images. Using partial least squares (PLS), we identify a network of subcortical and cortical regions whose collective atrophy is associated with a clinical phenotype encompassing motor and non-motor features. Despite the relatively early stage of the disease in the sample, the atrophy pattern encompassed lower brainstem, substantia nigra, basal ganglia and cortical areas, consistent with the Braak hypothesis. In addition, individual variation in this putative atrophy network predicted longitudinal clinical progression in both motor and non-motor symptoms. Altogether, these results demonstrate a pleiotropic mapping between neurodegeneration and the clinical manifestations of PD, and that this mapping can be detected even in de novo patients.

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bioRxiv2017

Network Connectivity Predicts Cortical Thinning and Cognitive Decline in Early Parkinson’s Disease

Parkinsons Disease (PD) is a progressive neurodegenerative disorder characterized by motor and cognitive deficits. The neurodegenerative process is thought to move stereotypically from the brainstem up to the cerebral cortex, possibly reflecting the spread of toxic alpha-synuclein molecules. Using a large, longitudinal, multi-center database of de novo PD patients, we tested whether focal reductions in cortical thickness could be explained by disease spread from a subcortical \"disease reservoir\" along the brains connectome. PD patients (n=105) and matched controls (n=57) underwent T1-MRI at entry and one year later. Over this period, PD patients demonstrated significantly greater loss of cortical thickness than healthy controls in parts of the left occipital and bilateral frontal lobes and right somatomotor-sensory cortex. Cortical regions with greater connectivity (measured functionally or structurally) to a \"disease reservoir\" evaluated via MRI at baseline demonstrated greater atrophy one year later. The atrophy pattern in the ventral frontal lobes resembled one described in certain cases of Alzheimers disease. Moreover, a multiple linear regression model suggested that cortical thinning was associated with impaired cognitive function at follow-up. Our findings suggest that disease propagation to the cortex in PD follows neural connectivity, and that disease spread to the cortex may herald the onset of cognitive impairment.

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