Core auditory processing deficits in primary progressive aphasia.

The extent to which non-linguistic auditory processing deficits may contribute to the phenomenology of primary progressive aphasia is not established. Using non-linguistic stimuli devoid of meaning we assessed three key domains of auditory processing (pitch, timing and timbre) in a consecutive series of 18 patients with primary progressive aphasia (eight with semantic variant, six with non-fluent/agrammatic variant, and four with logopenic variant), as well as 28 age-matched healthy controls. We further examined whether performance on the psychoacoustic tasks in the three domains related to the patients' speech and language and neuropsychological profile. At the group level, patients were significantly impaired in the three domains. Patients had the most marked deficits within the rhythm domain for the processing of short sequences of up to seven tones. Patients with the non-fluent variant showed the most pronounced deficits at the group and the individual level. A subset of patients with the semantic variant were also impaired, though less severely. The patients with the logopenic variant did not show any significant impairments. Significant deficits in the non-fluent and the semantic variant remained after partialling out effects of executive dysfunction. Performance on a subset of the psychoacoustic tests correlated with conventional verbal repetition tests. In sum, a core central auditory impairment exists in primary progressive aphasia for non-linguistic stimuli. While the non-fluent variant is clinically characterized by a motor speech deficit (output problem), perceptual processing of tone sequences is clearly deficient. This may indicate the co-occurrence in the non-fluent variant of a deficit in working memory for auditory objects. Parsimoniously we propose that auditory timing pathways are altered, which are used in common for processing acoustic sequence structure in both speech output and acoustic input.

Relearning of Writing Skills in Parkinson's Disease After Intensive Amplitude Training.

BACKGROUND: Micrographia occurs in approximately 60% of people with Parkinson's disease (PD). Although handwriting is an important task in daily life, it is not clear whether relearning and consolidation (ie the solid storage in motor memory) of this skill is possible in PD. The objective was to conduct for the first time a controlled study into the effects of intensive motor learning to improve micrographia in PD. METHODS: In this placebo-controlled study, 38 right-handed people with PD were randomized into 2 groups, receiving 1 of 2 equally time-intensive training programs (30 min/day, 5 days/week for 6 weeks). The experimental group (n = 18) performed amplitude training focused at improving writing size. The placebo group (n = 20) received stretch and relaxation exercises. Participants' writing skills were assessed using a touch-sensitive writing tablet and a pen-and-paper test, pre- and posttraining, and after a 6-week retention period. The primary outcome was change in amplitude during several tests of consolidation: (1) transfer, using trained and untrained sequences performed with and without target zones; and (2) automatization, using single- and dual-task sequences. RESULTS: The group receiving amplitude training significantly improved in amplitude and variability of amplitude on the transfer and automatization task. Effect sizes varied between 7% and 17%, and these benefits were maintained after the 6-week retention period. Moreover, there was transfer to daily life writing. CONCLUSIONS: These results show automatization, transfer, and retention of increased writing size (diminished micrographia) after intensive amplitude training, indicating that consolidation of motor learning is possible in PD. © 2016 International Parkinson and Movement Disorder Society.

Improved Sleep Correlates with Improved Quality of Life and Motor Symptoms with Foslevodopa/Foscarbidopa.

BACKGROUND: Foslevodopa/foscarbidopa is a subcutaneous infusion of levodopa/carbidopa prodrugs. OBJECTIVES: Assess correlations between sleep and efficacy from interim data of a phase 3 trial of foslevodopa/foscarbidopa (NCT03781167). METHODS: Pearson correlations between sleep (Parkinson's Disease Sleep Scale-2 [PDSS-2]) and quality of life (QoL; Parkinson's Disease Questionnaire-39), motor experiences of daily living (m-EDL; Movement Disorder Society-Unified Parkinson's Disease Scale Part II), and "Off"/"On" times were calculated for baseline and week 26 improvements. Regression analyses were adjusted for baseline PDSS-2 score. RESULTS: Baseline sleep correlated moderately with QoL (r = 0.44, P < 0.001) and weakly with m-EDL (r = 0.28; P < 0.001). Sleep improvement weakly correlated with improved "Off" time (r = 0.37; P < 0.001) and QoL (r = 0.36; P < 0.001). Regression analyses demonstrated significant positive associations for improved sleep, "Off" time, QoL, and m-EDL. CONCLUSIONS: Improved sleep with foslevodopa/foscarbidopa was associated with improved QoL and "Off" time.

Brain age as a biomarker for pathological versus healthy ageing - a REMEMBER study.

OBJECTIVES: This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. METHODS: The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject. RESULTS: MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers. CONCLUSIONS: Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health.

Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine.

Homozygous mutations in SLC4A4, encoding the electrogenic Na(+)-HCO(3)(-) cotransporter NBCe1, have been known to cause proximal renal tubular acidosis (pRTA) and ocular abnormalities. In this study, we report two sisters with pRTA, ocular abnormalities, and hemiplegic migraine. Genetic analysis ruled out pathological mutations in the known genes for familial hemiplegic migraine, but identified a homozygous 65-bp deletion (Delta65bp) in the C terminus of NBCe1, corresponding to the codon change S982NfsX4. Several heterozygous members of this family also presented glaucoma and migraine with or without aura. Despite the normal electrogenic activity in Xenopus oocytes, the Delta65bp mutant showed almost no transport activity due to a predominant cytosolic retention in mammalian cells. Furthermore, coexpression experiments uncovered a dominant negative effect of the mutant through hetero-oligomer formation with wild-type NBCe1. Among other pRTA pedigrees with different NBCe1 mutations, we identified four additional homozygous patients with migraine. The immunohistological and functional analyses of these mutants demonstrate that the near total loss of NBCe1 activity in astrocytes can cause migraine potentially through dysregulation of synaptic pH.

Recommendations for a paradigm shift in approach to increase the recognition and treatment of sialorrhea in Parkinson's disease.

Sialorrhea, or drooling, is defined as excessive saliva accumulation and unwanted loss of saliva from the mouth or over the tongue and into the pharynx. It constitutes one of the most frequent and bothersome complaints of patients with Parkinson's disease (PD), affecting up to 84% of them. Sialorrhea is a distressing and challenging condition that may result in social isolation, embarrassment, depression, skin infections, poor oral health, and aspiration pneumonia. To better understand the burden of sialorrhea on patients with PD, Parkinson's Europe carried out a worldwide patient survey which showed that sialorrhea remains an underrecognized and undertreated issue in patients with PD. This is especially problematic because effective therapeutic options are available. This article presents the results of the Parkinson's Europe Sialorrhea Survey, which were considered by a multidisciplinary panel of experts to provide recommendations for improving the awareness, diagnosis, management, and treatment of sialorrhea in patients with PD. A shift in the treatment paradigm for sialorrhea in patients with PD is emerging. It is essential to better educate patients, family members, caregivers, and healthcare professionals about sialorrhea; to engage all those involved to actively discuss sialorrhea and measure its impact on quality of life; and to recognize the role of botulinum toxin and speech and language therapy as first-line therapies.

The Lived Experiences of People with Progressive Supranuclear Palsy and Their Caregivers.

INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder initially characterised by disturbances in gait, balance and posture, with death occurring after several years of progressive physical and cognitive decline. This, along with a low index of suspicion, a high degree of diagnostic uncertainty and no approved treatment options, greatly impacts the lives of patients and caregivers. This research was conducted to (i) gain insight into the clinical and emotional journey of patients with PSP, (ii) assess experiences and perspectives, (iii) understand disease impact and (iv) identify key challenges and unmet needs. METHODS: A literature search and qualitative interviews with six PSP experts were conducted to map the clinical pathway and identify breakpoints. The pathway was validated by key opinion leaders in seven countries. Qualitative research was conducted over 6 months in seven countries with PSP stakeholders (N = 112) to explore the emotional journey. The approach included self-ethnography, 60-min telephone interviews and the completion of 7-day smartphone diaries. RESULTS: The current PSP clinical journey can take many different pathways, with patients cycling through the healthcare system before a correct referral is made and a possible/probable diagnosis received. Breakpoints contribute to delays in accessing appropriate clinical care, a high degree of diagnostic divergence and suboptimal management of the disease. The emotional journey is dominated by negative feelings, although some moments of positivity were noted. The research highlighted a lack of disease understanding amongst all stakeholders and a lack of support for patients/caregivers. The authors make a number of recommendations for care improvements, including longer consultation times, closer collaboration among healthcare professionals and patient organisations, and more varied support and information for patients/caregivers. CONCLUSION: This work represents a major collaborative effort to understand the lived experience of PSP. The research illustrates that a coordinated effort from all stakeholders is required to address ongoing needs and challenges within PSP.

Progressive supranuclear palsy (PSP) is a rare brain disorder caused by damaged nerve cells. PSP is often misdiagnosed as Parkinson's disease. Sufferers typically have issues with walking, eye movement, mood and memory, all of which worsen over time, and they often become entirely dependent on caregivers. Sadly, there is no cure, but day-to-day living can be supported. In this study, the researchers wanted to understand the lived experience of patients and families. First, researchers collected information from published sources about what it is like to live with PSP. Then they spoke with PSP experts, key opinion leaders, patients, caregivers, patient organisations, neurologists and nurses in the UK, France, Italy, Germany, Spain, the USA and Japan. This revealed important learnings about the clinical and emotional journey in PSP. There is a need for patients, caregivers and healthcare professionals to have open dialogue and build trust. Moreover, a closer collaboration between patient organisations and healthcare professionals could lead to improved care. Caregivers emerged as invisible heroes, and PSP care must prioritise support for them, in addition to patients. This study provides invaluable insights into the lived experience of patients and caregivers, as well as recommendations for supporting their clinical and emotional journey.

Effectiveness and safety of safinamide in routine clinical practice in a Belgian Parkinson's disease population: an open-label, levodopa add-on study.

BACKGROUND: Safinamide is a recent multimodal antiparkinsonian drug that inhibits monoamine oxidase B and modulates the glutamatergic system with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). This post-hoc analysis of the European SYNAPSES study provides first-time data on the use of safinamide in routine clinical practice in Belgium. OBJECTIVE: To describe the efficacy and safety of safinamide in Belgian PD patients in real-life conditions. METHODS: Post-hoc analysis of the Belgian cohort from the European SYNAPSES trial, which was an observational, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months. Analyses were performed in the overall population and according to different criteria such as the age limit (> 75 years), presence or absence of relevant comorbidities, presence or absence of psychiatric conditions such as depression and anxiety, patients on levodopa monotherapy or levodopa in combination with other treatments, patients on rasagiline before inclusion or not. RESULTS: Of the 172 patients included, 29.2% were > 75 years, 58.9% had relevant comorbidities and 32.7% had psychiatric conditions. Almost all the patients reported motor (98.8%) or non-motor (86.3%) symptoms. During the study, 36.3% of patients reported drug-related reactions. The adverse drug reactions were those already described in the patients' information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroups of patients. Almost 35% of the patients demonstrated a clinically significant improvement in the UPDRS and 50% of the patients with wearing-off at baseline, did not report wearing-off anymore after one year of treatment. Patients under levodopa monotherapy compared to patients receiving levodopa combined with other antiparkinsonian treatments benefit more from safinamide treatment. Patients switched from rasagiline to safinamide seemed also to benefit more from safinamide treatment. CONCLUSION: The study confirms the excellent safety and efficacy profile of safinamide, particularly in more vulnerable groups of patients such as the elderly and patients with significant comorbidities or psychiatric conditions such as depression or anxiety.

Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders.

Background and Objectives: Owing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset neurologic disorders. Methods: From January 2019 through April 2022, ES-based multigene panel testing was conducted in 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital. Gene panels were developed for ataxia and spasticity, leukoencephalopathy, movement disorders, paroxysmal episodic disorders, neurodegeneration with brain iron accumulation, progressive myoclonic epilepsy, and amyotrophic lateral sclerosis. Single nucleotide variants, small indels, and copy number variants were analyzed. Across all panels, our analysis covered a total of 725 genes associated with Mendelian inheritance. Results: A molecular diagnosis was established in 10% of the cases (144 of 1,411) representing 71 different monogenic disorders. The diagnostic yield depended significantly on the presenting phenotype with the highest yield seen in patients with ataxia or spastic paraparesis (19%). Most of the established diagnoses comprised disorders with an autosomal dominant inheritance (62%), and the most frequently mutated genes were NOTCH3 (13 patients), SPG7 (11 patients), and RFC1 (8 patients). 34% of the disease-causing variants were novel, including a unique likely pathogenic variant in APP (Ghent mutation, p.[Asn698Asp]) in a family presenting with stroke and severe cerebral white matter disease. 7% of the pathogenic variants comprised copy number variants detected in the ES data and confirmed by an independent technique. Discussion: ES and multigene panel testing is a powerful and efficient tool to diagnose patients with unexplained, adult-onset neurologic disorders.

Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson's Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study.

INTRODUCTION: Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. METHODS: Male and female patients with levodopa-responsive PD and ≥ 2.5 hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250 mg of LD per 24 hours) for 52 weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). RESULTS: Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. CONCLUSION: Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03781167.

Safinamide in the treatment pathway of Parkinson's Disease: a European Delphi Consensus.

Safinamide is a highly selective, reversible MAO B-inhibitor recently marketed in European and North American countries. To better define clinical indications regarding motor and non-motor symptoms, targeted population and safety of this compound, ten movement disorders specialists, experts in their field, convened and developed a panel of statements on: the role of glutamate in Parkinson's disease, introduction to fluctuations, efficacy of safinamide on motor symptoms, motor complications and non-motor symptoms, quality of life, safety of safinamide and target population for use. Strong consensus was reached for all the statements on the efficacy of safinamide on motor symptoms, motor fluctuations, quality of life and safety. Among non-motor symptoms, a positive consensus was reached for the symptoms sleep/fatigue, mood, and pain while there was a lack of consensus for the statements regarding the efficacy of safinamide in improving cognition, urinary and sexual functions. The statement on orthostatic hypotension obtained a negative consensus. The consistent and large agreement reached in this Delphi panel perfectly reflects the perception of efficacy, safety and tolerability of safinamide as evident from pivotal trials and clinical practice and shows how these findings may guide movement disorders specialists in their clinical therapeutic approach. The impact of non-motor symptoms in PD is considerable, and management remains an unmet need. In this context, the ability of safinamide to impact some non-motor symptoms may represent the most promising and distinctive feature of this compound and deserves further investigations.

Neurons generated from APP/APLP1/APLP2 triple knockout embryonic stem cells behave normally in vitro and in vivo: lack of evidence for a cell autonomous role of the amyloid precursor protein in neuronal differentiation.

Alzheimer's disease amyloid precursor protein (APP) has been implicated in many neurobiologic processes, but supporting evidence remains indirect. Studies are confounded by the existence of two partially redundant APP homologues, APLP1 and APLP2. APP/APLP1/APLP2 triple knockout (APP tKO) mice display cobblestone lissencephaly and are perinatally lethal. To circumvent this problem, we generated APP triple knockout embryonic stem (ES) cells and differentiated these to APP triple knockout neurons in vitro and in vivo. In comparison with wild-type (WT) ES cell-derived neurons, APP tKO neurons formed equally pure neuronal cultures, had unaltered in vitro migratory capacities, had a similar acquisition of polarity, and were capable of extending long neurites and forming active excitatory synapses. These data were confirmed in vivo in chimeric mice with APP tKO neurons expressing the enhanced green fluorescent protein (eGFP) present in a WT background brain. The results suggest that the loss of the APP family of proteins has no major effect on these critical neuronal processes and that the apparent multitude of functions in which APP has been implicated might be characterized by molecular redundancy. Our stem cell culture provides an excellent tool to circumvent the problem of lack of viability of APP/APLP triple knockout mice and will help to explore the function of this intriguing protein further in vitro and in vivo.

Parkinson's disease patients' short chain fatty acids production capacity after in vitro fecal fiber fermentation.

Animal models indicate that butyrate might reduce motor symptoms in Parkinson's disease. Some dietary fibers are butyrogenic, but in Parkinson's disease patients their butyrate stimulating capacity is unknown. Therefore, we investigated different fiber supplements' effects on short-chain fatty acid production, along with potential underlying mechanisms, in Parkinson's patients and age-matched healthy controls. Finally, it was investigated if this butyrate production could be confirmed by using fiber-rich vegetables. Different fibers (n = 40) were evaluated by in vitro fermentation experiments with fecal samples of Parkinson's patients (n = 24) and age-matched healthy volunteers (n = 39). Short-chain fatty acid production was analyzed by headspace solid-phase micro-extraction gas chromatography-mass spectrometry. Clostridium coccoides and C. leptum were quantified through 16S-rRNA gene-targeted group-specific qPCR. Factors influencing short-chain fatty acid production were investigated using linear mixed models. After fiber fermentation, butyrate concentration varied between 25.6 ± 16.5 µmol/g and 203.8 ± 91.9 µmol/g for Parkinson's patients and between 52.7 ± 13.0 µmol/g and 229.5 ± 42.8 µmol/g for controls. Inulin had the largest effect, while xanthan gum had the lowest production. Similar to fiber supplements, inulin-rich vegetables, but also fungal ß-glucans, stimulated butyrate production most of all vegetable fibers. Parkinson's disease diagnosis limited short-chain fatty acid production and was negatively associated with butyrate producers. Butyrate kinetics during 48 h fermentation demonstrated a time lag effect in Parkinson's patients, especially in fructo-oligosaccharide fermentation. Butyrate production can be stimulated in Parkinson's patients, however, remains reduced compared to healthy controls. This is a first step in investigating dietary fiber's potential to increase short-chain fatty acids in Parkinson's disease.

Impaired Weight-Shift Amplitude in People with Parkinson's Disease with Freezing of Gait.

BACKGROUND: People with Parkinson's disease and freezing of gait (FOG; freezers) suffer from pronounced postural instability. However, the relationship between these phenomena remains unclear and has mostly been tested in paradigms requiring step generation. OBJECTIVE: To determine if freezing-related dynamic balance deficits are present during a task without stepping and determine the influence of dopaminergic medication on dynamic balance control. METHODS: Twenty-two freezers, 16 non-freezers, and 20 healthy age-matched controls performed mediolateral weight-shifts at increasing frequencies when following a visual target projected on a screen (MELBA task). The amplitude and phase shift differences between center of mass and target motion were measured. Balance scores (Mini-BESTest), 360° turning speed and the freezing ratio were also measured. Subjects with Parkinson's disease were tested ON and partial OFF (overnight withdrawal) dopaminergic medication. RESULTS: Freezers had comparable turning speed and balance scores to non-freezers and took more levodopa. Freezers produced hypokinetic weight-shift amplitudes throughout the MELBA task compared to non-freezers (p = 0.002), which were already present at task onset (p < 0.001). Freezers also displayed an earlier weight-shift breakdown than controls when OFF-medication (p = 0.008). Medication improved mediolateral weight-shifting in freezers and non-freezers. Freezers decreased their freezing ratio in response to medication. CONCLUSION: Hypokinetic weight-shifting proved a marked postural control deficit in freezers, while balance scores and turning speed were similar to non-freezers. Both weight-shift amplitudes and the freezing ratio were responsive to medication in freezers, suggesting axial motor vigor is levodopa-responsive. Future work needs to test whether weight-shifting and freezing severity can be further ameliorated through training.

A European Observational Study to Evaluate the Safety and the Effectiveness of Safinamide in Routine Clinical Practice: The SYNAPSES Trial.

BACKGROUND: Safinamide modulates both dopaminergic and glutamatergic systems with positive effects on motor and non-motor symptoms of Parkinson's disease (PD). The drug utilization study SYNAPSES was designed to investigate the use of safinamide in routine clinical practice, as recommended by the European Medicines Agency. OBJECTIVE: To describe the occurrence of adverse events in PD patients treated with safinamide in real-life conditions. METHODS: The SYNAPSES trial is an observational, European, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months with analyses performed in the overall population and in patients aged >75 years, with relevant comorbidities and with psychiatric conditions. RESULTS: Of the 1610 patients included, 82.4% were evaluable after 12 months with 25.1% of patients >75 years, 70.8% with relevant comorbidities and 42.4% with psychiatric conditions. During observation 45.8% patients experienced adverse events, 27.7% patients had adverse drug reactions and 9.2% patients had serious adverse events. The adverse events were those already described in the patients' information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroup of patients. Clinically significant improvements were seen in the UPDRS motor score and in the UPDRS total score in ≥40% of patients, according to the criteria developed by Shulman et al.Conclusion:The SYNAPSES study confirms the good safety profile of safinamide even in special groups of patients. Motor complications and motor scores improved with clinically significant results in the UPDRS scale maintained in the long-term.

Diagnostic Performance of Automated MRI Volumetry by icobrain dm for Alzheimer's Disease in a Clinical Setting: A REMEMBER Study.

BACKGROUND: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer's disease (AD) dementia (ADD) patients in selected research cohorts. OBJECTIVE: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis. METHODS: The study population included HC (n = 90), subjective cognitive decline (SCD, n = 93), mild cognitive impairment (MCI, n = 357), and ADD (n = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm's (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages. RESULTS: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%). CONCLUSION: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting.

Multivariate analysis reveals anatomical correlates of naming errors in primary progressive aphasia.

Primary progressive aphasia (PPA) is an overarching term for a heterogeneous group of neurodegenerative diseases which affect language processing. Impaired picture naming has been linked to atrophy of the anterior temporal lobe in the semantic variant of PPA. Although atrophy of the anterior temporal lobe proposedly impairs picture naming by undermining access to semantic knowledge, picture naming also entails object recognition and lexical retrieval. Using multivariate analysis, we investigated whether cortical atrophy relates to different types of naming errors generated during picture naming in 43 PPA patients (13 semantic, 9 logopenic, 11 nonfluent, and 10 mixed variant). Omissions were associated with atrophy of the anterior temporal lobes. Semantic errors, for example, mistaking a rhinoceros for a hippopotamus, were associated with atrophy of the left mid and posterior fusiform cortex and the posterior middle and inferior temporal gyrus. Semantic errors and atrophy in these regions occurred in each PPA subtype, without major between-subtype differences. We propose that pathological changes to neural mechanisms associated with semantic errors occur across the PPA spectrum.

MicroRNA regulation of Alzheimer's Amyloid precursor protein expression.

Gene dosage effects of Amyloid precursor protein (APP) can cause familial AD. Recent evidence suggest that microRNA (miRNA) pathways, implicated in gene transcriptional control, could be involved in the development of sporadic Alzheimer's disease (AD). We therefore investigated whether miRNAs could participate in the regulation of APP gene expression. We show that miRNAs belonging to the miR-20a family (that is, miR-20a, miR-17-5p and miR-106b) could regulate APP expression in vitro and at the endogenous level in neuronal cell lines. A tight correlation between these miRNAs and APP was found during brain development and in differentiating neurons. We thus identify miRNAs as novel endogenous regulators of APP expression, suggesting that variations in miRNA expression could contribute to changes in APP expression in the brain during development and disease. This possibility is further corroborated by the observation that a statistically significant decrease in miR-106b expression was found in sporadic AD patients.

Myoclonus-dystonia: Distinctive motor and non-motor phenotype from other dystonia syndromes.

BACKGROUND: Myoclonus-dystonia (M-D) due to a pathogenic variant of SGCE is an autosomal dominant inherited movement disorder. Apart from motor symptoms, psychiatric disorders are highly prevalent in patients with M-D. Previous studies suggest, but never tested directly, that the type of psychiatric disorder differs between dystonia syndromes, probably related to disease specific pathology. Little is known about other non-motor symptoms (NMS) in M-D. Here, we systematically study NMS in M-D in direct comparison to other types of dystonia and healthy controls. METHODS: Standardized questionnaires were used to assess type and severity of psychiatric co-morbidity, sleep problems, fatigue and quality of life. Results of M-D patients with a pathogenic variant of SGCE were compared to results of idiopathic cervical dystonia (CD) patients, dopa-responsive dystonia (DRD) patients with a pathogenic variant of GCH1 and controls. RESULTS: We included 164 participants: 41 M-D, 51 CD, 19 DRD patients, 53 controls. Dystonia patients (M-D, CD and DRD) had an increased prevalence of psychiatric disorders compared to controls (56-74% vs. 29%). In M-D we found a significantly increased prevalence of obsessive-compulsive disorder (OCD) and psychosis compared to CD and DRD. All dystonia patients had more sleep problems (49-68% vs. 36%) and fatigue (42-73% vs. 15%) than controls. Compared to other dystonia subtypes, M-D patients reported less excessive daytime sleepiness and fatigue. CONCLUSION: Psychiatric comorbidity is frequent in all dystonia types, but OCD and psychosis are more common in M-D patients. Further research is necessary to elucidate underlying pathways.