Internuclear Ophthalmoplegia as an Isolated Symptom of Brainstem Wake-up Stroke Responsive to Intravenous Thrombolysis: Evidence from MRI.

BACKGROUND: Internuclear ophthalmoplegia (INO) is a disorder of eye movements caused by a lesion involving the medial longitudinal fasciculus (MLF) within the brainstem, and it is characterized by adduction impairment combined with contralateral dissociated abduction nystagmus. The frequency of acute ischemic stroke (AIS) presenting with INO as a predominant symptom is very low, and many patients suffering from this brainstem AIS are precluded from intravenous thrombolysis (IVT). OBJECTIVE: To provide for the first time a magnetic resonance imaging (MRI) evidence of response to the IVT in brainstem wake-up stroke presenting with INO as an isolated symptom. METHODS: Here, we described a rare case of pons AIS presenting with INO as a unique symptom of awakening. In order to differentiate an ischemic stroke from other stroke mimics, and to determine whether the patient was within the therapeutic window for IVT (wake-up stroke), brain MRI including DWI and FLAIR sequences was acquired. RESULTS: A left paramedian pontine DWI/FLAIR mismatch was detected and the patient was considered eligible for IVT. After IVT, the patient made a full recovery with complete resolution of INO. Follow-up MRI at 1 month demonstrates the absence of ischemic lesions. CONCLUSION: Our case provides neuroradiological evidence of IVT efficacy in brainstem stroke, and it should prompt clinicians to rapidly perform MRI in wake-up onset INO and to just as quickly administer IVT, since INO is a functionally disabling deficit. Finally, this case demonstrates the value of MRI in diagnostic, prognostic, and therapeutic workup of posterior circulation wake-up stroke.

Recurrent Miller-Fisher syndrome overlapping Guillain-Barrè syndrome and Bickerstaff brainstem encephalitis: A case report.

Miller-Fisher syndrome (MFS) together with Guillan-Barré syndrome (GBS) and Bickerstaff brainstem encephalitis (BBE) are considered to form a continuous clinical spectrum of the same disease, possibly affecting the peripheral and/or central nervous systems, with monophasic symptoms. The frequency of overlapping clinical signs and the risk of recurrence are independent and very low, but no cases of GQ1b-seropositive recurrent MFS overlapping with GBS and BBE have been described so far. Here, we describe for the first time an atypical case of recurrent GQ1b-seropositive MFS overlapping GBS and BBE, 12 years after a previous GQ1b-seronegative typical MFS episode. Our case expands the clinical spectrum of recurrent MFS, and it should prompt clinicians to investigate the presence of anti-ganglioside antibodies in recurrent MFS even when these were negative in the previous episode, especially in those presenting with overlapping spectrum symptoms and a critically ill picture during the second episode.

Magnetic Resonance Imaging Biomarkers Distinguish Normal Pressure Hydrocephalus From Progressive Supranuclear Palsy.

BACKGROUND: Idiopathic normal pressure hydrocephalus and PSP share several clinical and radiological features, making differential diagnosis, at times, challenging. OBJECTIVES: To differentiate idiopathic normal pressure hydrocephalus from PSP using MR volumetric and linear measurements. METHODS: Twenty-seven idiopathic normal pressure hydrocephalus patients, 103 probable PSP patients, and 43 control subjects were consecutively enrolled. Automated ventricular volumetry was performed using Freesurfer 6 on MR T1 -weighted images. Linear measurements, such as callosal angle and a new measure, termed MR Hydrocephalic Index, were calculated on MR T1 -weighted images. Receiver operating characteristic analyses were used for differentiating between patient groups. Generalizability and reproducibility of the results were validated, dividing each participant group in two cohorts used as training and testing subsets. RESULTS: Ventricular volumes and linear measurements (callosal angle and Magnetic Resonance Hydrocephalic Index) revealed greater ventricular enlargement in patients with idiopathic normal pressure hydrocephalus than in PSP patients and controls. PSP patients had ventricular volume larger than controls. Automated ventricular volumetry and Magnetic Resonance Hydrocephalic Index were the most accurate measures (98.5%) in differentiating patients with idiopathic normal pressure hydrocephalus from PSP patients, whereas callosal angle misclassified several PSP patients and showed low positive predictive value (70.0%) in differentiating between these two diseases. All measurements accurately differentiated idiopathic normal pressure hydrocephalus patients from controls. Accuracy values obtained in the training set (automated ventricular volumetry, 98.4%; Magnetic Resonance Hydrocephalic Index, 98.4%; callosal angle, 87.5%) were confirmed in the testing set. CONCLUSIONS: Our study demonstrates that AVV and Magnetic Resonance Hydrocephalic Index were the most accurate measures for differentiation between idiopathic normal pressure hydrocephalus and PSP patients. Magnetic Resonance Hydrocephalic Index is easy to measure and can be used in clinical practice to prevent misdiagnosis and ineffective shunt procedures in idiopathic normal pressure hydrocephalus mimics. © 2020 International Parkinson and Movement Disorder Society.

Hippocampal impairment in patients with Essential Tremor.

INTRODUCTION: There is growing evidence that a proportion of patients with Essential Tremor (ET) may develop a memory impairment over time. However, no studies have evaluated whether hippocampal damage really occur in ET. This study investigated the macro and micro-structural integrity of the hippocampus in ET subjects using a multimodal MRI approach. METHODS: Neuropsychological and MRI data were acquired from 110 participants (60 patients with ET and 50 age-, sex-, and education-matched healthy controls [HC]). Whole-brain T1-weighted and Diffusion Tensor Imaging (DTI) were performed to assess macro-and microstructural alterations. MRI parameters (volume; mean diffusivity [MD]; fractional anisotropy [FA]) of bilateral hippocampi were obtained. In order to evaluate the relationship between MRI alterations and neurocognitive impairment, hippocampal parameters were also correlated with cognitive test scores. RESULTS: Compared to controls, ET patients showed a subclinical memory impairment with significantly lower memory scores, but within the normal ranges. Despite the subclinical damage, however, ET patients showed a significant increase in MD values in the bilateral hippocampi in comparison with HC. A significant correlation was also found between MD and memory scores in ET. CONCLUSION: This study improves the knowledge on memory impairment in ET, as our results demonstrate for the first time the hippocampal microstructural damage related to subclinical memory impairment in ET patients. Further studies are needed before these findings can be considered predictive of a distinct ET subtype or suggestive of a co-occurent dementia.

The role of epsilon phenotype in brain glucose consumption in Alzheimer's disease.

OBJECTIVE: The aim of our study was to investigate the impact of the epsilon phenotype in brain glucose consumption in a population with Alzheimer's disease. METHODS: Statistical Parametric Mapping (SPM8) was used to investigate differences in brain glucose consumption (as detectable by means of 18F FDG-PET/CT) in the population examined. A total of 129 patients (72 females and 57 males) with a diagnosis of probable AD according to the NINCDS-ADRDA criteria underwent the PET/CT examination. The mean (SD) age of the patients was 70 (± 7) years; the mean Mini-Mental State Examination was 19(± 5.6). 59 expressed epsilon 4 phenotype (E4) and 70 expressed the epsilon 3 phenotype (E3). Cerebral spinal fluid amyloid, tau, and t-tau have been measured resulting equal to 367.4 (± 149.1), 584.7 (± 312.1), and 79.2(± 45.9) pg/ml, respectively. Patients with confirmed amyloid and Tau changes were classified as AD. Patients with amyloid changes but negative Tau, considered as high risk of AD, were classified as IAD. Age, sex, MMSE, scholarship, and CSF parameters were used as a covariate in the SPM analyses. RESULTS: We did not find significant differences in age, gender, and MMSE and CSF parameters among groups. In the analysis of the AD group as compared to AD-E3, AD-E4 subjects show a significant reduction of brain glucose consumption in inferior frontal gyrus bilaterally (BA 45, BA 47). In the analysis of the IAD group as compared to IAD-E3, IAD-E4 subjects show a significant reduction of brain glucose consumption in right in medial, middle, and superior frontal gyrus (BA10, BA11), and in left medial and middle frontal gyrus (BA10, BA11). The differences between IAD-E3 and AD-E3 and between IAD-E4 and AD-E4 (and vice versa analysis) resulted not significant. CONCLUSIONS: APO-e4 is related to a major involvement of the frontal cortex confirming its role of risk factor in AD, while APO-3 seems not related to a specific pattern, supporting the hypothesis of neutral/protective role in AD.

[18F] FBB cortical uptake is not related to the age of onset of Alzheimer's disease.

AIM: To investigate the relationships between amyloid burden in brain and the age of onset of Alzheimer's disease. MATERIALS AND METHODS: We examined 60 patients with clinical diagnosis of Alzheimer's disease. Of them, 22 were early-onset of Alzheimer's disease and 38 were late-onset of Alzheimer's disease. All of them underwent a brain PET scan 90 minutes after the injection of 4-[(E)-2-[4-[2-[2-(2-fluoranylethoxy)ethoxy]ethoxy]phenyl]ethenyl]-N-methylaniline ([F] FBB); 300 ± 10 MBq). Relationships between amyloid burden in brain and age of onset of Alzheimer's disease were assessed by means of statistical parametric mapping version 12. RESULTS: There were no significant differences [F] FBB uptake between early-onset of Alzheimer's disease and late-onset of Alzheimer's disease patients. CONCLUSION: In our study group, the age of onset is not related to brain amyloid burden in Alzheimer's disease patients.

Apomorphine-induced reorganization of striato-frontal connectivity in patients with tremor-dominant Parkinson's disease.

INTRODUCTION: Apomorphine is a dopamine agonist used in Parkinson's disease (PD), which matches levodopa in terms of the magnitude of effect on the cardinal motor features, such as tremor and bradykinesia. The beneficial effect of this treatment on PD patients with tremor-dominant has widely been demonstrated, although the underlying neural correlates are unknown. We sought to examine the effects of apomorphine on topological characteristics of resting-state functional connectivity networks in tremor-dominant PD (tdPD) patients. METHODS: Sixteen tdPD patients were examined using a combined electromyography-functional magnetic resonance imaging approach. Patients were scanned twice following either placebo (subcutaneous injection of 1 mL saline solution) or 1 mg of apomorphine injection. Graph analysis methods were employed to investigate the modular organization of functional connectivity networks before and after drug treatment. RESULTS: After injection of apomorphine, evident reduction of tremor symptoms was mirrored by a significant increase in overall connectivity strength and reorganization of the modular structure of the basal ganglia and of the fronto-striatal module. Moreover, we found an increase in the centrality of motor and premotor regions. No differences were found between pre- and post-placebo sessions. CONCLUSION: These results provide new evidence about the effects of apomorphine at a large-scale neural network level showing that drug treatment modifies the brain functional organization of tdPD, increasing the overall resting-state functional connectivity strength, the segregation of striato-frontal regions and the integrative role of motor areas.

Track density imaging: A reliable method to assess white matter changes in Progressive Supranuclear Palsy with predominant parkinsonism.

INTRODUCTION: Track density imaging (TDI) has been proven to be a useful approach able to investigate white matter (WM) anatomical integrity in several neurodegenerative conditions, such as Parkinson's disease (PD) and classical phenotype of Progressive Supranuclear Palsy (PSP) also known as Richardson's syndrome (RS). To the best of our knowledge, no studies have assessed WM changes in PSP-predominant parkinsonism (PSP-P) patients by using a TDI approach, and no studies have explored the potential role of these changes in discriminating patients with PSP-P from those with PSP-RS and PD. METHODS: We used TDI to characterize WM changes in 31 PSP-P compared to 36 PSP-RS, 36 PD and 37 healthy controls (HC). Then, a support vector machine (SVM) approach was used to evaluate the performance of TDI in discriminating between patient groups. RESULTS: Relative to HC and PD patients, decreased track density in PSP-P patients was found in several WM regions such as the midbrain, superior cerebellar peduncles, cerebellum and corticospinal tract. By contrast, higher values of track density were observed in PSP-P patients compared to PSP-RS. SVM approach using TDI differentiated patients with PSP-P from PD and PSP-RS with an area under the curve of 0.90 and 0.76, respectively. CONCLUSIONS: Our findings suggest that TDI may represent a useful approach for characterizing WM changes in PSP-P patients representing a potential new MRI biomarker in distinguishing this PSP phenotype from PD.

Value of Multimodal Imaging Approach to Diagnosis of Neurosarcoidosis.

BACKGROUND: Neurosarcoidosis is a highly variable condition with many clinical and radiological manifestations, that can lead to difficult identification of isolated central nervous system (CNS) forms, because it could mimic inflammatory, infective or neoplastic disorders. Conventional magnetic resonance imaging (MRI) is gold standard to evaluate CNS involvement in neurosarcoidosis, despite the reported high sensitivity but low specificity in the diagnosis. CASE PRESENTATION: Here, we describe a 52-year-old man that presented to our hospital with a 10-year history of focal seizures, progressive cognitive decline and motor impairment. Neurological examination revealed ataxic gait, bilateral telekinetic and postural tremor, brisk reflexes, left extensor plantar response and hypoesthesia to the right side of body. Brain 3T-magnetic resonance imaging (MRI) showed a leukoencephalopathy with multifocal nodular lesions hyperintense on T2/ fluid attenuated inversion recovery (FLAIR) weighted images involving basal ganglia, periventricular and deep white matter. The interpretation of this pattern on conventional MRI was unclear, opening a challenge on the differential diagnosis between inflammatory, infective or neoplastic disorders. Thus, to better understand the nature of these nodules, single-voxel 1H-magnetic resonance spectroscopy (1H-MRS), contrast enhanced computed tomography (CT) scan and fluorine-18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)/3T-MRI were performed. The parenchymal multifocal lesions exhibited slight N-acetyl-aspartate/creatine reduction without abnormal peaks on 1H-MRS, enhancement after the administration of contrast agent on CT and hypermetabolism on 18F-FDG-PET/3T-MRI. All these findings excluded primary neoplasms, metastasis, neurotuberculosis, neurocysticercosis and brain abscess, strongly suggesting a diagnosis of neurosarcoidosis. Therefore, a whole-body 18F-FDG-PET/CT was performed in order to identify subclinical extraneural sarcoidosis localizations, and a hypermetabolic nodule of the left lung upper lobe was found. Subsequently, a biopsy documented the presence of systemic sarcoidosis, supporting a diagnosis of probable neurosarcoidosis. CONCLUSIONS: This case demonstrated that a multimodal neuroimaging approach can provide different but complementary evidences to suspect sarcoidosis, especially in apparently CNS isolated forms.

Intracellular FMRpolyG-Hsp70 complex in fibroblast cells from a patient affected by fragile X tremor ataxia syndrome.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome is a late-onset neurodegenerative disorder that affects about 40% of carriers of CGG-repeat expansions in the premutation range within the fragile X gene (FMR1). Main clinical features include intention tremor, cerebellar ataxia, and parkinsonism. Recently, great emphasis on the deposition of soluble aggregates produced by a RAN translation process, as main pathogenic mechanism, has been given. These aggregates contain a small protein with a polyglycine stretch on the aminoterminal end named FMRpolyG and, so far, have been isolated and characterized in drosophila and mouse models, in post mortem brain of fragile X-associated tremor/ataxia syndrome patients, in fibroblasts of fragile primary ovarian insufficiency patients, but never in fibroblasts from a fragile X-associated tremor/ataxia living patients. In adult carriers the syndrome is frequently misdiagnosed due to the lack of specific markers. METHODS: We standardized immunocytochemistry, immunoprecipitation and western blot procedures to study and biochemically characterize the FMRpolyG protein in fibroblasts from human skin biopsy. RESULTS: We demonstrate for the first time, in fibroblasts from a patient affected by Fragile X-associated tremor/ataxia syndrome, the presence ex vivo of inclusions consisting of FMRpolyG- Hsp70 soluble aggregates. CONCLUSION: These observations can pave the way to develop a cellular model for studying ex vivo and in vitro the mechanisms involved in the production of FMRpolyG aggregates, their toxicity, and the role of the FMRpolyG-Hsp70 interaction in the pathogenesis of fragile X-associated tremor/ataxia syndrome.

The embodiment of language in tremor-dominant Parkinson's disease patients.

According to embodied cognition, processing language with motor content involves a simulation of this content by the brain motor system. Patients with brain lesions involving the motor system are characterized by deficits in action verbs processing in the absence of dementia. We sought to assess whether action verbs interfere with the motor behavior of patients with Parkinson's disease (PD) having tremor dominant symptoms. PD tremor is considered to result from dysfunction of cortical-subcortical motor circuits driven by dopamine depletion. In addition, PD tremor is reduced during active movement execution. Therefore, likewise movement execution, the motor simulation of bodily actions predicted by the embodiment may show to be effective in modifying tremor by interfering with a dysfunctional motor system. Here, we asked to simply read and repeat words expressing a hand-related bodily action. Abstract verbs served as control. Changes in tremor kinematics were evaluated using a monoaxial accelerometer. Seventeen PD patients with rest tremor of the upper limbs were enrolled. Tremor amplitude was significantly smaller when reading action verbs as compared to abstract verbs. We provide empirical evidence supporting the embodied cognition theory by showing that circuits mediating tremor of PD patients are distinctively affected by processing action language.

Brain metabolic patterns in patients with suspected non-Alzheimer's pathophysiology (SNAP) and Alzheimer's disease (AD): is [18F] FDG a specific biomarker in these patients?

PURPOSE: The present study was conducted to compare the pattern of brain [18F] FDG uptake in suspected non-Alzheimer's pathophysiology (SNAP), AD, and healthy controls using 2-deoxy-2-[18F]fluoroglucose ([18F] FDG) positron emission tomography imaging. Cerebrospinal fluid (CSF) biomarkers amyloid-ß1-42 peptide (Aß1-42) and tau were used in order to differentiate AD from SNAP. METHODS: The study included 43 newly diagnosed AD patients (female = 23; male = 20) according to the NINCDS-ADRDA criteria, 15 SNAP patients (female = 12; male =3), and a group of 34 healthy subjects that served as the control group (CG), who were found to be normal at neurological evaluation (male = 20; female = 14). A battery of neuropsychological tests was administrated in AD and SNAP subjects; cerebrospinal fluid assay was conducted in both AD and SNAP as well. Brain PET/CT acquisition was started 30 ± 5 min after [18F] FDG injection in all subjects. SPM12 [statistical parametric mapping] implemented in MATLAB 2018a was used for the analysis of PET scans in this study. RESULTS: As compared to SNAP, AD subjects showed significant hypometabolism in a wide cortical area involving the right frontal, parietal, and temporal lobes. As compared to CG, AD subjects showed a significant reduction in [18F] FDG uptake in the parietal, limbic, and frontal cortex, while a more limited reduction in [18F] FDG uptake in the same areas was found when comparing SNAP to CG. CONCLUSIONS: SNAP subjects show milder impairment of brain [18F] FDG uptake as compared to AD. The partial overlap of the metabolic pattern between SNAP and AD limits the use of [18F] FDG PET/CT in effectively discriminating these clinical entities.

Refining initial diagnosis of Parkinson's disease after follow-up: A 4-year prospective clinical and magnetic resonance imaging study.

BACKGROUND: No prospective study of patients with Parkinson's disease (PD) has investigated the appearance of vertical gaze abnormalities, a feature suggestive of progressive supranuclear palsy (PSP). OBJECTIVE: To identify, within a cohort of patients with an initial diagnosis of PD, those who developed vertical gaze abnormalities during a 4-year follow-up, and to investigate the performance of new imaging biomarkers in predicting vertical gaze abnormalities. METHODS: A total of 110 patients initially classified as PD and 74 controls were enrolled. All patients underwent clinical assessment at baseline and every year up to the end of the follow-up. The pons/midbrain area ratio 2.0 and the Magnetic Resonance Parkinsonism Index 2.0 were calculated. RESULTS: After 4-year follow-up, 100 of 110 patients maintained the diagnosis of PD, whereas 10 PD patients (9.1%) developed vertical gaze abnormalities, suggesting an alternative diagnosis of PSP-parkinsonism. At baseline, the Magnetic Resonance Parkinsonism Index 2.0 was the most accurate biomarker in differentiating PD patients who developed vertical gaze abnormalities from those who maintained an initial diagnosis of PD. At the end of follow-up, both of these biomarkers accurately distinguished PSP-parkinsonism from PD. CONCLUSIONS: Our results demonstrate that a number of patients with an initial diagnosis of PD developed vertical gaze abnormalities during a 4-year follow-up, and the diagnosis was changed from PD to PSP-parkinsonism. In PD patients, baseline Magnetic Resonance Parkinsonism Index 2.0 showed the best performance in predicting the clinical evolution toward a PSP-parkinsonism phenotype, enabling PSP-parkinsonism patients to be identified at the earliest stage of the disease for promising disease-modifying therapies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Imaging counterpart of postural instability and vertical ocular dysfunction in patients with PSP: A multimodal MRI study.

INTRODUCTION: We investigated the imaging counterpart of two functional domains (ocular motor dysfunction and postural instability) in progressive supranuclear palsy (PSP) patients classified according to the new clinical diagnostic criteria. METHODS: Forty-eight patients with probable PSP-Richardson's syndrome (PSP-RS), 30 with probable PSP-parkinsonism (PSP-P), 37 with Parkinson's disease (PD), and 38 controls were enrolled. For each functional domain, PSP patients were stratified by two certainty levels: vertical supranuclear gaze palsy (O1) and slowness of vertical saccades (O2) for ocular motor dysfunction; early unprovoked falls and tendency to fall on the pull-test for postural instability. Voxel-based morphometry (VBM), whole-brain fractional anisotropy (FA) and MR planimetric measurements were analysed and compared across patient groups. RESULTS: O1 was present in 64%, and O2 in 36% of all PSP patients. All PSP-RS patients showed early unprovoked falls. TBSS whole-brain analysis revealed that superior cerebellar peduncles (SCPs) were the only structures with significantly lower FA values in PSP-RS compared with PSP-P patients. PSP/O1 patients had lower FA values in midbrain than PSP/O2 patients. By contrast, VBM revealed no differences in grey matter volume between PSP patient groups. MR Planimetric measurements confirmed atrophy of midbrain and SCPs, in line with DTI findings. CONCLUSIONS: Our study demonstrates that SCPs were significantly more damaged in patients with PSP-RS in comparison with PSP-P patients, thus suggesting the role of SCPs in developing postural instability. Midbrain damage was less severe in O2 than in O1 patients, suggesting that the degree of vertical ocular dysfunction reflects the severity of midbrain atrophy.

In vivo evidence for decreased scyllo-inositol levels in the supplementary motor area of patients with Progressive Supranuclear Palsy: A proton MR spectroscopy study.

INTRODUCTION: Several structural and functional neuroimaging studies have shown that the Supplementary Motor Area (SMA) is affected by tau pathology in patients with Progressive Supranuclear Palsy (PSP). The aim of the study was to investigate the biochemical profile of SMA in PSP patients, using proton magnetic resonance spectroscopy (1H-MRS). METHODS: Sixteen PSP patients and 18 healthy controls participated in this study. 1H-MRS was performed by using a Point RESolving Spectroscopy (PRESS) single-voxel sequence implemented on a 3-T scanner. A voxel of 25 × 25 × 15 mm involving the right and left SMA was acquired in all subjects. Peak areas of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (NAA), creatine with phosphocreatine (Cr), glycerophosphocholine + phosphocholine (Cho), glutamate + glutamine (Glx), glutathione (GSH), myo-Inositol (mI) and Scyllo-Inositol (Scyllo) were calculated using a version 6.3-1K of the fitting program LCModel. Comparative analysis was performed on both absolute concentrations and ratio values relative to Cr. RESULTS: PSP patients showed a significant decrease in Scyllo concentration and Scyllo/Cr ratio values in SMA, compared to controls, whereas no difference between groups was found for the other ratio values. Of note, the attention and working memory functions were positively related to Scyllo and Scyllo/Cr values in PSP patients. CONCLUSIONS: Our study demonstrates that Scyllo and Scyllo/Cr were significantly reduced in the SMA of PSP patients. Because Scyllo seems to be able to protect against formation of toxic fibrils of amyloid-beta fragments and tau oligomers deposition, these preliminary findings may open new perspectives to investigate Scyllo as a new potential disease-modifying therapy for PSP.

Biological and clinical manifestations of juvenile Huntington's disease: a retrospective analysis.

BACKGROUND: Huntington's disease is a rare, neurodegenerative disease caused by an expanded CAG repeat mutation in the huntingtin gene. Compared with adult-onset Huntington's disease, juvenile Huntington's disease (onset ≤20 years) is even rarer and has not been studied extensively. We aimed to further characterise juvenile Huntington's disease by examining the effect of CAG repeat size on disease presentation, progression, and survival. METHODS: We did a retrospective analysis of patients with juvenile Huntington's disease aged 20 years or younger, according to the length of their CAG repeat and who had disabling psychiatric symptoms (with motor symptoms) or motor symptoms alone, and of patients with adult-onset Huntington's disease manifesting aged 30-60 years with 40 or more CAG repeats, from the REGISTRY and ENROLL-HD platforms and from two institutional databases (Lega Italiana Ricerca Huntington Foundation and the Instituto Neurociencias de Buenos Aires and the Sanatorio de la Trinidad Mitre). Patients with psychiatric but no motor symptoms were excluded. We compared symptoms at onset and longitudinally in patients with juvenile Huntington's disease with highly expanded (HE subgroup) or low expansion (LE subgroup) mutations, grouped by hierarchical clustering analysis. We also compared disease progression (longitudinal change in Unified Huntington's Disease Rating Scale-Total Motor Score) and survival of patients with juvenile and adult-onset Huntington's disease. FINDINGS: We extracted medical records from 580 patients entered into the studies or databases between June 23, 2004, and March 31, 2018, of whom 36 patients met our definition of juvenile Huntington's disease and 197 for adult-onset Huntington's disease. According to caregiver reports, gait disturbance was more often a first presenting symptom in the HE subgroup (eight [80%] of 10 patients) than in the LE subgroup (seven [27%] of 26 patients; p=0·0071), whereas loss of hand dexterity was more common in the LE subgroup (11 [42%] of 26 patients) than in the HE subgroup (0 [0%] of 10 patients; p=0·0160). Compared with the LE subgroup, development delay (0 [0%] in the LE subgroup vs nine [90%] in the HE subgroup; p<0·0001), severe gait impairment (nine [35%] in the LE subgroup vs nine [90%] in the HE subgroup; p=0·0072), and seizures (three [11%] in the LE subgroup vs eight [80%] in the HE subgroup; p<0·0001) prevailed over time in the HE subgroup. Disease progression was more rapid in juvenile Huntington's disease (n=14) than in adult-onset Huntington's disease (n=52; generalised estimating equation model, p=0·0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntington's disease (n=17) cohort than in adult-onset Huntington's disease (n=104) cohort (hazard ratio 2·18 [95% CI 1·08-4·40]; p=0·002). INTERPRETATION: Patients with HE juvenile Huntington's disease differ clinically from patients with LE juvenile Huntington's disease or adult-onset Huntington's disease, suggesting reclassification of this particularly aggressive form of Huntington's disease might be required. FUNDING: Lega Italiana Ricerca Huntington Foundation and IRCCS Ospedale Casa Sollievo della Sofferenza.

Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going.

The placebo effect is a phenomenon produced when an inert substance administered like a regular treatment improves the clinical outcome. Parkinson's disease (PD) is one of the main clinical disorders for which the placebo response rates are high. The first evidence of the neurobiological mechanisms underlying the placebo effect in PD stems from 2001, when de la Fuente-Fernandez and colleagues demonstrated that a placebo injection led to the release of dopamine in the striatal nuclei of PD measured with positron emission tomography technology. Since then, several studies have been conducted to investigate the neurobiological underpinnings of placebo responses. This article presents a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Of an initial yield of 143 papers, 19 were included. The lessons learned from these studies are threefold: (i) motor improvement is dependent on the activation of the entire nigrostriatal pathway induced by dopamine release in the dorsal striatum; (ii) the magnitude of placebo-induced effects is modulated by an expectancy of improvement, which is in turn related to the release of dopamine within the ventral striatum; (iii) the functioning of the neural pathways underlying the placebo response can be tuned by prior exposure and learning strategies. In conclusion, although the neural network underlying the placebo effect in PD has been largely confirmed and accepted, what remains to be established is how, when, and where the expectation of reward (mediated by the ventral striatum) interacts with the primary motor system (mediated by the dorsal striatum) to induce clinical improvement in motor symptoms. © 2018 International Parkinson and Movement Disorder Society.

A new MR imaging index for differentiation of progressive supranuclear palsy-parkinsonism from Parkinson's disease.

INTRODUCTION: Differentiating clinically progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) may be challenging, especially in the absence of vertical supranuclear gaze palsy (VSGP). The Magnetic Resonance Parkinsonism Index (MRPI) has been reported to accurately distinguish between PSP and PD, yet few data exist on the usefulness of this biomarker for the differentiation of PSP-P from PD. METHODS: Thirty-four patients with PSP-P, 46 with PSP-Richardson's syndrome (PSP-RS), 53 with PD, and 53 controls were enrolled. New consensus criteria for the clinical diagnosis of PSP were used as the reference standard. The MRPI, and a new index termed MRPI 2.0 including the measurement of the third ventricle width (MRPI multiplied by third ventricle width/frontal horns width ratio), were calculated on T1-weighted MR images. RESULTS: The MRPI differentiated patients with PSP-P from those with PD with sensitivity and specificity of 73.5% and 98.1%, respectively, while the MRPI 2.0 showed higher sensitivity (100%) and similar specificity (94.3%) in differentiating between these two groups. Both biomarkers showed excellent performance in differentiating PSP-P patients with VSGP from those with PD, but the MRPI 2.0 was much more accurate (95.8%) than MRPI in differentiating PSP-P patients with slowness of vertical saccades from PD patients. CONCLUSION: The MRPI 2.0 accurately differentiated PSP-P patients from those with PD. This new index was more powerful than MRPI in differentiating PSP patients in the early stage of the disease with slowness of vertical saccades from patients with PD, thus helping clinicians to consolidate the diagnosis based on clinical features, in vivo.