Disruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients.

BACKGROUND: Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. METHODS: The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. RESULTS: Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. CONCLUSION: This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.

Morphological MRI investigations of the hypothalamus in 232 individuals with Parkinson's disease.

BACKGROUND: The pathophysiology of the hypothalamic involvement in Parkinson's disease (PD) is not well understood. The objective of this study was the quantification of hypothalamic volumes in vivo in PD. METHODS: High-resolution T1 -weighted magnetic resonance imaging (MRI) data from 232 individuals with PD and 130 healthy non-PD individuals were used for quantification of the hypothalamic volumes. RESULTS: The hypothalamus in PD was not atrophied, as indicated by volumetric analyses in the prospectively collected subcohort (30 PD, V = 921 ± 78 mm3 vs 30 non-PD, V = 917 ± 67 mm3 ; P = 0.850) and validated in a large cohort (202 PD, V = 925 ± 88 mm3 vs 100 non-PD, V = 932 ± 114 mm3 ; P = 0.602). CONCLUSIONS: Hypothalamic involvement in PD as shown by a large body of histopathological evidence does not appear to be detectable by MRI-based volumetric quantification. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis.

OBJECTIVE: Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers. METHODS: High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI). RESULTS: We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (-21.8%, p<0.0001) and symptomatic ALS mutation carriers (-13.4%, p<0.001). The atrophy in patients with sporadic ALS was observed in both the anterior (-27.6% p<0.0001) and the posterior parts of the hypothalamus (-17.7%, p<0.0001). Notably, this atrophy was also observed in presymptomatic ALS mutation carriers (-15.5%, p<0.001) and was unrelated to whole brain volume atrophy or disease stage as assessed using DTI or functional status. Hypothalamic volume was correlated with body mass index (BMI) in patients with sporadic ALS (p=0.0434, ρ=+0.1579), and this correlation was much stronger in patients with familial ALS (fALS) (p=0.0060, ρ=+0.6053). Anterior hypothalamic volume was correlated with age at onset, but not with survival after MRI. CONCLUSIONS: Hypothalamus is atrophied in ALS, even in premorbid stages, and correlates with BMI, especially in fALS. Decreased anterior hypothalamic volume is associated with earlier onset of disease.

Intrinsic functional connectivity alterations in progressive supranuclear palsy: Differential effects in frontal cortex, motor, and midbrain networks.

BACKGROUND: The topography of functional network changes in progressive supranuclear palsy can be mapped by intrinsic functional connectivity MRI. The objective of this study was to study functional connectivity and its clinical and behavioral correlates in dedicated networks comprising the cognition-related default mode and the motor and midbrain functional networks in patients with PSP. METHODS: Whole-brain-based "resting-state" functional MRI and high-resolution T1-weighted magnetic resonance imaging data together with neuropsychological and video-oculographic data from 34 PSP patients (22 with Richardson subtype and 12 with parkinsonian subtype) and 35 matched healthy controls were subjected to network-based functional connectivity and voxel-based morphometry analysis. RESULTS: After correction for global patterns of brain atrophy, the 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 cognitive performance (P = 0.006). Of note, midbrain network connectivity in PSP patients showed increased connectivity with the thalamus, on the one hand, whereas, on the other hand, lower functional connectivity within the midbrain was significantly correlated with vertical gaze impairment, as quantified by video-oculography (P = 0.004). PSP Richardson subtype showed significantly increased functional motor network connectivity with the medial prefrontal gyrus. CONCLUSIONS: PSP-associated neurodegeneration was attributed to both decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (ie, dementia severity and gaze palsy), whereas the pattern of increased functional connectivity may be a potential adaptive mechanism. © 2017 International Parkinson and Movement Disorder Society.

Patterns of increased intrinsic functional connectivity in patients with restless legs syndrome are associated with attentional control of sensory inputs.

INTRODUCTION: Potential alterations of intrinsic functional connectivity in idiopathic restless legs syndrome (RLS) are to be assumed since RLS is considered a network disorder. Whole-brain-based investigation of intrinsic functional connectivity networks including the sensorimotor systems in patients with RLS was compared with matched healthy controls. METHODS: 'Resting-state' functional MRI (1.5 T) from 26 patients with RLS and 26 matched controls were analyzed using standardized seed-based analysis procedures. The motor/sensorimotor, sensory thalamic, ventral and dorsal attention, basal ganglia-thalamic, cingulate, and brainstem networks were used for voxel-based group comparisons between RLS patients and controls. RESULTS: Significantly increased connectivities were observed in the sensory thalamic, ventral and dorsal attention, basal ganglia-thalamic, and cingulate networks in RLS patients, whereas no differences could be demonstrated for the motor/sensorimotor and the brainstem system. The pattern of functional connectivity alterations was positively correlated with increasing symptom severity. CONCLUSIONS: Abnormally increased regional BOLD synchronization appears to be a key feature of intrinsic brain architecture in RLS. Alterations in cortical and sub-cortical functional networks support the notion that the underlying pathophysiology of RLS is beyond the sensorimotor and the brainstem system and may be also associated with altered attentional control of sensory inputs.

The cerebro-morphological fingerprint of a progeroid syndrome: white matter changes correlate with neurological symptoms in xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive progeroid syndrome. It has recently been shown that the underlying DNA repair defect plays a central role in the aging process. In addition to skin symptoms, various premature neurological abnormalities have been reported. METHODOLOGY/PRINCIPAL FINDINGS: We present the clinical neurological phenotype in 14 XP patients (seven subtypes), in seven of these patients together with conventional and multiparametric advanced MRI data to assess the macrostructural and microstructural cerebral morphology in comparison to controls, including volumetric measurements, MR spectroscopy ((1)H MRS), and diffusion tensor imaging (DTI). Clinical hallmarks were spinocerebellar ataxia, pyramidal tract signs, and mild cognitive deficits. DTI demonstrated significantly reduced WM directionality in all regions investigated, i.e. the thalamus, the corticospinal tracts and the dorsal corpus callosum. Single patients showed a marked relative hippocampal volume reduction, but the patients were not different from controls in the volumetric measurements of hippocampal and whole brain volumes at group level. However, (1)H MRS demonstrated that the hippocampal formation was metabolically altered. CONCLUSIONS: The most prominent feature was the white matter affectation, as assessed by DTI, with volume and directionality reductions of the fiber projections involving both the craniocaudal fibers and the interhemispheric connections. These findings, although heterogeneous among the study sample, could be correlated with the clinico-neurological symptoms. The imaging findings support the position that myelin structures degrade prematurely in the brain of XP patients.

Neuroimaging of multimodal sensory stimulation in amyotrophic lateral sclerosis.

AIM: Structural and functional imaging techniques were combined to investigate sensory system function in amyotrophic lateral sclerosis (ALS). METHODS: Functional MRI (fMRI) was used to investigate cortical activity during visual, auditory and somatosensory stimulation in 14 ALS patients and 18 control subjects. Changes in amplitude, latency and duration of the blood oxygen level dependent response were modelled. Furthermore, diffusion tensor imaging was used to investigate changes in white matter networks. RESULTS: During visual stimulation, fMRI demonstrated a decreased response in secondary visual areas in ALS, possibly related to demyelination of sensory nerve fibres. Increasing brain activity in associative cortices was linked to a decrease in physical functioning and might represent a compensatory process. Additionally, reduced white matter functioning became evident for fibres projecting to the extrastriate visual cortex. For auditory stimulation, a delayed response in secondary auditory areas probably linked to prolonged nerve conductance time and an altered cortical pattern in areas involved in target processing/detection became evident in ALS patients. Structural white matter changes in the primary and secondary auditory cortices were observed. For somatosensory stimulation, a prolonged/reduced response in sensory integration areas of the parietal lobe was observed, perhaps linked to the reduced visceral inflow due to immobility. CONCLUSION: Multiparametric MRI suggests a progressive functional deficit in secondary/higher order sensory processing areas in ALS, probably associated with reduction of re-afferent information flow due to progressive immobility. The changes described might also represent an expression of the disease process itself. Evidence for compensatory processes in multimodal associative cortices was found.