Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.

Fat-rich versus carbohydrate-rich nutrition in ALS: a randomised controlled study.

OBJECTIVE: There is growing evidence that the course of amyotrophic lateral sclerosis (ALS) may be influenced beneficially by applying high-caloric food supplements (HCSs). However, it is unknown which composition of nutrients offers optimal tolerability and weight gain. METHODS: We conducted a randomised controlled study (Safety and Tolerability of Ultra-high-caloric Food Supplements in Amyotrophic Lateral Sclerosis (ALS); TOLCAL-ALS study) in 64 patients with possible, probable or definite ALS according to El Escorial criteria. Patients were randomised into four groups: a high-caloric fatty supplement (HCFS; 405 kcal/day, 100% fat), an ultra-high-caloric fatty supplement (UHCFS; 810 kcal/day, 100% fat), an ultra-high-caloric, carbohydrate-rich supplement (UHCCS; 900 kcal/day, 49% carbohydrates) and an open control (OC) group without any supplement. The primary endpoint was tolerability. Patients were followed up over 4 weeks. RESULTS: Gastrointestinal side effects were most frequent in the UHCFS group (75.0%), while loss of appetite was most frequent in the UHCCS group (35.3%). During intervention, patients gained +0.9 kg/month of body weight (IQR -0.9 to 1.5; p=0.03) in the HCFS group and +0.9 kg/month (IQR -0.8 to 2.0; p=0.05) in the UHCFS group. A non-significant trend for weight gain (+0.6 kg/month (IQR -0.3 to 1.9; p=0.08)) was observed in the UHCCS group. Patients in OC group continued to lose body weight (-0.5 kg/month, IQR -1.4 to 1.3; p=0.42). INTERPRETATION: The findings suggest that HCSs frequently cause mild to moderate tolerability issues in patients with ALS, most notably gastrointestinal symptoms in high-fat supplements, and loss of appetite in high-carbohydrate supplements. All three HCSs tested are suited to increase body weight.

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.

Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motoneurons in the primary motor cortex (pMO) and in spinal cord. However, the pathogenic process involves multiple subnetworks in the brain and functional MRI studies demonstrate an increase in functional connectivity in areas connected to pMO despite the ongoing neurodegeneration. The extent and the structural basis of the motor subnetwork remodeling in experimentally tractable models remain unclear. We have developed a new retrograde AAV9 to quantitatively map the projections to pMO in the SOD1(G93A) ALS mouse model. We show an increase in the number of neurons projecting from somatosensory cortex to pMO at presymptomatic stages, followed by an increase in projections from thalamus, auditory cortex and contralateral MO (inputs from 20 other structures remains unchanged) as disease advances. The stage- and structure-dependent remodeling of projection to pMO in ALS may provide insights into the hyperconnectivity observed in ALS patients.

Electroencephalographic findings in patients with circumscribed thalamic lesions.

INTRODUCTION: Thalamo-cortical networks have mainly been studied in the generation of idiopathic (genetic) epilepsies. The purpose of this study was to analyze EEG patterns and the occurrence of focal (symptomatic) epileptic seizures in patients with acquired circumscribed thalamic lesions. PATIENTS AND METHODS: Among 596 patients with thalamic lesions, we identified 47 patients in whom circumscribed thalamic lesions were detected by MRI and who underwent an EEG examination at the same stay at hospital. EEG findings were divided into normal findings, unspecific pathological changes and epileptiform discharges. The EEG findings were correlated to the localisation of the lesion within the thalamus and to the patients symptoms. RESULTS: In 32 patients (68%) pathological EEG findings were observed. They were heterogeneous and comprised regional and generalized slowing, triphasic waves, generalized periodic and regional epileptiform discharges. However, some characteristic findings were seen: Regional slowing was associated with ipsilateral thalamic lesions independent of the thalamic subarea, epileptiform discharges were related to lesions in the ipsilateral medial thalamus and periodic generalized discharges/triphasic waves with lesions in the anterior-ventromedial thalamus. Epileptic seizures were also more common in patients with medial thalamic lesions. Patients with regional epileptiform discharges responded to antiepileptic treatment whereas patients with triphasic waves and generalized periodic patterns did not. In some cases, it remained difficult to decide whether the thalamic lesion was the cause or consequence of epileptic activity. CONCLUSION: Pathological EEG findings are common in patients with acute and chronic thalamic lesions. EEG patterns associated with circumscribed thalamic lesions were influenced by the affected thalamic subregion. As in idiopathic generalized epilepsy, also in symptomatic epilepsy, the medial thalamus revealed to play a role in the generation of epileptiform discharges. In the patients with generalized periodic discharges and acute lesions in the ventral-anterior-medial thalamus, however, EEG changes were more likely caused by a disinhibition of cortico-thalamic networks than by a status epilepticus and thus risks and benefits of an aggressive antiepileptic treatment must be thoroughly balanced.

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.

Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic lateral sclerosis mouse models based on TDP-43 (Tardbp) and FUS mutations. Finally, we demonstrate that the melanocortin defect is primarily caused by serotonin loss in mutant SOD1(G86R) mice. Altogether, the current study combined clinical evidence and experimental studies in rodents to provide a mechanistic explanation for abnormalities in food intake and weight control observed in patients with amyotrophic lateral sclerosis. Importantly, these results also show that amyotrophic lateral sclerosis progression impairs responsiveness to classical drugs leading to weight gain. This has important implications for pharmacological management of weight loss in amyotrophic lateral sclerosis.

Micronutrients supplementation and nutritional status in cognitively impaired elderly persons: a two-month open label pilot study.

BACKGROUND: Malnutrition is a widespread problem in elderly people and is associated with cognitive decline. However, interventional studies have produced ambiguous results. For this reason, we wanted to determine the effect of micronutrient supplementation on blood and tissue levels and on general nutritional status in persons with mild or moderate cognitive impairment. METHODS: We performed a 2-month, open-label trial, administering a daily micronutrient supplement to 42 memory clinic patients with mild cognitive deficits. Blood levels of antioxidants, zinc, and B vitamins were determined before and after supplementation. In addition, we assessed metabolic markers for B vitamins and intracellular (buccal mucosa cell [BMC]) antioxidant levels. Nutritional status was assessed by using the Mini Nutritional Assessment (MNA). RESULTS: Blood levels of B vitamins, folic acid, lutein, ß-carotene, α-carotene, and α-tocopherol increased significantly. Decreases in homocysteine levels and the thiamine pyrophosphate effect and an increase in holotranscobalamin were observed. We found no increase in intracellular antioxidant levels of BMC. The MNA score in subjects at risk for malnutrition increased significantly, mainly owing to better perception of nutritional and overall health status. CONCLUSIONS: Micronutrient supplementation improved serum micronutrient status, with improved metabolic markers for B vitamins but not for intracellular antioxidant status, and was associated with improved self-perception of general health status. Our data underline the necessity of determining micronutrient status and support the use of additional assessments for general health and quality of life in nutritional supplementation trials.

High-caloric food supplements in the treatment of amyotrophic lateral sclerosis: a prospective interventional study.

Weight loss is an independent prognostic factor in amyotrophic lateral sclerosis (ALS). We investigated whether the body weight of ALS patients who previously lost weight can be stabilized by a high-caloric diet. For this purpose we compared two different high-caloric food supplements: one with high fat content and one with high carbohydrate content. Twenty-six patients were randomly allocated to one of the therapeutic groups. Body weight, ALS functional rating scale-revised (ALSFRS-R), static vital capacity (SVC), bioelectrical impedance analysis (BIA), metabolic serum parameters, and adverse events were investigated. Results showed that body weight of ALS patients could be stabilized in both therapeutic groups after 12 weeks of therapy (p = 0.008). The effect was greater in the group with high fat supplement though not statistically significant (p = 0.37). In conclusion, high-caloric food supplements with high fat as well as high carbohydrate content are both suitable to stabilize the body weight of ALS patients. The effect of a high fat diet might be more pronounced. Since body weight is an independent prognostic factor in ALS it is possible that a high-caloric food supplement improves survival in ALS. However, this hypothesis can only be tested by conducting a placebo-controlled double-blinded trial of sufficient power.

Dietary antioxidants and dementia in a population-based case-control study among older people in South Germany.

Oxidative stress is believed to play a central role in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease. Antioxidants may prevent the onset AD as high dietary intake of vitamin C and E were reported to be associated with lower risk of the disease. The objective of this study was to evaluate the serum levels of antioxidants in persons with mild dementia to test whether it is associated with lower levels of antioxidants in a cross-sectional study in the population of the "Activity and Function in the Ederly in Ulm" (ActiFE) study. Main exposure measures were vitamin C, vitamin E, ß-carotene, lycopene, and coenzyme Q10 as analyzed by HPLC. Main outcome measures were mild cognitive impairment among 74 mildly demented compared to 158 age- and gender-matched controls. We found that blood vitamin C and ß-carotene concentrations were significantly lower in demented than in control persons even after adjusting for school education, intake of dietary supplements, smoking habits, body mass index, and alcohol consumption (3rd versus 1st tertile: OR: 0.29, 95% CI, 0.09-0.96 and 0.13, 95% CI, 0.03-0.55, respectively). No associations were found for vitamin E, lycopene, and coenzyme Q10. Our findings suggest an association of vitamin C and ß-carotene with dementia. However this is limited to the cross-sectional character of our study and longitudinal data will give further insight into this association.

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.

Guidelines for preclinical animal research in ALS/MND: A consensus meeting.

The development of therapeutics for ALS/MND is largely based on work in experimental animals carrying human SOD mutations. However, translation of apparent therapeutic successes from in vivo to the human disease has proven difficult and a considerable amount of financial resources has been apparently wasted. Standard operating procedures (SOPs) for preclinical animal research in ALS/MND are urgently required. Such SOPs will help to establish SOPs for translational research for other neurological diseases within the next few years. To identify the challenges and to improve the research methodology, the European ALS/MND group held a meeting in 2006 and published guidelines in 2007 (1). A second international conference to improve the guidelines was held in 2009. These second and improved guidelines are dedicated to the memory of Sean F. Scott.

Directional colour encoding of the human thalamus by diffusion tensor imaging.

The potential of diffusion tensor imaging (DTI) in brain imaging in terms of the in vivo mapping of neuroanatomy is generally accepted. Mostly, analyses of deep brain structures were based on complex methodical backgrounds. In the present study, the delineation of groups of thalamic nuclei with similar projection characteristics was investigated in healthy human subjects using a novel differentiated colour encoding approach of DTI data without the use of statistical calculations. With the application of this directional colour encoding of the longest eigenvector of every voxel-specific tensor, at least three functional groups in the thalamus with different projection directions could be differentiated. The method displayed, furthermore, a high symmetry and stability in the analysis of the individual subjects. In summary, substantial neuroanatomical information can be gained for deep subcortical gray matter structures such as the thalamus with an improved detection and directional differentiation of voxel-specific tensors.

Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: report on the 142nd ENMC international workshop.

A transgenic animal model for anterior horn cell loss was established in 1994. This model is based on the insertion of a high copy number of disease-causing human Cu/Zn SOD mutations into the intact mouse genome. It serves to establish hypotheses for the pathogenesis of anterior horn cell death, but also to test potential pharmacological approaches to therapy in human ALS. Today, more than 100 -- published and unpublished -- compounds have been tested in this animal model, a large part of them being reported as successful. However, it proved to be difficult to translate these therapeutic successes in the animal model into human trials. Also, a number of disease-modifying strategies were difficult to reproduce, even by the same group. On the other hand, the step from mice to men means a huge investment for the sponsors of clinical trials and the scientific community. Therefore, establishment of standard methods for drug testing in ALS models is mandatory. In this workshop, clinical and preclinical researchers established in the field of ALS/MND met in Holland in March 2006 in order to establish guidelines for the community for drug testing in mouse models.

In vivo quantification of spinal and bulbar motor neuron degeneration in the G93A-SOD1 transgenic mouse model of ALS by T2 relaxation time and apparent diffusion coefficient.

Magnetic resonance imaging (MRI) has provided important information in characterizing amyotrophic lateral sclerosis (ALS) in humans and in animal models. A frequently used animal model to study mechanisms of pathogenesis and the efficacy of drugs in ALS is a transgenic mouse over-expressing the human mutated G93A-superoxide dismutase 1 (G93A-SOD1). In our study, we applied MRI to find suitable progression markers, which can be used to monitor the development of ALS and to evaluate therapeutic approaches at early stages of the disease. Therefore, we generated parameter maps of the spin-spin relaxation time (T2) and the apparent diffusion coefficient (ADC) starting at day 70 after birth, i.e., before motor scores decline around day 90. Depending on the progression of the disease, G93A-SOD1 mice showed significantly increased values of T2 in the brain stem motor nuclei Nc. V (trigeminal nucleus), VII (facial nucleus), and XII (hypoglossal nucleus), and spinal cord compared to non-transgenic wild-type mice and transgenic mice over-expressing the non-mutated wild-type human SOD1 (tg-SOD1). Similar effects in these motor nuclei were revealed by ADC mapping. Furthermore, in the upper spinal cord, a dorsal-ventral difference with significantly higher T2 values in the ventral part was demonstrated by T2 mapping. While both T2 and ADC might prove useful as progression markers and enable the longitudinal non-invasive evaluation of ALS in G93A-SOD1 mice, the potential is limited by age-dependent effects in case of ADC mapping.

On the decline and etiology of high-incidence motor system disease in West Papua (southwest New Guinea).

The etiology of a high-incidence focus of amyotrophic lateral sclerosis and parkinsonism-dementia (ALS/P-D) in south West Papua (Irian Jaya, Indonesia), first described in the 1960s and 1970s, has been attributed to mineral deficiencies, hyperparathyroidism, and metal neurotoxicity arising from reliance on drinking water obtained from springs and shallow wells. More recent visits (1987 and 1990) to the south West Papua focus of neurodegenerative disease cast doubt on this explanation by revealing changes in disease prevalence in communities with an unchanged water supply. These communities have experienced a dramatic decline in ALS and a reversal in the relative prevalence of ALS and parkinsonism. The extrapyramidal disorder can be distinguished from Parkinson disease by pyramidal features (and dementia) reminiscent of Guam P-D. Topical use of cycad seed (termed kurru) gametophyte to treat large skin lesions is advanced as a plausible but unproven etiologic factor. Medicinal use of untreated cycad seed (Cycas sp.) has also been linked with ALS foci in Japan (oral use) and Guam (topical use), with the additional consumption on Guam of food items prepared from Cycas sp. seed or animals that consume cycad seed components.