Imis Dogan

Differentiated parietal connectivity of frontal regions for “what” and “where” memory

In a previous meta-analysis across almost 200 neuroimaging experiments, working memory for object location showed significantly stronger convergence on the posterior superior frontal gyrus, whereas working memory for identity showed stronger convergence on the posterior inferior frontal gyrus (dorsal to, but overlapping with Brodmann’s area BA 44). As similar locations have been discussed as part of a dorsal frontal—superior parietal reach system and an inferior frontal grasp system, the aim of the present study was to test whether the regions of working-memory related “what” and “where” processing show a similar distinction in parietal connectivity. The regions that were found in the previous meta-analysis were used as seeds for functional connectivity analyses using task-based meta-analytic connectivity modelling and task-independent resting state correlations. While the ventral seed showed significantly stronger connectivity with the bilateral intraparietal sulcus (IPS), the dorsal seed showed stronger connectivity with the bilateral posterior inferior parietal and the medial superior parietal lobule. The observed connections of regions involved in memory for object location and identity thus clearly demonstrate a distinction into separate pathways that resemble the parietal connectivity patterns of the dorsal and ventral premotor cortex in non-human primates and humans. It may hence be speculated that memory for a particular location and reaching towards it as well as object memory and finger positioning for manipulation may rely on shared neural systems. Moreover, the ensuing regions, in turn, featured differential connectivity with the bilateral ventral and dorsal extrastriate cortex, suggesting largely segregated bilateral connectivity pathways from the dorsal visual cortex via the superior and inferior parietal lobules to the dorsal posterior frontal cortex and from the ventral visual cortex via the IPS to the ventral posterior frontal cortex that may underlie action and cognition.

Investigating function and connectivity of morphometric findings — Exemplified on cerebellar atrophy in spinocerebellar ataxia 17 (SCA17)

Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia but also a broad spectrum of other neuropsychiatric signs. As anatomical and structural studies have shown severe cerebellar atrophy in SCA17 and a differentiation of the human cerebellum into an anterior sensorimotor and posterior cognitive/emotional partition has been implicated, we aimed at investigating functional connectivity patterns of two cerebellar clusters of atrophy revealed by a morphometric analysis in SCA17 patients. In particular, voxel-based morphometry (VBM) revealed a large cluster of atrophy in SCA17 in the bilateral anterior cerebellum (lobule V) and another one in the left posterior cerebellum (lobules IX, VIIb, VIIIA, VIIIB). These two cerebellar clusters were used as seeds for functional connectivity analyses using task-based meta-analytic connectivity modeling (MACM) and task-free resting state connectivity analysis. Results demonstrated first consistent functional connectivity throughout the cerebellum itself; the anterior cerebellar seed showed stronger connectivity to lobules V, VI and to some extent I-IV, and the posterior cerebellar seed to the posterior lobules VI-IX. Importantly, the cerebellar anterior seed also showed consistently stronger functional connectivity than the posterior one with pre- and motor areas as well as the primary somatosensory cortex. In turn, task-based task-independent functional connectivity analyses revealed that the cerebellar posterior seed was linked with fronto-temporo-parietal areas as well as partly the insula and the thalamus, i.e., brain regions implicated in cognitive and affective processes. Functional characterization of experiments activating either cerebellar seed further corroborated this notion, revealing mainly motor-related functions for the anterior cluster and predominantly cognitive functions were associated for the posterior one. The differential functional connectivity of the cerebellar anterior and posterior cluster highlights the manifold connections and dichotomy of the human cerebellum, providing additional valuable information about probably disrupted cerebellar-cerebral connections and reflecting the brunt of motor but also the broad spectrum of neuropsychiatric deficits in SCA17.

Biological and clinical characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data.

BACKGROUND Friedreichs ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report cross-sectional baseline data to establish the biological and clinical characteristics for a prospective, international, European Friedreichs ataxia database registry. METHODS Within the European Friedreichs Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreichs ataxia. The primary outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) and secondary outcome measures were the Inventory of Non-Ataxia Signs (INAS), the performance-based coordination test Spinocerebellar Ataxia Functional Index (SCAFI), the neurocognitive phonemic verbal fluency test, and two quality-of-life measures: the activities of daily living (ADL) part of the Friedreichs Ataxia Rating Scale and EQ-5D. The Friedreichs ataxia cohort was subdivided into three groups: early disease onset (≤14 years), intermediate onset (15-24 years), and late onset (≥25 years), which were compared for clinical characteristics and outcome measures. We used linear regression analysis to estimate the annual decline of clinical outcome measures based on disease duration. This study is registered with ClinicalTrials.gov, number NCT02069509. FINDINGS We enrolled 592 patients with genetically confirmed Friedreichs ataxia between Sept 15, 2010, and April 30, 2013, at 11 sites in seven European countries. Age of disease onset was inversely correlated with the number of GAA repeats in the frataxin (FXN) gene: every 100 GAA repeats on the smaller repeat allele was associated with a 2·3 year (SE 0·2) earlier onset. Regression analyses showed significant estimated annual worsening of SARA (regression coefficient 0·86 points [SE 0·05], INAS (0·14 points [0·01]), SCAFI Z scores (-0·09 [0·01]), verbal fluency (-0·34 words [0·07]), and ADL (0·64 points [0·04]) during the first 25 years of disease; the regression slope for health-related quality-of-life state from EQ-5D was not significant (-0·33 points [0·18]). For SARA, the predicted annual rate of worsening was significantly higher in early-onset patients (n=354; 1·04 points [0·13]) and intermediate-onset patients (n=137; 1·17 points [0·22]) than in late-onset patients (n=100; 0·56 points [0·10]). INTERPRETATION The results of this cross-sectional baseline analysis of the EFACTS cohort suggest that earlier disease onset is associated with larger numbers of GAA repeats and more rapid disease progression. The differential estimated progression of ataxia symptoms related to age of onset have implications for the design of clinical trials in Friedreichs ataxia, for which SARA might be the most suitable measure to monitor disease progression. FUNDING European Commission.

Altered Resting-State Connectivity in Huntington's Disease

Huntingtons disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Using resting‐state fMRI (rs‐fMRI) we investigated the functional integrity of resting‐state networks (RSN) in HD. 17 HD and 19 matched control participants were examined at a 3 Tesla MR scanner. After controlling for structural degeneration by means of voxel‐based morphometry, task‐free rs‐fMRI data were analyzed using Independent Component Analysis (ICA) and a dual‐regression approach in the context of genetic and clinical parameters. Further, we evaluated HD‐related differences in interregional connectivity between networks. RSN analysis showed a significant increase in intrinsic functional connectivity in the HD sample compared with controls, including the thalamus, striatum, prefrontal, premotor, and parietal maps. A subset of the Default Mode Network (DMN) was also affected. In the HD cohort, motor impairment correlated with higher network connectivity in mainly motor and parietal cortices. Deteriorating total functional capacity was additionally associated with higher connectivity in the striatum, thalamus, insular and frontal areas. This pattern of increased activity in intrinsic functional networks might suggest a reduced ability of intra‐network differentiation with clinical disease progression in HD. Finally, results showed reduced long‐range connectivity between parietal ICA components in HD compared to controls, indicating impaired functional coupling between interregional networks in HD. Our data demonstrates that functional connectivity is profoundly altered in HD, both within and between RSN. Rs‐fMRI analysis may provide additional valuable insights into neuronal dysfunctions beyond HD‐related structural degeneration and disruptions of functional circuits in HD. Hum Brain Mapp 35:2582–2593, 2014.

Consistent neurodegeneration and its association with clinical progression in Huntington's disease: a coordinate-based meta-analysis.

Background: The neuropathological hallmark of Huntingtons disease (HD) is progressive striatal loss starting several years prior to clinical onset. In the past decade, whole-brain magnetic resonance imaging (MRI) studies have provided accumulating evidence for widely distributed cortical and subcortical atrophy in the early course of the disease. Objective: In order to synthesize current morphometric MRI findings and to investigate the impact of clinical and genetic features on structural changes, we performed a coordinate-based meta-analysis of voxel-based morphometry (VBM) studies in HD. Methods: Twenty HD samples derived from 17 studies were integrated in the analysis comparing a total of 685 HD mutation carriers [345 presymptomatic (pre-HD) and 340 symptomatic (symp-HD) subjects] and 507 controls. Convergent findings across studies were delineated using the anatomical likelihood estimation approach. Effects of genetic and clinical parameters on the likelihood of observing VBM findings were calculated by means of correlation analyses. Results: Pre-HD studies featured convergent evidence for neurodegeneration in the basal ganglia, amygdala, thalamus, insula and occipital regions. In symp-HD, cerebral atrophy was more pronounced and spread to cortical regions (i.e. inferior frontal, premotor, sensorimotor, midcingulate, frontoparietal and temporoparietal cortices). Higher cytosine-adenosine-guanosine repeats were associated with striatal degeneration, while parameters of disease progression and motor impairment additionally correlated with cortical atrophy, especially in sensorimotor areas. Conclusion: This first quantitative meta-analysis in HD demonstrates the extent of striatal atrophy and further consistent extrastriatal degeneration before clinical conversion. Sensorimotor areas seem to be core regions affected in symp-HD and, along with widespread cortical atrophy, may account for the clinical heterogeneity in HD.

Neural correlates of impaired emotion processing in manifest Huntington’s disease

The complex phenotype of Huntingtons disease (HD) encompasses motor, psychiatric and cognitive dysfunctions, including early impairments in emotion recognition. In this first functional magnetic resonance imaging study, we investigated emotion-processing deficits in 14 manifest HD patients and matched controls. An emotion recognition task comprised short video clips displaying one of six basic facial expressions (sadness, happiness, disgust, fear, anger and neutral). Structural changes between patients and controls were assessed by means of voxel-based morphometry. Along with deficient recognition of negative emotions, patients exhibited predominantly lower neural response to stimuli of negative valences in the amygdala, hippocampus, striatum, insula, cingulate and prefrontal cortices, as well as in sensorimotor, temporal and visual areas. Most of the observed reduced activity patterns could not be explained merely by regional volume loss. Reduced activity in the thalamus during fear correlated with lower thalamic volumes. During the processing of sadness, patients exhibited enhanced amygdala and hippocampal activity along with reduced recruitment of the medial prefrontal cortex. Higher amygdala activity was related to more pronounced amygdala atrophy and disease burden. Overall, the observed emotion-related dysfunctions in the context of structural neurodegeneration suggest both disruptions of striatal-thalamo-cortical loops and potential compensation mechanism with greater disease severity in manifest HD.

Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study

BACKGROUND The European Friedreichs Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreichs ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. METHODS We enrolled patients with genetically confirmed Friedreichs ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits-baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. FINDINGS Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreichs ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (-0·02 points per year [0·01] per year of age) and lower SARA baseline scores (-0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, -0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and -0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. INTERPRETATION Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreichs ataxia. FUNDING European Commission.

Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) – A systematic review on potential biomarkers for neurodegeneration

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of physiological atonia of skeletal muscles with abnormal behavior during dream sleep. RBD may be the initial manifestation of neurodegenerative diseases, particularly of α-synucleinopathies such as Parkinsons disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, gauging the individual risk of subsequent phenoconversion and making assumptions on the type of disease that may subsequently follow RBD is challenging. Over the past years, a growing number of studies have sought to establish reliable neuroimaging markers to detect neurodegenerative brain changes in RBD subjects at the earliest possible stage. The present review summarizes recent advances in brain imaging in RBD and provides recommendations for the application of currently available structural and functional neuroimaging modalities to monitor disease progression and risk of subsequent phenoconversion. Further imaging research applying multimodal approaches is encouraged to enhance accuracy of prognoses. Additionally, more longitudinal studies are warranted to validate findings from cross-sectional studies on RBD progression and risk of subsequent phenoconversion. Aside from enabling reliable prognoses on a single-subject-level in the near future, this might give further insight into RBD pathophysiology, and finally augment the development of intervention strategies and disease-modifying therapies.

Evidence for Gender Differences in Cognition, Emotion and Quality of Life in Parkinson’s Disease?

A number of gender differences have been documented in the incidence and symptomatology of the second most common age-related neurodegenerative disorder, idiopathic Parkinsons disease (PD). Overall, previous reports suggest a less frequent incidence and a more benign phenotype in women mainly in Western populations, which is thought to be mediated by estrogens in particular in early stages of the disease. Not only motor symptoms seem to underlie gender effects, but also non-motor symptoms such as psychiatric and cognitive impairments, which can often precede motor manifestation. However, reliable results for gender differences in PD in particular of cognitive function and emotion processing, having a major impact on quality of life, are lacking. Moreover, studies investigating gender effects in PD in these areas have revealed highly heterogeneous results. The present review summarizes findings of currently available studies on gender effects on neuropsychological tests covering major cognitive domains, emotion processing as well as quality of life in patients with PD. Overall, the occurrence of cognitive impairment in PD seems to be associated with male gender, though inconsistent results were shown in cognitive screening tests. Regarding emotion recognition, men with PD were found to be less accurate than women with PD at identifying fearful expressions, whereas vice versa results appeared in healthy subjects. Lower quality of life and greater disability were reported by women compared to men with PD, which corresponds with the results in healthy subjects. Several disease-specific mediators as well as the question of a general gender and age-related effect as observed in healthy individuals are discussed. Increased knowledge on possible gender effects in PD would provide an enhanced insight in underlying pathological mechanisms, and has potential implications for the diagnosis and treatment of PD.

Cognition in Friedreich's ataxia: a behavioral and multimodal imaging study

Friedreichs ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico‐cerebellar dysfunctions underlying executive functioning in individuals with FRDA.