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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 < 0.05 (corrected for multiple comparisons). Fast progressing LMND showed substantial CST involvement, while slow progressors showed less CST alterations. In the tract-specific analysis according to the ALS-staging pattern ( Kassubek et al., 2014 ), fast progressing LMND showed significant alterations of ALS-related tract systems ( Müller 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 < 0.05, corrected) in the prefrontal cortex which was significantly correlated with the cognitive status ( p = 0.006). Of note, midbrain network connectivity in PSP patients revealed increased connectivity with the thalamus on the one hand, while regionally decreased functional connectivity within the midbrain was significantly correlated with vertical gaze palsy ( p = 0.004) as quantified by video-oculographically on the other hand. PSP-RS showed significantly increased functional motor network connectivity with the medial prefrontal gyrus, whereas PSP-P patients presented no significant difference in motor network connectivity. 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. [ABSTRACT FROM AUTHOR]

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 < 0.001) which was significantly correlated with cerebral brain atrophy ( p < 0.001, corrected), white matter impairment ( p < 0.01, corrected), and functional connectivity loss along the default mode network’s midline cores ( p < 0.001, corrected), respectively. Vertical gaze palsy is the eponymous feature in PSP and was significantly correlated with midbrain atrophy ( p < 0.01, corrected), midbrain microstructural damage ( p < 0.001, corrected), and regional functional connectivity loss in the midbrain ( p < 0.001, corrected). Pronounced saccadized pursuit ( p < 0.001) was a cardinal feature in MSA which was correlated with pontine atrophy and white matter damage in the middle cerebral peduncle ( p < 0.001). 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. [ABSTRACT FROM AUTHOR]

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; Müller 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 < 0.05, corrected for multiple comparisons).Out of the 52 longitudinally scanned ALS patients, 13 ALS patients showed an increase in ALS-stage, while the other ALS patients remained stable. 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. [ABSTRACT FROM AUTHOR]

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 < 0.001) and negatively correlated with the fractional anisotropy (FA) in the capsula interna ( p < 0.001, FDR corrected). As a cardinal oculomotor feature in MSA, smooth pursuit was disturbed by characteristic ‘catch-up’ saccades ( p < 0.001) and was significantly correlated with a FA reduction in the middle cerebral peduncle ( p < 0.001, FDR corrected). The hallmark of PSP are pathologically slowed vertical peak eye velocities compared with controls ( p < 0.001); the lower the peak eye velocity the more marked microstructural impairment in midbrain ( p < 0.001, FDR corrected). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 . [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Mutations in C9orf72 and SOD1 account for most of the familial and late-onset sporadic ALS cases. Mutations in FUS can be identified in around 5% of FALS and 1% of overall sporadic ALS cases. Methods We screened a large cohort of 15 very early onset (onset age <36 years) and 10 middle aged (36–53 years) sporadic ALS patients to determine the frequency of mutations in C9orf72 , SOD1 and FUS in this distinct patient cohort. Results In the cohort of the very early onset patients, we identified 6 subjects (40.0%) carrying a FUS mutation. Genetic testing of the patients’ parents was possible in 5 families and revealed that the mutation in these individuals arose de novo . Two of the identified mutations had not been described before (c.1484delG; c.1504delG). Three patients carried the already in younger ALS patients described FUS mutation p.P525L. No mutations were found in SOD1 , C9orf72 . Five of the six identified patients presented with rapidly progressive bulbar symptoms. Conclusion Our study identifies FUS mutations as the most frequent genetic cause in early-onset ALS and suggests that de novo FUS mutations may be more common for sporadic ALS cases than recognized so far. Genetic testing of the FUS gene seems worthwhile in early onset ALS patients showing predominant bulbar symptoms and an aggressive disease course. [ABSTRACT FROM AUTHOR]