Trial of Prasinezumab in Early-Stage Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS: A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS: Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

Mitochondrial dysfunction in myotonic dystrophy type 1.

The pathophysiological mechanism linking the nucleotide expansion in the DMPK gene to the clinical manifestations of myotonic dystrophy type 1 (DM1) is still unclear. In vitro studies demonstrate DMPK involvement in the redox homeostasis of cells and the mitochondrial dysfunction in DM1, but in vivo investigations of oxidative metabolism in skeletal muscle have provided ambiguous results and have never been performed in the brain. Twenty-five DM1 patients (14M, 39 ± 11years) underwent brain proton MR spectroscopy (1H-MRS), and sixteen cases (9M, 40 ± 13 years old) also calf muscle phosphorus MRS (31P-MRS). Findings were compared to those of sex- and age-matched controls. Eight DM1 patients showed pathological increase of brain lactate and, compared to those without, had larger lateral ventricles (p < 0.01), smaller gray matter volumes (p < 0.05) and higher white matter lesion load (p < 0.05). A reduction of phosphocreatine/inorganic phosphate (p < 0.001) at rest and, at first minute of exercise, a lower [phosphocreatine] (p = 0.003) and greater [ADP] (p = 0.004) were found in DM1 patients compared to controls. The post-exercise indices of muscle oxidative metabolism were all impaired in DM1, including the increase of time constant of phosphocreatine resynthesis (TC PCr, p = 0.038) and the reduction of the maximum rate of mitochondrial ATP synthesis (p = 0.033). TC PCr values correlated with the myotonic area score (ρ = 0.74, p = 0.01) indicating higher impairment of muscle oxidative metabolism in clinically more affected patients. Our findings provide clear in vivo evidence of multisystem impairment of oxidative metabolism in DM1 patients, providing a rationale for targeted treatment enhancing energy metabolism.

Plasma and White Blood Cells Show Different miRNA Expression Profiles in Parkinson's Disease.

Parkinson's disease (PD) diagnosis is based on the assessment of motor symptoms, which manifest when more than 50% of dopaminergic neurons are degenerated. To date, no validated biomarkers are available for the diagnosis of PD. The aims of the present study are to evaluate whether plasma and white blood cells (WBCs) are interchangeable biomarker sources and to identify circulating plasma-based microRNA (miRNA) biomarkers for an early detection of PD. We profiled plasma miRNA levels in 99 L-dopa-treated PD patients from two independent data collections, in ten drug-naïve PD patients, and in unaffected controls matched by sex and age. We evaluated expression levels by reverse transcription and quantitative real-time PCR (RT-qPCR) and combined the results from treated PD patients using a fixed effect inverse-variance weighted meta-analysis. We revealed different expression profiles comparing plasma and WBCs and drug-naïve and L-dopa-treated PD patients. We observed an upregulation trend for miR-30a-5p in L-dopa-treated PD patients and investigated candidate target genes by integrated in silico analyses. We could not analyse miR-29b-3p, normally expressed in WBCs, due to the very low expression in plasma. We observed different expression profiles in WBCs and plasma, suggesting that they are both suitable but not interchangeable peripheral sources for biomarkers. We revealed miR-30a-5p as a potential biomarker for PD in plasma. In silico analyses suggest that miR-30a-5p might have a regulatory role in mitochondrial dynamics and autophagy. Further investigations are needed to confirm miR-30a-5p deregulation and targets and to investigate the influence of L-dopa treatment on miRNA expression levels.

Treatment of withdrawal headache in patients with medication overuse headache: a pilot study.

BACKGROUND: Drug withdrawal still remains the key element in the treatment of Medication Overuse Headache (MOH), but there is no consensus about the withdrawal procedure. Still debated is the role of the steroid therapy. The aim of this study was to evaluate the effectiveness of methylprednisolone or paracetamol in the treatment of withdrawal headache in MOH. METHODS: We performed a pilot, randomized, single-blinded, placebo controlled trial. MOH patients, unresponsive to a 3 months prophylaxis, underwent withdrawal therapy on an inpatient basis. Overused medications were abruptly stopped and methylprednisolone 500 mg i.v (A) or paracetamol 4 g i.v. (B) or placebo i.v. (C) were given daily for 5 days. Patients were monitored at 1 and 3 months. RESULTS: Eighty three consecutive MOH patients were enrolled. Fifty seven patients completed the study protocol. Nineteen patients were randomized to each group. Withdrawal headache on the 5th day was absent in 21.0% of group A, in 31.6% of group B and in 12.5% of group C without significant differences. Withdrawal headache intensity decreased significantly after withdrawal without differences among the groups. Rregardless of withdrawal treatment, 52% MOH patients reverted to an episodic migraine and 62% had no more medication overuse after 3 months. CONCLUSIONS: This study suggests that in a population of severe MOH patients, withdrawal headache decreased significantly in the first 5 days of withdrawal regardless of the treatment used. Methylprednisolone and paracetamol are not superior to placebo at the end of the detoxification program.

White matter and cortical changes in atypical parkinsonisms: A multimodal quantitative MR study.

OBJECTIVES: To evaluate white matter and cortical changes in patients with parkinsonisms and healthy controls (HC), applying both hypothesis-free and regions of interest (ROI)-based advanced brain MR analyses. METHODS: Twenty-five patients with Progressive Supranuclear Palsy - Richardson's Syndrome (PSP-RS), nine with cerebellar and nine with parkinsonian Multiple System Atrophy variants (MSA-C and MSA-P), forty-seven with Parkinson's Disease (PD) and twenty-seven HC underwent a 1.5 T brain-MR protocol including high-resolution 3D T1-weighted and 25-direction diffusion tensor imaging sequences. We performed cortical and white matter analysis by using vertex-based cortical thickness evaluation and Tract Based Spatial Statistics (TBSS), followed by a ROI-based cortical thickness analysis and probabilistic tractography of cortico-spinal tract (CST), and middle and superior cerebellar peduncles (MCP and SCP). RESULTS: In PSP-RS, both ROIs-based and voxel-wise analyses demonstrated significant thinning of the pre-central cortices and diffuse white matter alterations involving supra- and infratentorial compartments. Along-tract tractography analysis of CST showed a significantly higher MD in PSP-RS vs PD and HC limited to the portion of the tract within the corona radiata. In MSA-C, a predominant involvement of MCPs was evident, while alterations in MCPs in MSA-P and in SCPs in PSP-RS and MSA-C were also present. CONCLUSION: Specific patterns of cortical and white matter changes in atypical parkinsonism patients reflect the neuropathological and clinical features of these disorders. This study shows that quantitative brain MR techniques can detect significant changes that help to elucidate the physiopathology of movement disorders and support their differential diagnosis.

Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is the commonest autosomal recessive ataxia, caused by GAA triplet expansion in the frataxin gene. Neuropathological studies in FRDA demonstrate that besides the primary neurodegeneration of the dorsal root ganglia, there is a progressive atrophy of the cerebellar dentate nucleus. Diffusion-weighted imaging (DWI) detected microstructural alterations in the cerebellum of FRDA patients. To investigate the biochemical basis of these alterations, we used both DWI and proton MR spectroscopy (1H-MRS) to study the same cerebellar volume of interest (VOI) including the dentate nucleus. DWI and 1H-MRS study of the left cerebellar hemisphere was performed in 28 genetically proven FRDA patients and 35 healthy controls. In FRDA mean diffusivity (MD) values were calculated for the same 1H-MRS VOI. Clinical severity was evaluated using the International Cooperative Ataxia Rating Scale (ICARS). FRDA patients showed a significant reduction of N-acetyl-aspartate (NAA), a neuroaxonal marker, and choline (Cho), a membrane marker, both expressed relatively to creatine (Cr), and increased MD values. In FRDA patients NAA/Cr negatively correlated with MD values (r = -0.396, p = 0.037) and with ICARS score (r = -0.669, p < 0.001). Age-normalized NAA/Cr loss correlated with the GAA expansion (r = -0.492, p = 0.008). The reduced cerebellar NAA/Cr in FRDA suggests that neuroaxonal loss is related to the microstructural changes determining higher MD values. The correlation between NAA/Cr and the severity of disability suggests that this biochemical in vivo MR parameter might be a useful biomarker to evaluate therapeutic interventions.

The effect of diffusion gradient direction number on corticospinal tractography in the human brain: an along-tract analysis.

OBJECTIVES: We evaluated diffusion imaging measures of the corticospinal tract obtained with a probabilistic tractography algorithm applied to data of two acquisition protocols based on different numbers of diffusion gradient directions (NDGDs). MATERIALS AND METHODS: The corticospinal tracts (CST) of 18 healthy subjects were delineated using 22 and 66-NDGD data. An along-tract analysis of diffusion metrics was performed to detect possible local differences due to NDGD. RESULTS: FA values at 22-NDGD showed an increase along the central portion of the CST. The mean of partial volume fraction of the orientation of the second fiber (f2) was higher at 66-NDGD bilaterally, because for 66-NDGD data the algorithm more readily detects dominant fiber directions beyond the first, thus the increase in FA at 22-NDGD is due to a substantially reduced detection of crossing fiber volume. However, the good spatial correlation between the tracts drawn at 22 and 66 NDGD shows that the extent of the tract can be successfully defined even at lower NDGD. CONCLUSIONS: Given the spatial tract localization obtained even at 22-NDGD, local analysis of CST can be performed using a NDGD compatible with clinical protocols. The probabilistic approach was particularly powerful in evaluating crossing fibers when present.

Brain structural profile of multiple system atrophy patients with cognitive impairment.

Current consensus diagnostic criteria for multiple system atrophy (MSA) consider dementia a non-supporting feature, although cognitive impairment and even frank dementia are reported in clinical practice. Mini-Mental State Examination (MMSE) is a commonly used global cognitive scale, and in a previous study, we established an MSA-specific screening cut-off score <27 to identify cognitive impairment. Finally, MSA neuroimaging findings suggest the presence of structural alterations in patients with cognitive deficits, although the extent of the anatomical changes is unclear. The aim of our multicenter study is to better characterize anatomical changes associated with cognitive impairment in MSA and to further investigate cortical and subcortical structural differences versus healthy controls (HC). We examined retrospectively 72 probable MSA patients [50 with normal cognition (MSA-NC) and 22 cognitively impaired (MSA-CI) based on MMSE <27] and compared them to 36 HC using gray- and white-matter voxel-based morphometry and fully automated subcortical segmentation. Compared to HC, MSA patients showed widespread cortical (bilateral frontal, occipito-temporal, and parietal areas), subcortical, and white-matter alterations. However, MSA-CI showed only focal volume reduction in the left dorsolateral prefrontal cortex compared with MSA-NC. These results suggest only a marginal contribution of cortical pathology to cognitive deficits. We believe that cognitive dysfunction is driven by focal fronto-striatal degeneration in line with the concept of "subcortical cognitive impairment".

Magnetic Resonance Parkinsonism Index: diagnostic accuracy of a fully automated algorithm in comparison with the manual measurement in a large Italian multicentre study in patients with progressive supranuclear palsy.

OBJECTIVES: To investigate the reliability of a new in-house automatic algorithm for calculating the Magnetic Resonance Parkinsonism Index (MRPI), in a large multicentre study population of patients affected by progressive supranuclear palsy (PSP) or Parkinson's disease (PD), and healthy controls (HC), and to compare the diagnostic accuracy of the automatic and manual MRPI values. METHODS: The study included 88 PSP patients, 234 PD patients and 117 controls. MRI was performed using both 3T and 1.5T scanners. Automatic and manual MRPI values were evaluated, and accuracy of both methods in distinguishing PSP from PD and controls was calculated. RESULTS: No statistical differences were found between automated and manual MRPI values in all groups. The automatic MRPI values differentiated PSP from PD with an accuracy of 95 % (manual MRPI accuracy 96 %) and 97 % (manual MRPI accuracy 100 %) for 1.5T and 3T scanners, respectively. CONCLUSION: Our study showed that the new in-house automated method for MRPI calculation was highly accurate in distinguishing PSP from PD. Our automatic approach allows a widespread use of MRPI in clinical practice and in longitudinal research studies. KEY POINTS: • A new automatic method for calculating the MRPI is presented. • Automatic MRPI values are in good agreement with manual values. • Automatic MRPI can distinguish patients with PSP from patients with PD. • The automatic method overcomes MRPI application limitations in routine practice. • The automatic method may allow a more widespread use of MRPI.

Precuneal Thickness and Depression in Parkinson Disease.

BACKGROUND: Depression-related gray matter changes in Parkinson disease (PD) patients have been reported, although studies investigating cortical thickness in early-stage disease are lacking. OBJECTIVE: We aimed to evaluate cortical changes related to depression in early-stage PD patients with an extensive neuropsychological evaluation. METHODS: 17 PD patients and 22 healthy controls underwent a 1.5-T brain MR protocol, and voxel-wise differences in cortical thickness among patients with (n = 6) and without (n = 11) depression and controls were evaluated using FreeSurfer software. RESULTS: Cortical thickness was increased in the precuneus bilaterally in PD patients with depression compared to the other groups (number of vertices >100; p < 0.001, uncorrected) with a direct correlation with the Beck Depression Inventory score (p < 0.001, uncorrected). CONCLUSION: Precuneal cortical thickening is evident in PD patients with mild-moderate depression even in the early stages of the disease. This finding may reflect the early involvement of this region in the development of PD-related depression.

Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update.

Brain magnetic resonance (MR) represents a useful and feasible tool for the differential diagnosis of Parkinson's disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen) suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution) the diagnosis of Corticobasal Syndrome.

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

Relationship of white and gray matter abnormalities to clinical and genetic features in myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) represents a multisystemic disorder in which diffuse brain white and gray matter alterations related to clinical and genetic features have been described. We aimed to evaluate in the brain of adult patients with DM1 (i) white and gray matter differences, including cortical-subcortical gray matter volume and cortical thickness and (ii) their correlation with clinical disability, global neuropsychological performance and triplet expansion. METHODS: We included 24 adult genetically-confirmed DM1 patients (14 males; age: 38.5 ± 11.8 years) and 25 age- and sex-matched healthy controls (14 males; age: 38.5 ± 11.3 years) who underwent an identical brain MR protocol including high-resolution 3D T1-weighted, axial T2 FLAIR and DTI sequences. All patients underwent an extensive clinical and neuropsychological evaluation. Voxel-wise analyses of white matter, performed by using Tract Based Spatial Statistics, and of gray matter, with Voxel-based Morphometry and Cortical Thickness, were carried out in order to test for differences between patients with DM1 and healthy controls (p < 0.05, corrected). The correlation between MRI measures and clinical-genetic features was also assessed. RESULTS: Patients with DM1 showed widespread abnormalities of all DTI parameters in the white matter, which were associated with reduced gray matter volume in all brain lobes and thinning in parieto-temporo-occipital cortices, albeit with less extensive cortical alterations when congenital cases were removed from the analyses. White matter alterations correlated with clinical disability, global cognitive performance and triplet expansions. CONCLUSION: In patients with DM1, the combined smaller overall gray matter volume and white matter alterations seem to be the main morpho-structural substrates of CNS involvement in this condition. The correlation of white matter differences with both clinical and genetic findings lends support to this notion.

Accuracy of MR markers for differentiating Progressive Supranuclear Palsy from Parkinson's disease.

BACKGROUND: Advanced brain MR techniques are useful tools for differentiating Progressive Supranuclear Palsy from Parkinson's disease, although time-consuming and unlikely to be used all together in routine clinical work. We aimed to compare the diagnostic accuracy of quantitative morphometric, volumetric and DTI metrics for differentiating Progressive Supranuclear Palsy-Richardson's Syndrome from Parkinson's disease. METHODS: 23 Progressive Supranuclear Palsy-Richardson's Syndrome and 42 Parkinson's disease patients underwent a standardized 1.5T brain MR protocol comprising high-resolution T1W1 and DTI sequences. Brainstem and cerebellar peduncles morphometry, automated volumetric analysis of brain deep gray matter and DTI metric analyses of specific brain structures were carried out. We determined diagnostic accuracy, sensitivity and specificity of MR-markers with respect to the clinical diagnosis by using univariate receiver operating characteristics curve analyses. Age-adjusted multivariate receiver operating characteristics analyses were then conducted including only MR-markers with a sensitivity and specificity exceeding 80%. RESULTS: Morphometric markers (midbrain area, pons to midbrain area ratio and MR Parkinsonism Index), DTI parameters (infratentorial structures) and volumetric analysis (thalamus, putamen and pallidus nuclei) presented moderate to high diagnostic accuracy in discriminating Progressive Supranuclear Palsy-Richardson's Syndrome from Parkinson's disease, with midbrain area showing the highest diagnostic accuracy (99%) (mean ± standard deviation: 75.87 ± 16.95 mm(2) vs 132.45 ± 20.94 mm(2), respectively; p < 0.001). CONCLUSION: Although several quantitative brain MR markers provided high diagnostic accuracy in differentiating Progressive Supranuclear Palsy-Richardson's Syndrome from Parkinson's disease, the morphometric assessment of midbrain area is the best single diagnostic marker and should be routinely included in the neuroradiological work-up of parkinsonian patients.

Rotigotine Objectively Improves Sleep in Parkinson's Disease: An Open-Label Pilot Study with Actigraphic Recording.

Sleep disturbances represent important predictors of poor quality of life (QoL) in Parkinson's disease (PD). This open-label pilot study aimed to objectively assess, by means of actigraphic recording, effect of rotigotine on sleep in PD patients with self-reported sleep complaints. 15 PD patients underwent one-week actigraphic recording before (T0) and during (T1) rotigotine treatment, which was titrated to the dose subjectively improving motor symptoms (4-8 mg/24 h). Sleep disturbances, daytime sleepiness, cognitive performance, QoL, and depression were also evaluated with questionnaires. Actigraphic recordings showed a significant reduction in nocturnal motor activity and mean duration of wake episodes after sleep onset during rotigotine treatment compared to baseline. In 10 patients presenting objective evidence of poor sleep quality at T0 (sleep efficiency ≤ 85%), rotigotine also significantly improved other sleep parameters and further reduced nocturnal motor activity and mean duration of wake episodes. A significant decrease in number and duration of daytime sleep episodes was also observed at T1. Finally we confirmed that rotigotine significantly improves perceived sleep quality and QoL. Our study showed for the first time that rotigotine is associated with an objective improvement of nocturnal and diurnal sleep disturbances in PD patients with self-reported sleep complaints. This study is registered with AIFA-observational study registry number 12021.

A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings.

BACKGROUND AND PURPOSE: Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare progressive neurological disorder caused by Lamin B1 duplication (LMNB1). Our aim was to investigate longitudinally the pattern of the autonomic dysfunction and the degree of neuropsychological involvement. METHODS: Three related ADLD patients and one asymptomatic carrier of LMNB1 duplication underwent a standardized evaluation of autonomic nervous system, including cardiovascular reflexes, pharmacological testing, microneurography, skin biopsy, Metaiodobenzylguanidine scintigraphy and a complete neuropsychological battery. RESULTS: An early neurogenic orthostatic hypotension was detected in all patients and confirmed by a low rise in noradrenaline levels on Tilt Test. However infusion of noradrenaline resulted in normal blood pressure rise as well as the infusion of clonidine. At the insulin tolerance test the increase in adrenaline resulted pathological in two out three patients. Microneurography failed to detect muscle sympathetic nerve activity bursts. Skin biopsy revealed a poor adrenergic innervation, while cardiac sympathetic nerves were normal. None of ADLD patients showed a global cognitive deficit but a selective impairment in the executive functions. CONCLUSION: Autonomic disorder in ADLD involves selectively the postganglionic sympathetic system including the sympatho-adrenal response. Cognitive involvement consisting in an early impairment of executive tasks that might precede brain MR abnormalities.

The Cooperative Health Research in South Tyrol (CHRIS) study: rationale, objectives, and preliminary results.

The Cooperative Health Research In South Tyrol (CHRIS) study is a population-based study with a longitudinal lookout to investigate the genetic and molecular basis of age-related common chronic conditions and their interaction with life style and environment in the general population. All adults of the middle and upper Vinschgau/Val Venosta are invited, while 10,000 participants are anticipated by mid-2017. Family participation is encouraged for complete pedigree reconstruction and disease inheritance mapping. After a pilot study on the compliance with a paperless assessment mode, computer-assisted interviews have been implemented to screen for conditions of the cardiovascular, endocrine, metabolic, genitourinary, nervous, behavioral, and cognitive system. Fat intake, cardiac health, and tremor are assessed instrumentally. Nutrient intake, physical activity, and life-course smoking are measured semi-quantitatively. Participants are phenotyped for 73 blood and urine parameters and 60 aliquots per participant are biobanked (cryo-preserved urine, DNA, and whole and fractionated blood). Through liquid-chromatography mass-spectrometry analysis, metabolite profiling of the mitochondrial function is assessed. Samples are genotyped on 1 million variants with the Illumina HumanOmniExpressExome array and the first data release including 4570 fully phenotyped and genotyped samples is now available for analysis. Participants' follow-up is foreseen 6 years after the first visit. The target population is characterized by long-term social stability and homogeneous environment which should both favor the identification of enriched genetic variants. The CHRIS cohort is a valuable resource to assess the contribution of genomics, metabolomics, and environmental factors to human health and disease. It is awaited that this will result in the identification of novel molecular targets for disease prevention and treatment.

Brain magnetic resonance metabolic and microstructural changes in adult-onset autosomal dominant leukodystrophy.

INTRODUCTION: adult-onset autosomal dominant leukodystrophy (ADLD) is a rare inherited disorder due to a duplication of lamin-B1 (LMNB1) gene. The aim of this study was to investigate brain metabolic and microstructural alterations by using advanced MR techniques. METHODS: we performed brain MR scans including single-voxel proton-MR Spectroscopy ((1)H-MRS) of the lateral ventricles and parietal white matter and diffusion tensor imaging (DTI) in 4 subjects with LMNB1 gene duplication, 6 non-mutated relatives and 7 unrelated healthy controls. Cervical and thoracic spinal cord MR was performed in three symptomatic subjects with LMNB1 mutation. All participants underwent clinical and neuropsychological evaluation. RESULTS: all subjects with LMNB1 gene duplication presented pathological accumulation of lactate in lateral ventricles CSF and no alterations of brain white matter absolute metabolites concentrations or metabolites/Cr ratios. We found increased white matter intra- and extracellular water transverse relaxation times. Tract-based spatial statistics analysis detected a significantly reduced fractional anisotropy in the genu of the corpus callosum in mutated cases compared to unrelated healthy controls and non-mutated relatives. Moreover, we detected different degrees of the typical white matter signal intensity alterations and brain and spinal atrophy at conventional MRI in symptomatic subjects with LMNB1 mutation. A mild impairment of executive functions was found in subjects with LMNB1 gene mutation. CONCLUSION: in subjects with LMNB1 gene duplication, we found a pathological increase in CSF lactate, likely due to active demyelination along with glial activation, and microstructural changes in the genu of the corpus callosum possibly underpinning the mild neuropsychological deficits.

The contribution of cerebellar proton magnetic resonance spectroscopy in the differential diagnosis among parkinsonian syndromes.

INTRODUCTION: The in vivo differential diagnosis between idiopathic Parkinson's disease (PD) and atypical parkinsonian syndromes (PS), such as multiple system atrophy [MSA with a cerebellar (C) and parkinsonian (P) subtype] and progressive supranuclear palsy - Richardson's Syndrome (PSP-RS) is often challenging. Previous brain MR proton spectroscopy ((1)H-MRS) studies showed biochemical alterations in PS, despite results are conflicting. Cerebellum plays a central role in motor control and its alterations has been already demonstrated in atypical PS. The main aim of this study was to evaluate diagnostic accuracy of cerebellar (1)H-MRS in the differential diagnosis between PD and atypical PS. METHODS: We obtained (1)H-MRS spectra from the left cerebellar hemisphere of 57 PS (21 PD, and 36 atypical PS) and 14 unaffected controls by using a 1.5 T GE scanner. N-acetyl-aspartate (NAA)/Creatine (Cr), choline-containing compounds (Cho)/Cr, myoinositol (mI)/Cr, and NAA/mI ratios were calculated. RESULTS: NAA/Cr and NAA/mI ratios were significantly lower (p < 0.01) in atypical PS compared to PD and controls, and in MSA-C compared to PD, MSA-P, PSP-RS and controls. PSP-RS group showed reduced NAA/Cr ratios compared to PD (p < 0.05) and controls (p < 0.05), and reduced NAA/mI compared to controls (p < 0.01). NAA/Cr ratio values higher than 1.016 showed 100% sensitivity and negative predictive value, 62% positive predictive value and 64% specificity in discriminating PD. CONCLUSION: Cerebellar biochemical alterations detected by using (1)H-MRS could represent an adjunctive diagnostic tool to improve the differential diagnosis of PS.

Overexpression of blood microRNAs 103a, 30b, and 29a in L-dopa-treated patients with PD.

OBJECTIVE: The aims of the present study were to profile the expression of several candidate microRNAs (miRNAs) in blood from L-dopa-treated and drug-naive patients with Parkinson disease (PD) vs unaffected controls and to interpret the miRNA expression data in a biological context. METHODS: We analyzed RNAs from peripheral blood of 36 L-dopa-treated, 10 drug-naive patients with PD and unaffected controls matched 1:1 by sex and age. We evaluated expression by reverse transcription-quantitative real-time PCR, and we analyzed data using a 2-tailed paired t test. To detect miRNA targets, several miRNA resources were combined to generate an overall score for each candidate gene using weighted rank aggregation. RESULTS: Significant overexpression of miR-103a-3p (p < 0.0001), miR-30b-5p (p = 0.002), and miR-29a-3p (p = 0.005) in treated patients with PD was observed, and promising candidate target genes for these were revealed by an integrated in silico analysis. CONCLUSIONS: We revealed 3 candidate biomarkers for PD. miRNAs 30b-5p and 29a-3p replicated a documented deregulation in PD albeit opposite to published data, while for miR-103a-3p, we demonstrated for the first time an overexpression in treated patients with PD. Expression studies in patients and/or in isolated peripheral blood mononuclear cells before and after L-dopa administration are necessary to define the involvement of L-dopa treatment in the observed overexpression. Our in silico analysis to prioritize targets of deregulated miRNAs identified candidate target genes, including genes related to neurodegeneration and PD. Despite the preliminary character of our study, the results provide a rationale for further clarifying the role of the identified miRNAs in the pathogenesis of PD and for validating their diagnostic potential.