Multi-modal Imaging and Cognitive Profiles in de novo Parkinson’s Disease

The overall aim of my PhD was to study the correlations between cognitive functions, neurodegeneration and functional alterations in diffuse projection systems. To this aim we plan to combine formal neuropsychological testing, structural and functional imaging and in-vivo quantitative assessments of the dopaminergic, serotonergic and cholinergic systems. Through a multi-modal imaging approach, we had the chance to deeply understand neuroanatomical and neurochemical basis of cognition in its whole, in a large cohort of de novo Parkinson’s Disease (PD) patients. Our study cohort ranges from 30 to 96 of de novo PD patients, who underwent 18F- fluorodeoxyglucose Positron Emission Tomography ([18F]FDG-PET), used as a marker of regional neurodegeneration; [123I]Ioflupane Single Photon Emission Computed Tomography ([123I]FP-CIT-SPECT, as a marker of dopaminergic impairment in the basal ganglia and in the cortex as well as a proxy marker of serotonergic deafferentation in the thalamus; and quantitative electroencephalography (qEEG) recordings, used instead as a marker of cholinergic deafferentation. We combined these imaging methods with formal neuropsychological testing, a social cognition test and multiple clinical variables. In this work we aim to answer to three main scientific questions: i) Does social cognition in de novo PD patients have a specific cortical and neurochemical signature? ii) Is there a mediated effect between diffuse projection systems degeneration and cortical metabolism as well as on regional expression of monoaminergic transmission in the deep grey matter? iii) Are specific cognitive domains impaired in de novo PD patients and are they differently affected by regional metabolism and diffuse projection systems degeneration? In Chapter 3 we investigated the topographical and neurochemical bases of Theory of Mind (ToM), which refers to the ability to attribute mental states to others and to predict, describe, and explain behaviour based on such mental states, using multi-tracer molecular imaging and quantitative electroencephalography in a group of 30 drug-naïve, de novo PD patients. ToM was assessed using the “Reading the Mind in the Eyes Task” (RMET), while general cognition with the Mini Menta State examination (MMSE). We found that PD patients performed significantly worse at RMET compared to 60 healthy controls, as well as a significant positive correlation between RMET performance and regional metabolism in the superior temporal gyrus and the insula, and an inverse correlation with [123I]FP-CIT thalamic specific binding ratio values, as expression of serotonin deafferentation. On the other hand, MMSE correlated with qEEG posterior Theta/Alpha power, confirming its independency from social cognition. In Chapter 4, using multi-tracer molecular imaging, we assessed in a cohort of 96 drug-naïve, de novo PD patients the association between cortical metabolism and dopaminergic and serotonergic systems deafferentation of either striatum or thalamus, and whether this association was mediated by either striatum or thalamus metabolism. We found that the impact of deep grey matter monoaminergic deafferentation on cortical function is mediated by striatal and thalamic metabolism in this population. We showed a significant direct correlation between bilateral temporo-parietal metabolism and caudate dopaminergic innervation, as well as a significant correlation between prefrontal metabolism and thalamus serotonergic innervation, which were, respectively, mediated by striatal and thalamic metabolism. In Chapter 5, we evaluate the association between neurotransmitter impairment, brain metabolism and cognition in a cohort of 95 drug-naïve, de novo PD patients, using [18F]FDG-PET images as a marker of brain glucose metabolism and proxy measure of neurodegeneration, [123I]FP-CIT-SPECT for dopaminergic deafferentation in the striatum and frontal cortex, as well as a marker of serotonergic deafferentation in the thalamus, and quantitative electroencephalography (qEEG) as an indirect measure of cholinergic deafferentation. Patients also underwent a complete neuropsychological tests battery. We found positive correlations between (i) executive functions and left cerebellar cortex metabolism, (ii) prefrontal dopaminergic expression and working memory, (iii) qEEG slowing in the posterior leads and both memory and visuo-spatial functions

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

Measuring cortical connectivity in Alzheimer's disease as a brain neural network pathology: Toward clinical applications

Objectives: The objective was to review the literature on diffusion tensor imaging as well as resting-state functional magnetic resonance imaging and electroencephalography (EEG) to unveil neuroanatomical and neurophysiological substrates of Alzheimer’s disease (AD) as a brain neural network pathology affecting structural and functional cortical connectivity underlying human cognition. Methods: We reviewed papers registered in PubMed and other scientific repositories on the use of these techniques in amnesic mild cognitive impairment (MCI) and clinically mild AD dementia patients compared to cognitively intact elderly individuals (Controls). Results: Hundreds of peer-reviewed (cross-sectional and longitudinal) papers have shown in patients with MCI and mild AD compared to Controls (1) impairment of callosal (splenium), thalamic, and anterior–posterior white matter bundles; (2) reduced correlation of resting state blood oxygen level-dependent activity across several intrinsic brain circuits including default mode and attention-related networks; and (3) abnormal power and functional coupling of resting state cortical EEG rhythms. Clinical applications of these measures are still limited. Conclusions: Structural and functional (in vivo) cortical connectivity measures represent a reliable marker of cerebral reserve capacity and should be used to predict and monitor the evolution of AD and its relative impact on cognitive domains in pre-clinical, prodromal, and dementia stages of AD. (JINS, 2016, 22, 138–163

Early changes in brain structure correlate with language outcomes in children with neonatal encephalopathy.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6 months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6 months, and assessed neurodevelopmental outcomes at 30 months. All subjects underwent T1-weighted imaging at 3 T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30 months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6 months are correlated with language outcome at 30 months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes

Brain networks involved in decision making: an electroencephalography and magnetic resonance imaging study

Executive function describes high-level cognitive-abilities including planning, decision-making, set switching and response inhibition. Impairments of the executive functions in disease states may be subtle but can greatly reduce the quality of life and independence. The overarching theme of this project was to investigate the network of brain regions that are needed to support executive function. This was undertaken using a two-fold approach: one, to apply network analysis to resting state functional Magnetic Resonance Imaging (rs-fMRI) and Diffusion Tensor Imaging (DTI) data in order to describe how differences in morphometry and connectivity correlate to executive function differences of individuals with Mild Cognitive Impairment (MCI), and two, to describe the brain networks involved in one form of executive function, decision-making under uncertain conditions, in young, healthy individuals. Impaired decision-making can dramatically impact day-to-day functioning and understanding the underlying network of regions that support this task can provide a target for future intervention studies. Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used in the studies of MCI. Individuals were grouped by their executive abilities. A regions-of-interest approach was used to parcel and label various brain regions and a network of connections was constructed out of these regions. Differences between the networks were then compared between the MCI subjects with good and poor executive functions. Those with high executive abilities showed decreased functional network connectivity and increased structural network connectivity. The second arm of these studies was based an original decision-making paradigm that was used to compare of networks involved in decision-making at times of uncertainty in healthy young individuals using both electroencephalography (EEG) and task-based functional magnetic resonance imaging (fMRI). Overall we found greater network connectivity in the uncertain condition of the task than in the certain condition. This suggests that with increased uncertainty comes increased organized connectivity. Taken together, the results of this study re-iterate the notion that cognition depends upon the efficient communication between a network of brain regions rather than on isolated regions. They also highlight the importance of having a well-defined network of nodes and connections for optimal executive functioning

Neuroimaging findings in chronic hepatitis C virus infection: correlation with neurocognitive and neuropsychiatric manifestations

Chronic hepatitis C virus (HCV) infection is commonly associated with neurocognitive dysfunction, altered neuropsychological performance and neuropsychiatric symptoms. Quantifiable neuropsychological changes in sustained attention, working memory, executive function, verbal learning and recall are the hallmark of HCV-associated neurocognitive disorder (HCV-AND). This constellation is at variance with the neuropsychological complex that is seen in minimal hepatic encephalopathy, which is typified by an array of alterations in psychomotor speed, selective attention and visuo-constructive function. Noncognitive symptoms, including sleep disturbances, depression, anxiety and fatigue, which are less easily quantifiable, are frequently encountered and can dominate the clinical picture and the clinical course of patients with chronic HCV infection. More recently, an increased vulnerability to Parkinson's disease among HCV-infected patients has also been reported. The degree to which neurocognitive and neuropsychiatric changes are due to HCV replication within brain tissues or HCV-triggered peripheral immune activation remain to be determined. Without absolute evidence that clearly exonerates or indicts HCV, our understanding of the so-called "HCV brain syndrome", relies primarily on clinical and neuropsychological assessments, although other comorbidities and substance abuse may impact on neurocognitive function, thus confounding an appropriate recognition. In recent years, a number of functional and structural brain imaging studies have been of help in recognizing possible biological markers of HCV-AND, thus providing a rationale for guiding and justifying antiviral therapy in selected cases. Here, we review clinical, neuroradiological, and therapeutic responses to interferon-based and interferon-free regimens in HCV-related cognitive and neuropsychiatric disorder

The dysfunctional brain dynamic of Lewy body dementia and its behavioural and clinical correlates : an fMRI and EEG analysis

PhD ThesisBackground: Lewy body dementia (LBD), which comprises dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is characterised by transient clinical symptoms such as cognitive fluctuations which may be caused by alterations of intrinsic brain dynamics. The aim of this thesis is to investigate how dysfunctional brain connectivity and dynamics relate to the cognitive LBD phenotype, especially to attentional impairment and cognitive fluctuations. Methods: In order to investigate behavioural aspects of cognitive fluctuations in LBD, reaction time (RT) data from an attention task were analysed to study how attentional impairment in LBD differs from Alzheimer’s disease (AD) and healthy controls. Additionally, brain structural correlates of attentional dysfunction were assessed using voxel-based morphometry. Subsequently, resting-state fMRI data were analysed using static and dynamic functional connectivity and dynamic network analyses. Faster brain dynamics were assessed by EEG microstate analysis. Results: AD and LBD patients exhibited slower and more variable RTs than controls, with greater impairment in LBD than AD. Extremely slow responses occurred with comparable frequency in both dementia groups. There were widespread correlations between RT abnormalities and structural changes in AD patients, but not LBD. Functional connectivity was decreased in DLB patients compared to controls, mainly in motor, temporal, and frontal networks with sparing of the DMN. Differences between AD and DLB were subtle. Considering time-varying connectivity, AD and DLB patients spent more time in sparse connectivity configurations than controls and switched less often into more highly connected states. Compared to controls, variability of global network efficiency was reduced in patients with DLB. Microstate analysis revealed a marked and generalised increase in microstate duration in LBD patients compared to controls, which was not seen in AD and was related to a loss of dynamic connectivity between basal ganglia/thalamic and large-scale cortical networks. Microstate slowing was correlated with fluctuation severity in the DLB group and with RT slowing and variability across all participants. Conclusions: Different aspects of RT performance are differentially affected by AD and LBD, with a ii difference in structural neural correlates. The dynamic connectivity and microstate results indicate a loss of brain dynamics in LBD which might lead to a breakdown of the intricate dynamic properties of the brain, thereby causing loss of flexibility that is crucial for healthy brain function. This might lead to a network configuration which gives rise to the cognitive LBD phenotype characterised by attentional impairment and cognitive fluctuations.the Alzheimer’s Societ

Investigating the relationship between cholinergic system integrity and Parkinson’s disease symptoms using MRI and EEG

Cholinergic cells of the basal forebrain (cBF) and pedunculopontine nucleus (PPN) are implicated in Parkinson’s disease (PD), but current understanding of their role in PD symptomology is limited. Neuropathological and recent in vivo imaging research implies that cBF and PPN degeneration is associated with PD cognitive and mobility impairments. There remains a need to identify and validate widely accessible markers of cholinergic system degeneration to better understand its contribution to these symptoms. The aim of this thesis was to investigate how structural changes in the cBF and PPN relate to cortical activity and cognitive and mobility performance in people with PD, people with mild cognitive impairment (MCI), and healthy age-matched controls. T1 and diffusion-weighted images were used in combination with stereotactic maps of the cBF and PPN to extract volumetric and diffusivity metrics from these regions as in vivo surrogate markers of structural integrity. These structural measures were assessed for their relationship with resting-state EEG, and cognitive and functional mobility performance. People with PD showed reduced cBF volumes compared to healthy controls, and elevated PPN diffusivity compared to people with MCI. Subregional cBF volumes correlated with EEG changes in the theta-alpha range in people with PD and people with MCI. Volume loss in the cBF was also shown to mediate the relationship between executive function and Timed Up and Go dual-task performance in people with PD. PPN diffusivity metrics demonstrated correlations with cognitive performance and EEG changes in the alpha range in people with PD, and in the beta-gamma range in people with MCI. Cortical activity measured with EEG may hold physiological relevance for structural changes occurring in the cBF and PPN. Volumetric loss in the cBF may impair the attentional-executive control of mobility functions. Elevated PPN diffusivity may impair attentional performance during tasks that require sensorimotor integration