Corticobasal syndrome: neuroimaging and neurophysiological advances

Corticobasal degeneration (CBD) is a neurodegenerative condition characterized by 4R-tau protein deposition in several brain regions that clinically manifests itself as a heterogeneous atypical parkinsonism typically expressing in the adulthood. The prototypical clinical phenotype of CBD is corticobasal syndrome (CBS). Important insights into the pathophysiological mechanisms underlying motor and higher cortical symptoms in CBS have been gained by using advanced neuroimaging and neurophysiological techniques. Structural and functional neuroimaging studies often showed asymmetric cortical and subcortical abnormalities, mainly involving perirolandic and parietal regions and basal ganglia structures. Neurophysiological investigations including electroencephalography and somatosensory evoked potentials provided useful information on the origin of myoclonus and on cortical sensory loss. Transcranial magnetic stimulation demonstrated heterogeneous and asymmetric changes in the excitability and plasticity of primary motor cortex and abnormal hemispheric connectivity. Neuroimaging and neurophysiological abnormalities in multiple brain areas reflect the asymmetric neurodegeneration, leading to the asymmetric motor and higher cortical symptoms in CBS. This article is protected by copyright. All rights reserved

Physiology and neuroanatomy of emotional reactivity in frontotemporal dementia

ABSTRACT AND SUMMARY OF EXPERIMENTAL FINDINGS The frontotemporal dementias (FTD) are a heterogeneous group of neurodegenerative diseases that cause variable profiles of fronto-insulo-temporal network disintegration. Loss of empathy and dysfunctional social interaction are a leading features of FTD and major determinants of care burden, but remain poorly understood and difficult to measure with conventional neuropsychological instruments. Building on a large body of work in the healthy brain showing that embodied responses are important components of emotional responses and empathy, I performed a series of experiments to examine the extent to which the induction and decoding of somatic physiological responses to the emotions of others are degraded in FTD, and to define the underlying neuroanatomical changes responsible for these deficits. I systematically studied a range of modalities across the entire syndromic spectrum of FTD, including daily life emotional sensitivity, the cognitive categorisation of emotions, interoceptive accuracy, automatic facial mimicry, autonomic responses, and structural and functional neuroanatomy to deconstruct aberrant emotional reactivity in these diseases. My results provide proof of principle for the utility of physiological measures in deconstructing complex socioemotional symptoms and suggest that these warrant further investigation as clinical biomarkers in FTD. Chapter 3: Using a heartbeat counting task, I found that interoceptive accuracy is impaired in semantic variant primary progressive aphasia, but correlates with sensitivity to the emotions of others across FTD syndromes. Voxel based morphometry demonstrated that impaired interoceptive accuracy correlates with grey matter volume in anterior cingulate, insula and amygdala. Chapter 4: Using facial electromyography to index automatic imitation, I showed that mimicry of emotional facial expressions is impaired in the behavioural and right temporal variants of FTD. Automatic imitation predicted correct identification of facial emotions in healthy controls and syndromes focussed on the frontal lobes and insula, but not in syndromes focussed on the temporal lobes, suggesting that automatic imitation aids emotion recognition only when social concepts and semantic stores are intact. Voxel based morphometry replicated previously identified neuroanatomical correlates of emotion identification ability, while automatic imitation was associated with grey matter volume in a visuomotor network including primary visual and motor cortices, visual motion area (MT/V5) and supplementary motor cortex. Chapter 5: By recording heart rate during viewing of facial emotions, I showed that the normal cardiac reactivity to emotion is impaired in FTD syndromes with fronto-insular atrophy (behavioural variant FTD and nonfluent variant primary progressive aphasia) but not in syndromes focussed on the temporal lobes (right temporal variant FTD and semantic variant primary progressive aphasia). Unlike automatic imitation, cardiac reactivity dissociated from emotion identification ability. Voxel based morphometry revealed grey matter correlates of cardiac reactivity in anterior cingulate, insula and orbitofrontal cortex. Chapter 6: Subjects viewed videos of facial emotions during fMRI scanning, with concomitant recording of heart rate and pupil size. I identified syndromic profiles of reduced activity in posterior face responsive regions including posterior superior temporal sulcus and fusiform face area. Emotion identification ability was predicted by activity in more anterior areas including anterior cingulate, insula, inferior frontal gyrus and temporal pole. Autonomic reactivity related to activity in both components of the central autonomic control network and regions responsible for processing the sensory properties of the stimuli

Being a morning man has causal effects on the cerebral cortex: a Mendelian randomization study

IntroductionNumerous studies have suggested a connection between circadian rhythm and neurological disorders with cognitive and consciousness impairments in humans, yet little evidence stands for a causal relationship between circadian rhythm and the brain cortex.MethodsThe top 10,000 morningness-related single-nucleotide polymorphisms of the Genome-wide association study (GWAS) summary statistics were used to filter the instrumental variables. GWAS summary statistics from the ENIGMA Consortium were used to assess the causal relationship between morningness and variates like cortical thickness (TH) or surficial area (SA) on the brain cortex. The inverse-variance weighted (IVW) and weighted median (WM) were used as the major estimates whereas MR-Egger, MR Pleiotropy RESidual Sum and Outlier, leave-one-out analysis, and funnel-plot were used for heterogeneity and pleiotropy detecting.ResultsRegionally, morningness decreased SA of the rostral middle frontal gyrus with genomic control (IVW: β = −24.916 mm, 95% CI: −47.342 mm to −2.490 mm, p = 0.029. WM: β = −33.208 mm, 95% CI: −61.933 mm to −4.483 mm, p = 0.023. MR Egger: β < 0) and without genomic control (IVW: β = −24.581 mm, 95% CI: −47.552 mm to −1.609 mm, p = 0.036. WM: β = −32.310 mm, 95% CI: −60.717 mm to −3.902 mm, p = 0.026. MR Egger: β < 0) on a nominal significance, with no heterogeneity or no outliers.Conclusions and implicationsCircadian rhythm causally affects the rostral middle frontal gyrus; this sheds new light on the potential use of MRI in disease diagnosis, revealing the significance of circadian rhythm on the progression of disease, and might also suggest a fresh therapeutic approach for disorders related to the rostral middle frontal gyrus-related

Severity and Progression of White Matter Changes in Frontotemporal Dementia Subtypes Using Diffusion Tensor Imaging

The three main subtypes of frontotemporal dementia (FTD): behavioural-variant FTD (bvFTD), primary progressive aphasia-nonfluent variant (nfv-PPA) and semantic variant (sv-PPA) are characterised by progressive brain atrophy in the frontotemporal regions. The brain white matter also undergoes marked pathological alterations but is less studied. This thesis aimed to study i) the patterns of white matter changes in the three FTD subtypes, ii) the progression of white matter changes in the same FTD subtypes, and iii) the white matter changes in bvFTD with or without the C9orf72 gene expansions. Chapter 3 revealed distinctive patterns of white matter changes in each FTD subtype. White matter alterations were observed in orbitofrontal and anterior temporal tracts in bvFTD, bilateral (left>right) frontotemporal tracts in nfv-PPA and circumscribed left temporal lobe in sv-PPA. These white matter changes greatly overlapped with grey matter changes in bvFTD and nfv-PPA but not in sv-PPA. The white matter abnormalities varied depending on the diffusion tensor imaging (DTI) measurements used, with mean diffusivity being the most sensitive metric for all FTD subtypes. Chapter 4 showed the 12-month longitudinal assessment of white matter changes in the same participants. White matter alterations appeared in regions shown at baseline but with additional changes extending beyond the original regions affected in all FTD subtypes. White matter abnormalities extended far beyond sites of grey matter atrophy in the same time period. Fractional anisotropy and radial diffusivity were most sensitive in detecting white matter abnormalities in this longitudinal assessment. Chapter 5 compared bvFTD cases with or without C9orf72 expansion carriers. C9orf72 expansion carriers did not exhibit the typical frontotemporal white matter changes as shown in non-carriers. Stereotypical behaviour was less prevalent in C9orf72 expansion carriers than non-carriers and the left cingulum and anterior thalamic radiation were predictive of stereotypical behavioural scores. Semantic knowledge was less affected in C9orf72 expansion carriers and the left uncinate fasciculus was predictive of changes in semantic knowledge. These predictions significantly differentiated C9orf72 expansion carriers from non-carriers. Investigations using DTI presented in this thesis improved the understanding of white matter changes in FTD and contributed to the characterisation of the different FTD subtypes

Neural mechanisms of cognitive reserve in Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of age-related dementia, where neuropathological changes develop gradually over years before the onset of dementia symptoms. Yet, despite the progression of AD pathology, the decline in cognitive abilities such as episodic memory can be relatively slow. A slower decline of cognition and delayed onset of dementia relative to the progression of neuropathology has been associated with particular intellectual and lifestyle factors such as more years of education and IQ. Thus education and IQ are seen as protective factors that are associated with an increased ability to cope with brain pathology, i.e. cognitive reserve. While numerous studies showed that education, IQ and other lifestyle factors are associated with relatively high cognitive abilities in AD, little is known about the underlying brain mechanisms of reserve. Most previous studies tested the association between protective factors such as education or IQ and differences in brain structure and function in order to identify brain mechanisms underlying reserve. Since such protective factors are global in nature and unspecific with regard to reserve, the results were highly variable. So far, there is a lack of knowledge of brain features that are associated with a higher ability to maintain cognition in the face of AD pathology. The overall aim of this dissertation was to test a priori selected functional network features that may underlie cognitive reserve. We focused on resting-state functional networks, and in particular the fronto-parietal control network as correlate of cognitive reserve. Such functional networks are thought to be composed of brain regions that are co-activated during a particular task, where the interaction between brain regions may be critical to support cognitive function. During task-free resting-state periods, the different and often distant brain regions of such network show correlated activity, i.e. functional connectivity. For the fronto-parietal control network, and in particular its globally connected hub in the left frontal cortex (LFC), higher resting-state connectivity has been previously shown to be associated with higher cognitive abilities as well as higher education and IQ, i.e. protective factors associated with reserve. Since that network and its LFC hub are relatively spared in AD, in contrast to more posterior parietal networks, we investigated whether higher connectivity of the fronto-parietal control network is associated with higher reserve in AD. We argued that the fronto-parietal control network is relatively stable during the initial stages of AD and may thus be well posited to subserve reserve in AD. In contrast, networks like the default mode network (DMN) that cover midline brain structures including the medial frontal lobe and the posterior cingulate may be highly vulnerable to AD pathology, given the previous observations of altered DMN connectivity and posterior parietal FDG-PET hypometabolism in AD. In particular, the resting-state connectivity between the DMN and the dorsal attention network (DAN) may be predictive of lower episodic memory in AD. Both networks interact in a competitive (i.e. anti-correlated) way during task and resting-state, which is critical for cognitive processes such as episodic memory. In a first step, we tested whether the resting-state connectivity between the DMN and theDAN (i.e. anti-correlated activity) is associated with lower episodic memory in subjects with amnestic mild cognitive impairment (MCI), i.e. subjects at increased risk to convertto AD dementia. Furthermore, we tested whether protective factors such as higher education moderate the association between the DMN-DAN anti-correlation andcognition. Here, the DMN-DAN anti-correlation was a measure of AD relatedpathological change rather than a substrate of reserve.We could show in two independent samples of patients at risk of AD dementia that a weaker DMN-DAN anti-correlation was associated with lower episodic memory, where the decrements in episodic memory were however weaker in subjects with higher education or IQ (interaction DMN-DAN x education/IQ). These results suggest that MCI subjects with higher protective factors (education, IQ) maintain episodic memory relatively well at a given level of AD-related brain changes. In the second step, we sought to identify those network differences that support cognitive reserve, i.e. that may explain the association between higher education and milder cognitive impairment in AD. Here, we could show that greater resting-state fMRI assessed global connectivity of the LFC, i.e. a key hub of the fronto-parietal control network, was associated with greater education and attenuated effects of neurodegeneration (measured by parietal FDG-PET hypometabolism) on memory in prodromal AD. Together, these results support the idea that global connectivity of a fronto-parietal control network hub supports cognitive reserve in AD. Based on this finding, we developed a novel restingstate fMRI index of fronto-parietal control network connectivity as a functional imaging marker of cognitive reserve. This marker is highly correlated with education and may thus be used as an imaging-based index of cognitive reserve. Together, our results provide for the first time evidence that cognitive reserve in AD is supported by higher functional connectivity of the fronto-parietal control network, in particular its LFC hub

The impact of aerobic exercise on brain's white matter integrity in the Alzheimer's disease and the aging population

The brain is the most complex organ in the body. Currently, its complicated functionality has not been fully understood. However, in the last decades an exponential growth on research publications emerged thanks to the use of in-vivo brain imaging techniques. One of these techniques pioneered for medical use in the early 1970s was known as nuclear magnetic resonance imaging based (now called magnetic resonance imaging [MRI]). Nowadays, the advances of MRI technology not only allowed us to characterize volumetric changes in specific brain structures but now we could identify different patterns of activation (e.g. functional MRI) or changes in structural brain connectivity (e.g. diffusion MRI). One of the benefits of using these techniques is that we could investigate changes that occur in disease-specific cohorts such as in the case of Alzheimer’s disease (AD), a neurodegenerative disease that affects mainly older populations. This disease has been known for over a century and even though great advances in technology and pharmacology have occurred, currently there is no cure for the disease. Hence, in this work I decided to investigate whether aerobic exercise, an emerging alternative method to pharmacological treatments, might provide neuroprotective effects to slow down the evident brain deterioration of AD using novel in-vivo diffusion imaging techniques. Previous reports in animal and human studies have supported these exercise-related neuro-protective mechanisms. Concurrently in AD participants, increased brain volumes have been positively associated with higher cardiorespiratory fitness levels, a direct marker of sustained physical activity and increased exercise. Thus, the goal of this work is to investigate further whether exercise influences the brain using structural connectivity analyses and novel diffusion imaging techniques that go beyond volumetric characterization. The approach I chose to present this work combined two important aspects of the investigation. First, I introduced important concepts based on the neuro-scientific work in relation to Alzheimer’s diseases, in-vivo imaging, and exercise physiology (Chapter 1). Secondly, I tried to describe in simple mathematics the physics of this novel diffusion imaging technique (Chapter 2) and supported a tract-specific diffusion imaging processing methodology (Chapter 3 and 4). Consequently, the later chapters combined both aspects of this investigation in a manuscript format (Chapter 5-8). Finally, I summarized my findings, include recommendations for similar studies, described future work, and stated a final conclusion of this work (Chapter 9)

18F-FDG-PET and Neuropsychological Testing in Different Types of Neurodegenerative Dementias

Demenz ist ein Syndrom, das durch einen Verlust der kognitiven Funktionen wie Gedächtnis, Orientierung und Denken sowie eine Beeinträchtigung der Alltagsrelevanz charakterisiert ist. Patienten mit einer Demenz zeigen ein regionales Defizit des Glucosemetabolismus im Gehirn. Das Ziel dieser Studie ist, einen Zusammenhang zwischen der neuropsychologischen Untersuchung und des regionalen Glucosemetabolismus des Gehirns bei Demenz-Patienten zu finden. In dieser Studie wurden 24 Patienten mit einer Demenz im Alter 69.2 7.5 Jahren, die nach den Kriterien der ICD-10 und der DSM-IV diagnosziert wurden, eingeschlossen. Die kognitiven Leistungen wurden mit Hilfe der CERAD-NP Testbatterie, des Uhrentests nach Shulman und des Stroop-Paradigmas nach dem Nürnberger-Alters-Inventar (NAI) getestet. Die MRT- und FDG-PET Untersuchungen wurden bei allen Patienten durchgeführt. Die Bildgebungsdatensätze wurden mit Hilfe der Medical Image Processing, Analysis and Visualisation software (MIPAV) nach der Region of Interest (ROI) – Methode in neun Gehirnregionen (die rechten und linken Hemisphären, der rechte und linke Gyrus frontalis inferior, der rechte und linke Hippocampus, der rechte und linke Parietallappen) ausgewertet. Die Daten wurden mittels des Spearman-Koeffizierten korreliert. In dieser Studie wurde eine signifikante Korrelation zwischen dem MMSE–Wert und dem Hypometabolismus im linken und rechten Parietallappen ermittelt. Beeinträchtigungen in der verbalen Lernleistung (Wortliste Lernen im CERAD-NP) korrelierten mit einem Hypometabolismus in der linken Hemisphäre, dem linken und rechten Hippocampus und dem linken Parietallappen. Zusätzlich wurde eine signifikante Korrelation zwischen der Wortliste Wiedererkennen (CERAD-NP) und einem reduzierten zerebralen Metabolismus des linken Gyrus frontalis inferior gefunden. Die konstruktive Praxis (CERAD-NP) korrelierte mit einem verringerten Glukosemetabolismus in der rechten Hemisphäre. Die visuokonstruktive Praxis (Uhrentest) konnte nicht signifikant mit spezifischen Gehirnregionen in Verbindung gebracht werden. Auffälligkeiten im Stroop-Paradigma korrelierten mit einem Hypometabolismus im rechten Gyrus frontalis inferior. Die Ergebnisse dieser Studie zeigen, dass spezifische kognitive Defizite Aufschluss über die entsprechende Lokalisation der neurodegenerativen Erkrankung im Gehirn geben können