Comparing Essential Tremor with and without Soft Dystonic Signs and Tremor Combined with Dystonia: The TITAN Study.

BACKGROUND: Tremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high. OBJECTIVES: To compare the clinical features of Essential Tremor without other features (pure ET), ET plus soft dystonic signs (ET + DS), and tremor combined with dystonia (TwD). METHODS: We compared the clinical features of patients with pure ET, ET + DS, and TwD enrolled in The ITAlian tremor Network (TITAN). Linear regression models were performed to determine factors associated with health status and quality of life. RESULTS: Three-hundred-eighty-three patients were included. Sex distribution was significantly different between the groups with males being more represented in pure ET and females in TwD. The initial site of tremor was different between the groups with about 40% of TwD having head tremor and ET + DS unilateral upper limb tremor at onset. This pattern mirrored the distribution of overt dystonia and soft dystonic signs at examination. Sensory trick, task-specificity, and position-dependence were more common, but not exclusive, to TwD. Pure ET patients showed the lowest degree of alcohol responsiveness and ET + DS the highest. Midline tremor was more commonly encountered and more severe in TwD than in the other groups. Regression analyses demonstrated that tremor severity, sex, age, and to a lesser degree the variable "group", independently predicted health status and quality of life, suggesting the existence of other determinants beyond tremor. CONCLUSIONS: Pure ET and TwD manifest with a phenotypic overlap, which calls for the identification of diagnostic biomarkers. ET + DS shared features with both syndromes, suggesting intra-group heterogeneity.

Functional Study of SNCA p.V15A Variant: Further Linking α-Synuclein and Glucocerebrosidase.

BACKGROUND: SNCA p.V15A was reported in five families. In vitro models showed increased aggregation and seeding activity, mitochondrial damage, and apoptosis. Mutant flies had reduced flying ability and survival. OBJECTIVES: To clinically and functionally evaluate SNCA p.V15A in a large Italian family with Parkinson's disease (PD). METHODS: Genetic diagnosis was reached through next-generation sequencing. Pathogenicity was assessed by molecular dynamics simulation and biochemical studies on peripheral blood mononuclear cells (PBMCs). RESULTS: Five siblings carried SNCA p.V15A; three developed bradykinetic-rigid PD in their 50s with rapid motor progression and variable cognitive impairment. A fourth sibling had isolated mood disturbance, whereas the fifth was still unaffected at age 47. The mutant protein showed decreased stability and an unstable folded structure. Proband's PBMCs showed elevated total and phosphorylated α-synuclein (α-syn) levels and significantly reduced glucocerebrosidase activity. CONCLUSION: This study demonstrates accumulation of α-synV15A in PBMCs and strengthens the link between α-syn pathophysiology and glucocerebrosidase dysfunction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Blood D-serine levels correlate with aging and dopaminergic treatment in Parkinson's disease.

We recently described increased D- and L-serine concentrations in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, the post-mortem caudate-putamen of human Parkinson's disease (PD) brains and the cerebrospinal fluid (CSF) of de novo living PD patients. However, data regarding blood D- and L-serine levels in PD are scarce. Here, we investigated whether the serum profile of D- and L-serine, as well as the other glutamate N-methyl-D-aspartate ionotropic receptor (NMDAR)-related amino acids, (i) differs between PD patients and healthy controls (HC) and (ii) correlates with clinical-demographic features and levodopa equivalent daily dose (LEDD) in PD. Eighty-three consecutive PD patients and forty-one HC were enrolled. PD cohort underwent an extensive clinical characterization. Serum levels of D- and L-serine, L-glutamate, L-glutamine, L-aspartate, L-asparagine and glycine were determined using High Performance Liquid Chromatography. In age- and sex-adjusted analyses, no differences emerged in the serum levels of D-serine, L-serine and other NMDAR-related amino acids between PD and HC. However, we found that D-serine and D-/Total serine ratio positively correlated with age in PD but not in HC, and also with PD age at onset. Moreover, we found that higher LEDD correlated with lower levels of D-serine and the other excitatory amino acids. Following these results, the addition of LEDD as covariate in the analyses disclosed a selective significant increase of D-serine in PD compared to HC (Δ ≈ 38%). Overall, these findings suggest that serum D-serine and D-/Total serine may represent a valuable biochemical signature of PD.

Are patients with GBA-Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort.

BACKGROUND: GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce. OBJECTIVE: To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort. METHODS: We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS. RESULTS: We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up. CONCLUSIONS: Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up.

Complications of deep brain stimulation in Parkinson's disease: a single-center experience of 517 consecutive cases.

BACKGROUND: The number of deep brain stimulation (DBS) procedures is rapidly rising as well as the novel indications. Reporting adverse events related to surgery and to the hardware used is essential to define the risk-to-benefit ratio and develop novel strategies to improve it. OBJECTIVE: To analyze DBS complications (both procedure-related and hardware-related) and further assess potential predictive factors. METHODS: Five hundred seventeen cases of DBS for Parkinson's disease were performed between 2006 and 2021 in a single center (mean follow-up: 4.68 ± 2.86 years). Spearman's Rho coefficient was calculated to search for a correlation between the occurrence of intracerebral hemorrhage (ICH) and the number of recording tracks. Multiple logistic regression analyzed the probability of developing seizures and ICH given potential risk factors. Kaplan-Meier curves were performed to analyze the cumulative proportions of hardware-related complications. RESULTS: Mortality rate was 0.2%, while permanent morbidity 0.6%. 2.5% of cases suffered from ICH which were not influenced by the number of tracks used for recordings. 3.3% reported seizures that were significantly affected by perielectrode brain edema and age. The rate of perielectrode brain edema was significantly higher for Medtronic's leads compared to Boston Scientific's (Χ2(1)= 5.927, P= 0.015). 12.2% of implants reported Hardware-related complications, the most common of which were wound revisions (7.2%). Internal pulse generator models with smaller profiles displayed more favorable hardware-related complication survival curves compared to larger designs (X2(1)= 8.139, P= 0.004). CONCLUSION: Overall DBS has to be considered a safe procedure, but future research is needed to decrease the rate of hardware-related complications which may be related to both the surgical technique and to the specific hardware's design. The increased incidence of perielectrode brain edema associated with certain lead models may likewise deserve future investigation.

Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Variants in the GBA1 gene, which encodes lysosomal acid glucocerebrosidase, are among the most common genetic risk factors for Parkinson's disease and are associated with faster disease progression. The mechanisms involved are unresolved but might include accumulation of glucosylceramide. Venglustat is a brain-penetrant glucosylceramide synthase inhibitor that, in previous studies, reduced amounts of the glycosphingolipid. We aimed to assess the safety, efficacy, and target engagement of venglustat in people with early-stage Parkinson's disease carrying pathogenic GBA1 variants. METHODS: MOVES-PD part 2 was a randomised, double-blinded, placebo-controlled phase 2 study done at 52 centres (academic sites, specialty clinics, and general neurology centres) in 16 countries. Eligible adults aged 18-80 years with Parkinson's disease (Hoehn and Yahr stage ≤2) and one or more GBA1 variants were randomly assigned using an interactive voice-response system (1:1) to 52 weeks of treatment with oral venglustat (15 mg/day) or matching placebo. Investigators, site personnel, participants, and their caregivers were masked to treatment allocation. The primary outcome measure was the change from baseline to 52 weeks in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score (a higher score indicates greater impairment), and it was analysed in a modified intention-to-treat population (ie, all randomly assigned participants with a baseline and at least one post-baseline measurement during the treatment period). This study was registered with ClinicalTrials.gov (NCT02906020) and is closed to recruitment. FINDINGS: Between Dec 15, 2016, and May 27, 2021, 221 participants were randomly assigned to venglustat (n=110) or placebo (n=111). The least squares mean change in MDS-UPDRS parts II and III combined score was 7·29 (SE 1·36) for venglustat (n=96) and 4·71 (SE 1·27) for placebo (n=105); the absolute difference between groups was 2·58 (95% CI -1·10 to 6·27; p=0·17). The most common treatment-emergent adverse events (TEAEs) were constipation and nausea (both were reported by 23 [21%] of 110 participants in the venglustat group and eight [7%] of 111 participants in the placebo group). Serious TEAEs were reported for 12 (11%) participants in each group. There was one death in the venglustat group owing to an unrelated cardiopulmonary arrest and there were no deaths in the placebo group. INTERPRETATION: In people with GBA1-associated Parkinson's disease in our study, venglustat had a satisfactory safety profile but showed no beneficial treatment effect compared with placebo. These findings indicate that glucosylceramide synthase inhibition with venglustat might not be a viable therapeutic approach for GBA1-associated Parkinson's disease. FUNDING: Sanofi.

Levodopa Equivalent Dose of Safinamide: A Multicenter, Longitudinal, Case-Control Study.

Background: Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO-B inhibitors (iMAO-B) safinamide and rasagiline are still based on empirical approaches. Objectives: To estimate LED of safinamide 50 and 100 mg. Methods: In this multicenter, longitudinal, case-control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg (N = 130), safinamide 50 mg (N = 144), or rasagiline 1 mg (N = 97) for 9 ± 3 months and a control group of patients never treated with any iMAO-B (N = 129). Results: Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS-II scores and Levodopa dose than control subjects. After a mean follow-up of 8.8-to-10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS-III and OFF-related UPDRS-IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO-B groups. After adjusting for age, disease duration, duration of follow-up, baseline values and taking change in UPDRS-III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1 mg equally corresponded to 100 mg LED. Conclusions: We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings.

Evaluation of iron overload in nigrosome 1 via quantitative susceptibility mapping as a progression biomarker in prodromal stages of synucleinopathies.

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, such as Parkinson's disease (PD), which are characterized by the loss of dopaminergic neurons in substantia nigra, associated with abnormal iron load. The assessment of presymptomatic biomarkers predicting the onset of neurodegenerative disorders is critical for monitoring early signs, screening patients for neuroprotective clinical trials and understanding the causal relationship between iron accumulation processes and disease development. Here, we used Quantitative Susceptibility Mapping (QSM) and 7T MRI to quantify iron deposition in Nigrosome 1 (N1) in early PD (ePD) patients, iRBD patients and healthy controls and investigated group differences and correlation with disease progression. We evaluated the radiological appearance of N1 and analyzed its iron content in 35 ePD, 30 iRBD patients and 14 healthy controls via T2*-weighted sequences and susceptibility (χ) maps. N1 regions of interest (ROIs) were manually drawn on control subjects and warped onto a study-specific template to obtain probabilistic N1 ROIs. For each subject the N1 with the highest mean χ was considered for statistical analysis. The appearance of N1 was rated pathological in 45% of iRBD patients. ePD patients showed increased N1 χ compared to iRBD patients and HC but no correlation with disease duration, indicating that iron load remains stable during the early stages of disease progression. Although no difference was reported in iron content between iRBD and HC, N1 χ in the iRBD group increases as the disease evolves. QSM can reveal temporal changes in N1 iron content and its quantification may represent a valuable presymptomatic biomarker to assess neurodegeneration in the prodromal stages of PD.

Troubleshooting Gait Disturbances in Parkinson's Disease With Deep Brain Stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus or the globus pallidus is an established treatment for Parkinson's disease (PD) that yields a marked and lasting improvement of motor symptoms. Yet, DBS benefit on gait disturbances in PD is still debated and can be a source of dissatisfaction and poor quality of life. Gait disturbances in PD encompass a variety of clinical manifestations and rely on different pathophysiological bases. While gait disturbances arising years after DBS surgery can be related to disease progression, early impairment of gait may be secondary to treatable causes and benefits from DBS reprogramming. In this review, we tackle the issue of gait disturbances in PD patients with DBS by discussing their neurophysiological basis, providing a detailed clinical characterization, and proposing a pragmatic programming approach to support their management.

Diagnostic accuracy of quantitative susceptibility mapping in multiple system atrophy: The impact of echo time and the potential of histogram analysis.

The non-invasive quantification of iron stores via Quantitative Susceptibility Mapping (QSM) could play an important role in the diagnosis and the differential diagnosis of atypical Parkinsonisms. However, the susceptibility (χ) values measured via QSM depend on echo time (TE). This effect relates to the microstructural organization within the voxel, whose composition can be altered by the disease. Moreover, pathological iron deposition in a brain area may not be spatially uniform, and conventional Region of Interest (ROI)-based analysis may fail in detecting alterations. Therefore, in this work we evaluated the impact of echo time on the diagnostic accuracy of QSM on a population of patients with Multiple System Atrophy (MSA) of either Parkinsonian (MSAp) or cerebellar (MSAc) phenotypes. In addition, we tested the potential of histogram analysis to improve QSM classification accuracy. We enrolled 32 patients (19 MSAp and 13 MSAc) and 16 healthy controls, who underwent a 7T MRI session including a gradient-recalled multi-echo sequence for χ mapping. Nine histogram features were extracted from the χ maps computed for each TE in atlas-based ROIs covering deep brain nuclei, and compared among groups. Alterations of susceptibility distribution were found in the Putamen, Substantia Nigra, Globus Pallidus and Caudate Nucleus for MSAp and in the Substantia Nigra and Dentate Nucleus for MSAc. Increased iron deposition was observed in a larger number of ROIs for the two shortest TEs and the standard deviation, the 75th and the 90th percentile were the most informative features yielding excellent diagnostic accuracy with area under the ROC curve > 0.9. In conclusion, short TEs may enhance QSM diagnostic performances, as they can capture variations in rapidly-decaying contributions of high χ sources. The analysis of histogram features allowed to reveal fine heterogeneities in the spatial distribution of susceptibility alteration, otherwise undetected by a simple evaluation of ROI χ mean values.

A multinational consensus on dysphagia in Parkinson's disease: screening, diagnosis and prognostic value.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor and non-motor dysfunction. Dysphagia is a common symptom in PD, though it is still too frequently underdiagnosed. Consensus is lacking on screening, diagnosis, and prognosis of dysphagia in PD. OBJECTIVE: To systematically review the literature and to define consensus statements on the screening and the diagnosis of dysphagia in PD, as well as on the impact of dysphagia on the prognosis and quality of life (QoL) of PD patients. METHODS: A multinational group of experts in the field of neurogenic dysphagia and/or PD conducted a systematic revision of the literature published since January 1990 to February 2021 and reported the results according to PRISMA guidelines. The output of the research was then analyzed and discussed in a consensus conference convened in Pavia, Italy, where the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. RESULTS: Eighty-five papers were used to inform the Panel's statements even though most of them were of Class IV quality. The statements tackled four main areas: (1) screening of dysphagia: timing and tools; (2) diagnosis of dysphagia: clinical and instrumental detection, severity assessment; (3) dysphagia and QoL: impact and assessment; (4) prognostic value of dysphagia; impact on the outcome and role of associated conditions. CONCLUSIONS: The statements elaborated by the Consensus Panel provide a framework to guide the neurologist in the timely detection and accurate diagnosis of dysphagia in PD.

Parkinsonism and cerebrospinal fluid disorders.

BACKGROUND: Although various motor manifestations can be seen in patients with cerebrospinal fluid (CSF) disorders, such as hydrocephalus or intracranial hypotension, the clinical presentation with parkinsonism is not clearly elucidated. METHODS: We searched the literature for studies describing the occurrence of parkinsonism in subjects with normal pressure hydrocephalus (NPH), obstructive hydrocephalus, and intracranial hypotension. We analyzed the clinical presentation (particularly with respect to bradykinesia, rigidity, rest tremor, and gait disturbance/postural instability) as well as the response to treatment. RESULTS: Parkinsonism was most commonly reported in NPH patients. Although gait disturbance/postural instability is a well-known motor symptom of NPH, other cardinal signs include upper limb involvement or asymmetric presentation. As for obstructive hydrocephalus, parkinsonism was mainly observed in subjects with aqueductal stenosis and more often after shunt surgery. Patients with NPH or obstructive hydrocephalus rarely improved with levodopa therapy, while most subjects only improved with shunt surgery. Although the mechanism is still controversial, a functional involvement of nigrostriatal pathway has been hypothesized based on imaging studies and case reports. Brain imaging is also helpful for atypical cases of intracranial hypotension presenting with parkinsonism. Parkinsonism improved after treatment in such cases as well. CONCLUSIONS: Studies exploring the relationship between CSF disorders and parkinsonism are mainly descriptive and their quality is generally poor. However, considering that these disorders can be treated, clinicians' awareness of the differential diagnosis is important and future studies better exploring the underlying pathophysiological mechanisms are warranted. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

Consensus on the treatment of dysphagia in Parkinson's disease.

BACKGROUND: Dysphagia is common in Parkinson's disease (PD). The effects of antiparkinsonian drugs on dysphagia are controversial. Several treatments for dysphagia are available but there is no consensus on their efficacy in PD. OBJECTIVE: To conduct a systematic review of the literature and to define consensus statements on the treatment of dysphagia in PD and related nutritional management. METHODS: A multinational group of experts in the field of neurogenic dysphagia and/or Parkinson's disease conducted a systematic evaluation of the literature and reported the results according to PRISMA guidelines. The evidence from the retrieved studies was analyzed and discussed in a consensus conference organized in Pavia, Italy, and the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. RESULTS: The literature review retrieved 64 papers on treatment and nutrition of patients with PD and dysphagia, mainly of Class IV quality. Based on the literature and expert opinion in cases where the evidence was limited or lacking, 26 statements were developed. CONCLUSIONS: The statements developed by the Consensus panel provide a guidance for a multi-disciplinary treatment of dysphagia in patients with PD, involving neurologists, otorhinolaryngologists, gastroenterologists, phoniatricians, speech-language pathologists, dieticians, and clinical nutritionists.

Neurophysiological evaluation of visual function in iRBD: potential role in stratifying RBD conversion risk.

STUDY OBJECTIVES: To evaluate neurophysiological alterations of visual function in idiopathic REM sleep Behavior Disorder (iRBD) both as markers and predictors of neurodegenerative disorders. METHODS: In a longitudinal follow-up study of 46 consecutive iRBD patients (follow-up duration 8.4 ± 3.4 years), the baseline parameters in luminance-contrast pattern (VEPp), red-green color (VEPc) and motion-onset (VEPm) Visual Evoked Potentials in iRBD were compared to early (ePD) and advanced (aPD) Parkinson's Disease subjects. Parameters of latency and amplitude of iRBD converters to neurodegenerative disease were compared with those of the non-converters. RESULTS: The VEP P100 mean latency values for both eyes and for both stimulation checks (30' and 15') were significantly longer in all the three groups of patients as compared to controls; moreover latencies were longer in aPD than in the iRBD group who did not differ from the ePD group. The same held true when we analyzed the number of abnormal subjects belonging to each diagnostic group with a higher number of abnormal subjects in the aPD group compared to both the ePD and in iRBD groups. Chromatic and motion potentials were not different from controls and did not differ in the 3 diagnostic groups. The iRBD subjects who converted to a neurodegenerative disorder showed longer P100 latencies and a higher occurrence of VEPp abnormalities than those who did not convert. Again chromatic and motion VEPs were not different depending on conversion. CONCLUSIONS: In iRBD patients the detection of an abnormal VEPp should be considered as a red flag for possible synnucleinopathy, eventually contributing in stratifying the risk of phenoconversion.

Clinical Outcome and Striatal Dopaminergic Function After Shunt Surgery in Patients With Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Participants with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [123I]-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years. RESULTS: We enrolled 115 patients with iNPH. Of 102 patients without significant levodopa response and no signs of atypical parkinsonism, 92 underwent FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery (p < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 (p < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in patients who declined surgery (p < 0.01). CONCLUSIONS: This prospective interventional study highlights the pathophysiologic relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and postsurgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with iNPH.

PSEN1 Compound Heterozygous Mutations Associated with Cerebral Amyloid Angiopathy and Cognitive Decline Phenotype.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the deposition of amyloid beta-peptide (Aß) aggregates. Aß aggregates lead to vessel rupture and intracerebral hemorrhages, detected by magnetic resonance imaging (MRI). Presenile CAA is usually genetically determined by mutations in the amyloid precursor protein (APP) gene. However, mutations after codon 200 in the presenilin 1 (PSEN1) gene have been reported to facilitate CAA onset. Here, we analyzed the genetic bases in a patient of 55 years old affected by CAA and cognitive decline. DNA was isolated and genetic analysis was performed by Next-Generation Sequencing (NGS). RNA was extracted and retro-transcribed to perform segregation analysis by TOPO-TA cloning. WB analysis was carried out to check the impact of the mutations on protein. Two compound heterozygous mutations in PSEN1 exon 10, such as a novel stop-gain mutation (c.1070C > G) and a pathogenic splice variant (c.1129A > T), were found by NGS. Both mutations altered the presenilin 1 protein, truncating its C-terminal portion. This is the first case of CAA and cognitive decline caused by two compound mutations in PSEN1. With this report, we suggest extending the genetic analysis to PSEN1 when cerebral microbleeds are observed by MRI investigation in a patient affected by presenile cognitive decline.

Dysphagia in multiple system atrophy consensus statement on diagnosis, prognosis and treatment.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure plus cerebellar syndrome and/or parkinsonism. Dysphagia is a frequent and disabling symptom in MSA and its occurrence within 5 years of motor onset is an additional diagnostic feature. Dysphagia can lead to aspiration pneumonia, a recognized cause of death in MSA. Guidelines for diagnosis and management of dysphagia in MSA are lacking. An International Consensus Conference among experts with methodological support was convened in Bologna to reach consensus statements for the diagnosis, prognosis, and treatment of dysphagia in MSA. Abnormalities of the oral and pharyngeal phases of swallowing, esophageal dysfunction and aspiration occur in MSA and worsen as the disease progresses. According to the consensus, dysphagia should be investigated through available screening questionnaires and clinical and instrumental assessment (videofluoroscopic study or fiberoptic endoscopic evaluation of swallowing and manometry) at the time of MSA diagnosis and periodically thereafter. There is evidence that dysphagia is associated with poor survival in MSA, however effective treatments for dysphagia are lacking. Compensatory strategies like diet modification, swallowing maneuvers and head postures should be applied and botulinum toxin injection may be effective in specific conditions. Percutaneous endoscopic gastrostomy may be performed when there is a severe risk of malnutrition and pulmonary complications, but its impact on survival is undetermined. Several research gaps and unmet needs for research involving diagnosis, prognosis, and treatment were identified.

Profiling the Biochemical Signature of GBA-Related Parkinson's Disease in Peripheral Blood Mononuclear Cells.

BACKGROUND: GBA mutations are the commonest genetic risk factor for Parkinson's disease (PD) and also impact disease progression. OBJECTIVE: The objective of this study was to define a biochemical profile that could distinguish GBA-PD from non-mutated PD. METHODS: 29 GBA-PD, 37 non-mutated PD, and 40 controls were recruited; α-synuclein levels in plasma, exosomes, and peripheral blood mononuclear cells were analyzed, GCase and main GCase-related lysosomal proteins in peripheral blood mononuclear cells were measured. RESULTS: Assessment of plasma and exosomal α-synuclein levels did not allow differentiation between GBA-PD and non-mutated PD; conversely, measurements in peripheral blood mononuclear cells clearly distinguished GBA-PD from non-mutated PD, with the former group showing significantly higher α-synuclein levels, lower GCase activity, higher LIMP-2, and lower Saposin C levels. CONCLUSION: We propose peripheral blood mononuclear cells as an easily accessible and manageable model to provide a distinctive biochemical profile of GBA-PD, potentially useful for patient stratification or selection in clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Is DAT imaging abnormality in normal pressure hydrocephalus always suggestive of degeneration?

Idiopathic normal pressure hydrocephalus (iNPH) is a debated entity with controversial pathogenesis, diagnostic criteria, and predictors of response after ventriculoperitoneal shunt (VPS). Parkinsonian signs are frequently reported in the clinical picture, sometimes due to the coexistence of an underlying neurodegenerative parkinsonism and sometimes in the absence thereof. To distinguish these two scenarios is crucial, since they may carry different long-term response to CSF drainage. 123I-FP-CIT-SPECT was believed to be helpful in this regard, however its role in predicting surgical outcome has been disputed. We illustrate a patient presented with gait disturbance, urinary incontinence, and asymmetrical parkinsonian signs, who underwent a 3T brain MRI and a 123I-FP-CIT-SPECT. VPS was performed. The patient repeated a 123I-FP-CIT-SPECT, 18 months after the operation, and was clinically followed up for 24 months. Our patient displayed clinical and radiological criteria for iNPH and an abnormal asymmetrical uptake in 123I-FP-CIT-SPECT, consistent with her asymmetrical parkinsonism. However, the organization of the substantia nigra studied with iron-sensitive sequences in 3T brain MRI scan appeared intact. The patient revealed an improvement both clinically and in 123I-FP-CIT-SPECT at postsurgical follow-up. Our report suggests that abnormal 123I-FP-CIT-SPECT may not necessarily reveal an overlap with neurodegenerative parkinsonism; its partial reversibility may suggest that the mechanical effect exerted on the striatum by ventriculomegaly ultimately leads to downregulation of dopaminergic transporters which may improve after VPS.

Striatal Dopamine Deficit and Motor Impairment in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus can present with parkinsonism. However, abnormalities of the striatal dopamine reuptake transporter are unclear. OBJECTIVES: To explore presence and features of striatal dopaminergic deficit in subjects with idiopathic normal pressure hydrocephalus as compared to Parkinson's disease (PD) patients and healthy controls. METHODS: We investigated 50 subjects with idiopathic normal pressure hydrocephalus, 25 with PD, and 40 healthy controls. All participants underwent [123 I]-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane and single-photon emission computed tomography to quantify the striatal dopamine reuptake transporter binding. All subjects with idiopathic normal pressure hydrocephalus underwent a levodopa (l-dopa) challenge test and magnetic resonance imaging to evaluate ventriculomegaly and white matter changes. Gait, cognition, balance, and continence were assessed with the Idiopathic Normal Pressure Hydrocephalus Rating Scale, and parkinsonism with the motor section of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale. All patients completed a 2-year follow-up. RESULTS: A total of 62% of patients with idiopathic normal pressure hydrocephalus featured a reduced striatal dopamine reuptake transporter binding, which correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike PD, this dopaminergic deficit in idiopathic normal pressure hydrocephalus was more symmetric and prominent in the caudate nucleus. CONCLUSIONS: Subjects with idiopathic normal pressure hydrocephalus can present a reduction of striatal dopamine reuptake transporter binding, which is consistent with the severity of parkinsonism and qualitatively differs from that found in PD patients. Longitudinal interventional studies are needed to prove a role for striatal dopamine reuptake transporter deficit in the pathophysiology of idiopathic normal pressure hydrocephalus. © 2020 International Parkinson and Movement Disorder Society.