Search

Introduction. For progressive supranuclear palsy (PSP), oculomotor function is one of the core features on which the diagnosis is based upon according to the diagnostic criteria by the Movement Disorder Society (MDS) supported PSP-Study-Group from 2017 (“O criterion”). The aim of this study was to analyze the value of specific oculomotor parameters. Material/Method. An analysis of the videooculographic examinations of smooth pursuit eye movements and visually guided reactive saccades in 100 PSP patients and 49 matched control subjects was performed. Group differences as well as correlations were tested at a two-sided level α=0.05. Cut-off values for the development of new subgroups were defined by the fifth or 95th percentile of specific parameters of the control group. ROC-analyses were used to determine sensitivity and specificity. Results. Each of the investigated oculomotor parameters (for smooth pursuit eye movements gain, for saccades latency, gain, peak eye velocity, asymmetry of velocities up- and downwards, rate of saccadic intrusions (SI)) was significantly altered in PSP compared with the control population (p Discussion. The results for vertical saccade velocity and SI, respectively, emphasized their relevance as part of the MDS-PSP diagnostic criteria, whereas the significance of the asymmetry of the vertical velocities was limited. With respect to directional tendency, the findings are still heterogeneous. In future evaluations, unbiased quantifications of clinical parameters offer a good possibility to further develop the quality of the diagnostic procedures used for PSP. Fig. 1.

Introduction. The diagnosis of progressive supranuclear palsy (PSP) involves head MRI, including detection of atrophy patterns of the mesencephalon and frontoparietal regions. In this study, MRI-based alterations of the texture in the corpus callosum (CC) in PSP patients compared with Parkinson's disease (PD) patients and healthy controls were investigated. Methods. In sagittal T1-weighted MRI scans of 66 PSP patients, 66 PD patients and 44 healthy controls the corpus callosum was segmented by atlas-based volumetry and TIFT [1] in areas I-V based on the Hofer & Frahm scheme [2]. The texture parameters entropy and homogeneity were calculated separately for areas I-V and results were compared for PSP patients (including phenotypes Richardson-syndrome and PSP-parkinsonism) vs. PD patients vs. healthy controls. Results. A significant increase of parameters entropy and homogeneity compared to controls was detected for PSP as well as for PD for areas I, II, and III of the CC; here PSP patients showed a higher increase compared to PD patients. Highest alterations were detected in area II where the increase of (in)homogeneity of PSP compared with PD was significant. Differences between the phenotypes Richardson-syndrome und PSP-parkinsonism could not be shown. Discussion. Texture analysis of the CC could contribute to diagnosis, screening and differentiation between PSP and PD. References [1] Muller HP, et al. Neuroimage Clin. 2020; 26:102223. [2] Hofer S, Frahm J. Neuroimage. 2006; 32,989-994.

Introduction. Neuropathological studies in amyotrophic lateral sclerosis (ALS) show that ALS may disseminate in a sequential regional pattern during four disease stages. The in vivo transfer of this propagation scheme can be performed by diffusion tensor imaging (DTI) based analysis of specific tracts [1]. This study investigates if these alterations can already be detected in asymptomatic ALS mutation carriers. Methods. The analysis of fractional anisotropy (FA) was performed by whole brain-based spatial statistics (WBSS) as well as by a tract-of-interest (TOI)-analysis for 45 positively tested asymptomatic ALS mutation carriers vs age- and gender-matched controls to detect specific white matter alterations. Furthermore, a longitudinal analysis was performed with a time-interval of 300 days of data of 20 positively tested asymptomatic ALS mutation carriers. Results. Neither WBSS nor TOI-based analysis were able to detect significant characteristic alteration patterns for asymptomatic ALS mutation carriers. Discussion. This study shows that microstructural alterations in ALS specific tracts in asymptomatic mutation carriers are not detectable by DTI-based analyses. That way, these tract alterations seem to be detectable with the beginning of the symptomatic stage. [1] Kassubek J, et al. J Neurol Neurosurg Psychiatry 2018; 89:374–381.

Background The use of in vivo diffusion tensor imaging (DTI) has substantially improved the understanding of the in vivo cerebral neuropathology of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS) ( Filippi et al., 2015 ) as a rapidly progressive neurodegenerative disease with a well-defined neuroanatomical propagation pattern according to the Braak stages ( [Muller et al., 2016] , [Kassubek et al., in press] ). Objective Investigation of DTI-based in vivo ALS metadata for the validation of the proposed sequential disease spread in ALS. Methods A meta-analysis on whole-brain based DTI analysis in ALS patients compared with controls using MEDLINE database was performed. Fifty-five studies, including 1319 ALS patients and 1183 controls, were enrolled. Results The data analysis demonstrated a characteristic pattern of significant white matter alterations in regions that are known to become sequentially involved. In particular, the hypothesis-guided computation revealed the highest prevalence of significant DTI based alterations in regions associated with stage I followed by stage II and III while the prevalence was demonstrated to be low in regions associated with stage IV. Conclusion The DTI-based meta-analysis results were in line with present findings of white matter alterations in ALS and support the model of the corticofugal disease spread in four stages and put further in vivo evidence to the proposed ALS staging scheme.

Introduction Neuropathological studies in amyotrophic lateral sclerosis (ALS) have shown that ALS may disseminate in a regional sequence in four disease-related patterns ( Braak et al., 2013 ). Recently, our group reported the diffusion tensor imaging (DTI)-based analysis of sequential spreading of disease in ALS ( Kassubek et al., 2014 , Muller et al., 2016 ). The aim of this study was to show that longitudinal data support the pathological findings and to establish DTI as an in vivo tool to image pathological ALS stages by testing for longitudinal consistency of the categorization results. Methods The application of in vivo DTI analysis to fiber structures that are prone to be involved at each neuropathological pattern of ALS was performed in a large-scale monocentre sample of ALS patients. A total of 584DTI datasets from ALS patients (N = 425) and controls (N = 159) were analyzed by tract of interest (TOI)-based fiber tracking; 52 ALS patients and 22 controls obtained at least one follow-ups can with different time-intervals of 10 months ( ± 9 months) in average. Results At the individual level, a categorization into ALS staging patterns was possible. At the group level, longitudinal ALS data showed significant differences for the stage-related tract systems (p Conclusion In summary, in vivo imaging of the disease patterns in ALS has become feasible cross-sectionally and longitudinally and has potential to be used as a non-invasive readout in ALS trials.

Background The neurophysiology of eye movement control provides a window into brain pathology in neurodegenerative diseases such as Parkinson’s disease (PD), Multisystem Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) ( Gorges et al., 2016 ). Structural and functional brain architecture can be investigated using Diffusion tensor imaging (DTI), Atlas-based morphometry (ABV) and “resting-state” fMRI. Objective To investigate the association between impaired oculomotor control and both volumetric as well as structural and functional brain connectivity changes in PD, MSA, and PSP patients. Methods A total of 152 patients including 71 PD, 56 PSP, and 25 MSA patients together with 56 matched healthy controls underwent video-oculographic examination (EyeSeeCam®) and whole-brain based DTI, high-resolution3DT1-weighted, and ‘resting-state’ MRI. Results Impaired executive oculomotor control was a prominent feature in PD as measured for the rate of saccadic intrusions (p Conclusions Worse oculomotor performance in the disease-specific domain was associated with more severely impaired regional macro- and microstructure and reduced regional functional connectivity in disease-specific brain structures. These findings increase our pathophysiological knowledge of the underlying parkinsonism-associated pathology and pave the way towards a video-oculographic surrogate marker.

Background It is still a topic of research if specific clinical presentations of motoneuron disease (MND) patients should be classified as amyotrophic lateral sclerosis (ALS) variants, i.e. primary lateral sclerosis (PLS) with predominant upper motor neuron on the one hand and pure lower motor neuron disease (LMND) on the other hand. Objective markers for ALS are to be investigated in these patients. Objective The aim of the study was to investigate white matter damage by a hypothesis-guided tract-of-interest-based approach in patients with classical ALS, LMND, and PLS in contrast to healthy controls in order to challenge the hypothesis that brain structural changes according to the neuropathologically defined ALS affectation pattern ( Kassubek et al., 2014 ) can be observed. LMND data were pooled from previous studies at two different study sites (Ulm, Germany and Milano, Italy). Methods DTI-based white matter integrity mapping was performed by voxelwise statistical comparison and by a tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 65 LMND patients (clinically differentiated in fast and slow progressors), 42 PLS patients, and 101 ALS patients with a ’classical’ phenotype vs 92 matched controls to identify white matter structural alterations. Results The analysis of predefined tracts-of-interest according to the neuropathological spreading pattern demonstrated regional characteristic alteration patterns (FA reductions) fast LMND progressors and in ALS compared to controls. ( Muller et al., 2018 ) The degree of involvement correlated with the clinical phenotype. PLS also presented substantial tract involvement in the tract-of-interest-based approach. Conclusion In the tract-specific analysis according to the ALS-staging pattern, upper (PLS) as well as lower motor neuron disease (LMND) pathology showed alterations of ALS-related corticoefferent fibers. The neuroimaging results confirm the clinical approach to these phenotypes as ALS variants, in accordance with the latest revision of the El Escorial criteria for ALS, in favour of the consequence to treat these patients like ALS and also to include them into clinical trials of ALS.

Background In multisystem atrophy (MSA), the functional brain connectivity within cortical and subcortical networks and its clinical correlates is a challenging topic of research. Objective Assessment of functional brain connectivity alterations in MSA. Methods Whole-brain based ‘intrinsic functional connectivity’ MRI data were obtained from 22 MSA patients and 22 matched healthy controls, together with standardized clinical assessment and video-oculographic recordings (EyeLink®). Results MSA patients vs. controls showed significantly increased ponto-cerebellar functional connectivity and decreased default mode network connectivity ( p 0.05 , corrected). No differences were observed in the motor network. Saccadized smooth pursuit significantly correlated with increased functional ponto-cerebellar connectivity ( p 0.05 , corrected). Conclusion This intrinsic functional connectivity analysis supports a network-dependent combination of hyper- and hypoconnectivity states in MSA, in agreement with adaptive compensatory responses (hyperconnectivity) and a function disconnection syndrome (hypoconnectivity) ( Gorges et al., 2017 ) that may occur in a consecutive sequence.

Background Characteristically impaired oculomotor functions are recognized in Parkinsonian syndromes including idiopathic Parkinson disease (PD), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) ( Pinkhardt and Kassubek, 2011 ). Atrophy of specific brain structures has been reported in Parkinsonian syndromes ( Brenneis et al., 2007 , Focke et al., 2011 ). The aim of this study was to investigate possible relationships between oculomotor alterations and volumetric alterations in PD, PSP and MSA. Methods Forty-two PD, 18 MSA, and 32 PSP patients together with 26 healthy controls underwent standardized video-oculographic testing and MRI at a clinical 1.5T scanner. Whole-brain based T1-weighted MRI-images were analyzed using atlas-based volumetry ( Kassubek et al., 2011 ). Data of 5 brain structures (forebrain, brainstem, cerebellum, midbrain, pons) and 5 oculomotor parameters (smooth pursuit gain, peak eye velocity, rate of saccadic intrusions, anti-saccade errors) were used for group comparisons in PD, MSA and PSP with healthy controls. Oculomotor parameters were correlated with regional brain volumes in the patients. Results PD patients compared with control showed a significantly increased rate of saccadic intrusions (p). Conclusions The worse the oculomotor performance the lower the regional brain volume, suggesting a relationship between regional brain atrophy and cerebral oculomotor network disturbances. Deficits in eye movement control in PD appear to be characterized by executive abnormalities, whereas oculomotor dysfunctions in MSA and PSP were associated with impaired pontine and midbrain pathways.

Background A common feature of Parkinsonism – including idiopathic Parkinson’s disease (PD), Multisystem Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) – are characteristic alterations of eye movement control ( Gorges et al., 2014 ). Regional microstructural alterations assessed by diffusion tensor imaging (DTI) have been reported in PD ( Agosta et al., 2014 ), MSA ( Prakash et al., 2009 ) and PSP ( Rosskopf et al., 2015 ). Objective To investigate the association between eye movement disturbances and microstructural impairment in patients with PD, MSA and PSP. Methods Video-oculographic recordings (EyeSeeCam®) of smooth pursuit and visually guided reactive saccades as well as whole-brain based fractional anisotropy (FA) maps computed from diffusion tensor imaging (1.5T) data were analyzed for 37 IPS, 31 PSP, 19 MSA and 36 matched healthy control subjects. Results The prevalence of saccadic intrusions as a measure for inhibitory control was significantly increased in PD patients compared with controls (p Conclusions Eye movements alterations are predominantly the result of executive dysfunction in PD and reflect impaired infratentorial oculomotor control pathways in MSA and PSP. The worse the performance of the characteristic oculomotor parameter the more impaired was the associated regional microstructure.

Background Recordings of eye movements have demonstrated that oculomotor dysfunction in patients with amyotrophic lateral sclerosis (ALS) follows a two-staged pattern ( Gorges et al., 2015 ) that is consistent with the model of sequential corticofugal axonal spread of pTDP-43 pathology ( Brettschneider et al., 2013 ). Eye movement abnormalities in ALS include anti- and delayed saccades errors (stage 1) as well as additional infratentorial-network associated oculomotor functions such as gaze-palsy or a cerebellar type of smooth pursuit disturbance (stage 2). We aimed to investigate whether this model can be confirmed in a larger cohort (N = 164) and in longitudinal testing. Methods Eye movement recordings using video-oculography (EyeSeeCam®) together with clinical (ALS-FRS) and neuropsychological scores (ECAS) from 164 ALS patients and 31 matched healthy controls were used for the analysis. Longitudinal data were available from 16 ALS patients ( ∼ 6 months after initial testing). Results At the time of the first investigation, 60 patients presented no oculomotor deficits (‘nd’) compared with controls. 78 patients showed stage 1 symptoms with only executive dysfunction and 26 patients showed stage 2 pathology with additional cerebellar type of smooth pursuit and/or gaze palsy. The sequential appearance of impaired eye movement control as hypothesized by Gorges et al. (2015) was confirmed by the categorization of eye movement abnormalities over time: four patients with no deficits at timepoint 1 (out of 16) developed only executive dysfunctions (nd ⩾ stage 1) and one patient (categorized as stage 1 at timepoint 1) developed to stage 2, accompanied by a gradual worsening of executive functions. The oculomotor stages were significantly correlated (p). Conclusion According to the cross sectional approach the model of a two-staged sequential pattern of eye movement abnormalities in ALS could be confirmed by a lager cohort. Additional preliminary longitudinal data in 16 patients showed a progression from stage 0 to 1 or from 1 to 2 respectively. Thus our data favor the hypothesis that oculomotor decline in ALS depicts the neuropathological sequential spreading of the disease instead of being the consequence of different phenotypes of ALS. Oculomotor staging may serve as a technical marker of the neuropathological disease progression in correlation to the clinical phenotype.

Objective In-vivo assessment of ALS-associated white matter alteration patterns by diffusion tensor imaging (DTI)-based metrics have been included in the NiSALS neuroimaging concept (Turner et al., LancetNeurol 2011). The objective of this multicenter study was to assess structural connectivity in ALS at a large sample-size. Methods Four-hundred-and-seven DTI data sets from patients with ALS ( N = 239) and controls ( N = 168) were collected from 8 international centers with different scanner systems and different DTI-protocols. Comparability of data with the aim of pooling was tested and differences were regressed out. Results Beyond patterns of alterations in the corticospinal tracts, whole brain-based statistical analysis, after pooling of data sets from all centers, additionally captured significant white matter tract changes in the frontal lobe, brainstem and hippocampal regions, in keeping with the DTI-based correlates of post mortem neuropathological ALS-stages 1–4 (Kassubek et al., Brain 2014). Conclusion This study using an unprecedented number of subjects has detected more wide spread changes than typical single-site studies.The observed pattern of fiber tract pathology has the potential to serve as a biomarker of disease and progression and as a read-out for future clinical trials. Key message By this multi-centre approach, it was possible to non-invasively confirm the pathoanatomy of ALS in vivo .

Introduction Criteria for assessing upper motor neuron pathology in lower motor neuron disease (LMND) still remain a major issue in clinical diagnosis. This study was designed to investigate patients with the clinical diagnosis of adult pure LMND by use of whole-brain based diffusion tensor imaging (DTI) in order to delineate alterations of corticoefferent pathways in vivo. Methods Comparison of fractional anisotropy (FA) maps was performed by whole brain-based spatial statistics for 37 LMND patients vs. 53 matched controls to detect white matter structural alterations. LMND patients were clinically differentiated in fast and slow progressors. Tract specific alterations were investigated by fiber tracking techniques according to the staging hypothesis for amyotrophic lateral sclerosis (ALS). Results The analysis of white matter structural connectivity demonstrated widespread and characteristic patterns of alterations in patients with LMND, predominantly along the corticospinal tract (CST), with multiple clusters of regional FA reductions in the motor system at p Kassubek et al., 2014 ), fast progressing LMND showed significant alterations of ALS-related tract systems ( Muller et al., xxxx ) beyond the CST compared to slow progressors and controls. Conclusion In clinically pure LMND patients, the involvement of corticoefferent tracts was demonstrated, in particular along the CST, supporting the hypothesis that LMND is a phenotypical variant of ALS. This finding suggests to treat these patients like ALS, including the opportunity to participate in clinical trials.

Impaired energy expenditure parallels ongoing motor neuron degeneration in patients with amyotrophic lateral sclerosis (ALS). Translational animals provide evidence that energy metabolism is associated with impaired hypothalamic function. We aimed at analyzing the hypothalamic volumes in ALS patients compared with controls. Hypothalamic volume of 281 ALS patients and 116 healthy matched controls were manually delineated based on high-resolution anatomic T1-weighted MRI images using a dedicated segmentation technique.The volume of the hypothalamus, was normalized to the intracranial volume and adjusted with age.The total hypothalmic volume was significantly decreased in ALS patients compared with controls ( p 0.0001 ); morespecifically the posterior part of the hypothalamus was more severely atrophied compared with the anterior part. The volume loss didnotcorrelate significantly with clinical and metabolic parameters which suggests an early affection of hypothalamic function possibly preceding motor symptom onset in ALS. Volumetric alterations of the hypothalamus could be an early feature of ALS.

Background Assessment of eye movement control in Parkinson’s disease (PD), multisystematrophy (MSA), and progressive supranuclear palsy (PSP) shows disease-related oculomotor alterations ( Pinkhardt and Kassubek, 2011 ). Volumetric 3D MRI analysisis a tool of growing relevance inthe differential diagnosis in neurodegenerative Parkinsonism ( Huppertz et al., 2016 ). Objective To investigate the association between impaired eye movement control and regional volume loss in PD, MSA, and PSP patients. Methods Video-oculographic data (EyeLink®) and high resolution 3-dimensional T1-weighted MRI images from 39 PD, 32 PSP, 18 MSA patients, and 24 matched healthy control subjects wereincluded in the analysis. Atlas based volumetry (ABV) was used to investigate for regional volumetric alterations ( Huppertz et al., 2016 ). Results In PD, saccadic intrusions were commonly observed as a measure for executive control (pppp). Conclusions The worse the characteristically impaired eye movement parameter in PD, MSA and PSP, the more severe was the disease-specific regional volume loss.

Background The underlying pathological process in neurodegenerative diseases is associated with altered functional brain organization. Objective To study functional connectivity and its possible behavioral correlates in specific networks in patients with progressive supranuclear palsy (PSP). Methods Whole-brain based “resting-state” fMRI data from 34 PSP patients (Richardson subtype (PSP-RS): n = 22; Parkinsonian subtype (PSP-P): n = 12) and 35 matched healthy controls were subjected to network-based functional connectivity analysis. Results Group comparison between PSP patients and controls revealed significantly decreased functional connectivity (p Conclusion PSP-associated neurodegeneration may be attributed to both, decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (i.e. cognitive decline, gaze palsy), whereas the pattern of increased functional connectivity may be attributed to adaptive changes.

Introduction The potential of magnetic resonance imaging (MRI) as a technical biomarker for cerebral alterations is under investigation in neurodegenerative diseases. In this study, a framework for the longitudinal analysis of diffusion tensor imaging (DTI)-based mapping with a series of follow-up scans was applied to longitudinal microstructure assessment of predefined white matter tracts in the course of amyotrophic lateral sclerosis (ALS), as an example for a rapidly progressive neurodegenerative disease. Methods Fifty-four longitudinal DTI datasets from 6 patients with ALS and 3 controls were recorded each 3 months (with up to 15 follow-up scans), yielding a total of 54 longitudinal DTI data sets. After individual alignment and stereotaxic normalization, an averaged DTI data set was created for fibertracking. Fractional anisotropy (FA) values of the tract structures were used to calculate progression rates based on DTI metrics. Results Patients with ALS showed an FA decline along the corticospinal tract (CST) which has been identified as the first affected tract structure in ALS and as the tract correlating with Braak‘s neuropathological stage 1 ( Kassubek et al., 2014 ). FA of controls remained stable in longitudinal DTI scans, whereas, FA decrease progression in the CST ranged from 0.5% to 6% per year in ALS-patients, i.e. four patients showed low progression rates between 0.5% and 2% per year and two patients showed fast progression rates between 3% and 6% per year. The ALS-FRS-R decline correlated significantly with FA decline over time. Conclusion On the basis of the longitudinal DTI data assessment with multiple follow-up measures, FA values were shown to be an in vivo marker for ALS-associated disease progression. That way, imaging-based progression rates at the individual patient level can be determined from DTI scans.

Introduction Eye movements provide a valuable window into complex forms of human behavior. Impaired eye movement control in patients with Parkinson's disease (PD) has been consistently demonstrated besides the well-known motor symptoms (Pinkhardt and Kassubek, 2011). Saccadic intrusions are a common oculomotor manifestation in PD and interrupt smooth pursuit and fixation during tracking a 'jumping' target (visually guided reactive saccades) (Pinkhardt and Kassubek, 2011; Gorges et al., 2014). The default mode network (DMN) as observed with 'resting-state' functional MRI is crucially involved in higher cognitive processes such as attention (Buckner et al., 2008). We hypothesized that prevalence of saccadic intrusions in patients with PD reflects executive deficits which are closely associated with intrinsic functional connectivity (iFC) within the DMN. Methods The analysis was based on 31 patients with PD and 22 age-matched healthy controls. We acquired 'resting-state' functional MRI (3Tesla; BOLD-sensitive T2 ∗ -sequence) and video-oculographic recordings (VOG, Eye-Link I operating on 250 Hz sampling rate) of smooth pursuit eye movements and visually guided reactive saccades. 'Resting-state' functional MRI analysis followed standardized procedures (Gorges et al., 2014) with the DMN computed by seeding the posterior cingulate cortex (Buckner et al., 2008). The posterior cingulate cortex is known to be both a major node of the DMN (Buckner et al., 2008) and to play a critical role in eye movement control (Olson et al., 1996). Both smooth pursuit gain as a measure for saccadic intrusions and the saccadic intrusion rate during reactive saccades were analyzed in patients vs. controls and correlated with iFC within the DMN. Results VOG analysis revealed a significantly higher prevalence of saccadic intrusions during smooth pursuit ( p p p Conclusions A high prevalence of saccadic intrusions in patients with PD appears to be closely related to a lack of attention, pointing towards an increased distractibility that might be associated with the neuroimaging correlate of a disrupted DMN. This supports the hypothesis that impaired oculomotor control in PD reflects a behavioral correlate of disturbed higher functions rather than impaired oculomotor circuits in the brainstem.

Introduction Cognitive decline is a burdensome non-motor symptom in patients with Parkinson's disease (PD). Functional MRI in the 'resting-state' provides a valuable measure of intrinsic functional connectivity (iFC) between brain areas; alterations of iFC in PD have been demonstrated in several studies (Prodoehl et al., 2014). However, these studies did not distinguish between cognitively unimpaired and impaired PD patients. This study aimed at investigating the iFC in PD depending on the patients' cognitive status. Methods "Resting-state" fMRI (3 Tesla; BOLD-sensitive T2 ∗ -sequence) data were acquired in 14 cognitively unimpaired (PD-Cu) and 17 cognitively impaired PD patients (PD-CI) in comparison with 22 age-matched healthy controls. The classification of patients into subgroups (PD-Cu, PD-CI) was based on thorough neuropsychological testing according to recently proposed guidelines (Litvan et al., 2012). The data analysis followed standardized procedures using the seed-based approach (Gorges et al., 2014) in order to identify the default mode, frontoparietal control, visualspatial, the ventral and dorsal attention networks (Smith et al., 2009). Results We observed significantly increased iFC (hyper-connectivity) in the sense of network expansions ( p Conclusions In PD patients confirmed to be free of cognitive deficits, we demonstrated pronounced alterations of iFC as marked network expansions in the sense of recruiting additional resources as an adaptive (compensatory) mechanism in the progressive pathological process in PD. The cognitive reserve appears to be exhausted in the advanced stages of the disease due to increasing neuronal cell loss, resulting in functional disruption predominantly in cognition-associated brain areas.

Introduction In Huntington’s disease (HD), cerebral white matter changes have been reported in a number of studies using diffusion tensor imaging (DTI) or T1-weighted magnetic resonance imaging (MRI). A key question is how brain structure changes (both grey and white matter) influence brain function. Intrinsic functional connectivity (ifc) MRI investigates intrinsic connectivity networks (ICN), i.e. large-scale distributed functionally coupled brain regions observed in the absence of a specific task. The objective of our study was to integrate structural connectivity data as assessed by DTI with ifcMRI changes in order to obtain a comprehensive picture of structural and functional changes with an emphasis on motor and basal ganglia thalamic networks. Methods Thirty-five early HD subjects (TFC stage 1 and 2) and 32 age- and sex-matched healthy controls underwent3T-MRI (T1w, DTI and ifcMRI sequences). DTI and ifcMRI data analyses were performed using the Tensor Imaging and Fiber Tracking (TIFT) software ( Muller et al., 2007 ) for complementary DTI fiber tracking (FT) and ifcMRI data analysis. For the motor ICN ifcMRI analyses, the dominant M1 was used as the seed, for the basal ganglia-thalamic ICN the thalamus was used. In addition, the cortico-spinal tract (CST) and the thalamocortical pathway were used for comparisons at the group level. Results Structural connectivity measured by DTI at the group level showed an increase of FA values in the basal ganglia as well as FA reductions in the external and internal capsule, in parts of the thalamus, and in subcortical white matter. Intrinsic functional connectivity (brain function) showed hyper-connectivity in the motor ICN, i.e. the insula was less connected in HD than in controls. The basal ganglia-thalamic ICN connectivity differed between HD and controls in the insula and the basal ganglia in both hemispheres. Conclusion At the group level, we confirmed microstructural changes identified in previous DTI studies in HD (e.g. ( Rosas et al., 2006 )). There is evidence that the insula becomes disconnected from the motor cortex. The caudatum seems to lose its functional integration with widely distributed cortical areas (basal ganglio-thalamic ICN). Abnormal connectivity of the insula and caudatum may be relevant in the emergence of clinical signs of HD. Acknowledgements This work was partially supported by the European Union under the Seventh Framework programme - PADDINGTON Project, Grant Agreement No.261358, and the European Huntington’s Disease Network (EHDN), project 070 - PADDINGTON.

Introduction Diffusion tensor imaging (DTI)-based metrics are increasingly used for analyzing ALS-associated whitematter alteration patterns and were included inthe Neuroimaging Society in Amyotrophic Lateral Sclerosis (NiSALS) concept ( Turner et al., 2011 ). The objective of this multicenter study was to assess structural connectivity in ALS at a large sample size to address the challenges of DTI data analysis from multiple study sites. Methods Four-hundred and ninety DTI data sets from patients with ALS ( N = 268) and controls ( N = 222) were collected from 8 study centers (Dublin, Ireland; Edinborough, UK; Jena, Germany; Miami, US; Milan, Italy; Oxford, UK; Rostock, Germany, Ulm, Germany). Data were obtained by different MRI-systems and by use of different DTI-protocols. In a first step, comparability of data with the aim of pooling was tested by a statistical analysis of fractional anisotropy (FA) in controls’ data. All analyses were performed by use of the Tensor Imaging and Fiber Tracking (TIFT) software. Statistical comparisons in terms of average FA-values ( Muller et al., 2013 ) were performed for the controls’ groups of the different centers. In a consecutive step, the calculated 3D correction matrices were then applied to the corresponding ALS patient subgroups of the different centers. Results Data collection and data quality control resulted in 442 DTI data sets (253 ALS patients and 189 controls) useful for this study, i.e. 48 data sets had to be excluded. All data samples of all centers showed a characteristic pattern (FA decrease along the corticospinal tracts) for comparison at the group level. Inter-center pooling of data showed ALS affectations in the CST (“horseshoe” configuration) as well as affectations in regions that have recently been reported to be relevant in ALS (frontocortical whitematter regions, hippocampal regions, as well as midbrain and brainstem) ( Kassubek et al., 2014 ). Conclusion This large scale multicenter NiSALS study investigated solutions to challenges in the process of pooling MRI data recorded at various study centers in ALS. This approach is of utmost importance in order to establish MRI-based techniques as read-outs both fornatural history assessment and for potential upcoming disease-modifying multicenter studies in ALS ( Roskopf et al., in press ).

Introduction Recently, the characteristic longitudinal distribution pattern of the underlying phosphorylated TDP-43 (pTDP-43) pathology in the behavioral variant of frontotemporal dementia (bvFTD) across specific brain regions was described ( Brettschneider et al., 2013 ). The aim of the present study was the transfer of these neuropathological findings to a diffusion tensor imaging (DTI)-based in vivo staging protocol. Methods Thirty-one bvFTD patients and 49 controls underwent DTI in a bicentric study design. Out of these, 14 bvFTD patients and 17 controls had a follow-up scan after 12 months. A second follow-up scan was performed in 4 bvFTD patients and in 7 controls, again after 12 months. Cross-sectional and longitudinal alterations were assessed by a two-fold analysis, i.e. voxelwise comparison of fractional anisotropy (FA) maps and a tract of interest-based (TOI) approach, which identifies tract structures that could be assigned to brain regions associated with disease progression ( Kassubek et al., 2014 ). Results Cross-sectional whole brain-based spatial statistics showed white matter alterations predominantly in the frontal lobes but no longitudinal alterations. The TOIs of bvFTD-stages 1 and 2 (uncinate fascicle – bvFTD-pattern I; corticostriatal pathway – bvFTD-pattern II) showed highly significant differences between bvFTD patients and controls. The corticospinal tract-associated TOI (bvFTD-pattern III) did not differ between groups in this group, whereas the differences in the optic radiation (bvFTD-pattern IV) were significant. Longitudinal TOI analysis allowed for individual patient categorization of one subgroup according to the pTDP-43 staging scheme. Longitudinally, disease progression (N = 5) or stable stage (N = 5) were observed. Conclusion The TOI-based in vivo staging approach was successfully applied to bvFTD and demonstrated a plausible pattern of damage to the involved major white matter pathways. Therefore, the TOI-based staging approach may also have potential as an in vivo biomarker for bvFTD.

Objective To see whether the sequential corticofugal spreading of pTDP-43 pathology in amyotrophic lateral sclerosis (ALS) (Brettschneider et al., Ann Neurol 2013) permit the categorization of eye movement disturbances in a corresponding oculomotor staging scheme. Methods Saccadic and smooth pursuit eye movements were video-oculographically recorded from 68 ALS patients and 31 matched healthy controls in order to compute parameters for executive oculomotor functions and brainstem oculomotor circuitry performance. Results Thirty patients had no oculomotor abnormalities compared to controls, all other presented a broad spectrum of impaired eye movement control including increased anti- and delayed saccades errors, a high prevalence of saccadic intrusions, gaze-palsy and a cerebellar type of smooth pursuit disturbance. Oculomotor deficits manifested sequentially witch permits a categorization of two stages: Stage 1, exclusively executive dysfunctions, and Stage 2, executive deficits plus impaired ,genuine‘ oculomotor control such as gaze-palsy or impaired pre-cereballary circuits. Conclusions Impaired executive eye movements appear as the initial manifestation, followed by disturbed infratentorial oculomotor control pathways. Key message Alterations in eye movement control in ALS follow a sequential pattern and may serve as a technical marker of the corticofugal axonal spread of the disease.

Background Autopsy-controlled studies in Amyotrophic lateral sclerosis (ALS) proposed a 4-stage sequential spreading of the underlying TDP-43 pathology ( Brettschneider et al., 2013 ). Recently the in vivo transfer of the neuropathological stages by use of tract of interest-based diffusion-tensor-imaging (DTI) has been performed ( Kassubek et al., 2014 ). Based upon the DTI findings, we have expanded the imaging approach by complementary investigation of ifc-fMRI in order to trace the pathology spreading in well-defined intrinsic functional connectivity networks (ICNs). Methods We used a 3.0T resting state-fMRI protocol for 76 ALS patients and 28 healthy controls. The preprocessing followed standardized procedures including motion correction, MNI normalization, spatial filtering, temporal linear detrending and bandpass filtering. ICNs were identified utilizing the seed-based approach ( Gorges et al., 2014 ). These ICNs comprised the motor (neuropathological stage 1), frontoparietal, frontal executive and brainstem (stage 2), basal ganglia (stage 3), and hippocampal (stage 4) networks; we used the visual ICN as reference. Results ALS patients compared with healthy controls demonstrated a large-scale pattern of increased functional connectivity (hyperconnectivity) in all networks with the exception of the reference network. More specifically, the hyperconnectivity pattern extended spatially into adjacent brain structures following the neuropathological spreading. The hyperconnectivity in stage 1 extended into frontal areas, in stage 2 into prefrontal and postcentral areas, in stage 3 into prefrontal and postcentral areas, and in stage 4 within the hippocampal formation. Moreover, the disease stages as observed in vivo by DTI significantly correlated with increasing functional connectivity in the ICNs. Conclusion Ifc-fMRI provides a promising approach to functionally trace pathological spreading in ALS. As recently suggested ( Douaud et al., 2011 ), the loss of the inhibitory influence may be most likely attributable to the pattern of hyperconnectivity in ALS. With increasing stages of disease, hyperconnectivity seems to spread sequentially into more frontal and postcentral regions following the neuropathological spreading.