Increased glucosylsphingosine levels and Gaucher disease in GBA1-associated Parkinson's disease.

INTRODUCTION: Gaucher's disease (GD) is caused by biallelic mutations in the GBA1 gene, leading to reduced glucocerebrosidase (GCase) activity and substrate (glucosylceramide and glucosylsphingosine, GlcSph) accumulation. GBA1 variant carriers are at risk of Parkinson's disease (PD), but only those with biallelic mutations cross the threshold of GCase reduction, leading to substrate accumulation and GD. The link between GBA1 mutations, GD and PD is not fully understood. Here we aimed at reporting the results of a large PD population screening with dried blood spot tests for GD. METHODS: We measured GCase activity and GlcSph levels in 1344 PD patients with dried blood spot tests, and performed GBA1 genetic sequencing. RESULTS: While the GCase activity was reduced in GBA1-PD carriers compared to wild type PD, GlcSph was increased in GBA1-PD compared to GBA1-controls, regardless of the underlying type of GBA1 variant. 13.6 % and 0.4 % of PD patients had mono- or biallelic GBA1 mutations respectively. GCase deficiency, lipid accumulation and clinical manifestations of GD was detected in five PD patients with biallelic GBA1 mutations, of whom four had a risk combined with a GD causing variant. CONCLUSIONS: GlcSph appearing higher in PD may represent a reliable biomarker of the disease and deserves to be further investigated. This study highlights the importance of screening PD patients for possible underlying GD, which is a treatable condition that should not be missed. We diagnosed GD cases carrying a "risk" variant in one allele, which is an unprecedented finding deserving further investigation.

The chronic use of serotonin norepinephrine reuptake inhibitors facilitates dyskinesia priming in early Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) patients are frequently exposed to antidepressant medications (ADMs). Norepinephrine (NE) and serotonin (5HT) systems have a role in levodopa-induced dyskinesias (LID) pathophysiology. METHODS: We performed a longitudinal analysis on the PPMI cohort including drug-naïve PD patients, who are progressively exposed to dopamine replacement therapies (DRTs) to test the effect of ADM exposure on LID development by the 4th year of follow-up. RESULTS: LID prevalence (according to MDS UPDRS score 4.1 ≥ 1) was 16% (42/251); these patients were more likely women (p = 0.01), had higher motor (p < 0.001) and depression scores (p = 0.01) and lower putaminal DAT binding ratio (p = 0.01). LID were associated with the exposure time to L-DOPA (2.2 ± 1.07 vs 2.6 ± 0.9, p = 0.02) and to the exposure to ADMs, in particular to SNRI (4.8% vs 21.4%, p < 0.001). The latter persisted after correcting for significant covariates (e.g., disease duration, cognitive status, motor impairment, depression, dopaminergic denervation). A similar difference in LID prevalence in PD patients exposed vs non-exposed to SNRI was observed on matched data by the real-world TriNetX repository (22% vs 13%, p < 0.001). DISCUSSION: This study supports the presence of an effect of SNRI on LID priming in patients with early PD. Independent prospective cohort studies are warranted to further verify such association.

Emotional atypical arousal ratings for unpleasant stimuli in patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including alteration in emotional processing and recognition of emotions. We explored the effects of PD on the emotional behavioral ratings using a battery of affective visual stimuli selected from the International Affective Picture System (IAPS). METHODS: Twenty-two patients diagnosed with idiopathic PD and 22 healthy controls (HC), matched by age, gender, and education, were enrolled in the study. Following a clinical assessment, each participant was asked to evaluate the arousal and valence of affective visual stimuli, and response time was recorded. Disease-specific measures including the MDS Unified Parkinson's Disease Rating Scale (MDS UPDRS) and the Non-Motor Symptom Scale (NMSS) were also collected. RESULTS: PD patients exhibited higher arousal responses compared to HC for negative/unpleasant pictures (scoring 7.32 ± 0.88 vs 5.43 ± 2.06, p < 0.001). The arousal response to negative/unpleasant pictures was correlated with measures of non-motor burden in PD (MDS UPDRS I and NMSS, rho = 0.480 and p = 0.023, rho = 0.533 and p = 0.010, respectively). CONCLUSION: Impaired emotional processing characterizes PD patients with mild disease and is related to the non-motor symptom burden. Given the importance of emotional processing for the development and maintenance of close interpersonal relationship and for coping with specific medical situations, it is crucial to direct PD patients towards therapeutic interventions focused on the recognition and processing of emotions.

Transcranial direct current stimulation in semantic variant of primary progressive aphasia: a state-of-the-art review.

The semantic variant of primary progressive aphasia (svPPA), known also as "semantic dementia (SD)," is a neurodegenerative disorder that pertains to the frontotemporal lobar degeneration clinical syndromes. There is currently no approved pharmacological therapy for all frontotemporal dementia variants. Transcranial direct current stimulation (tDCS) is a promising non-invasive brain stimulation technique capable of modulating cortical excitability through a sub-threshold shift in neuronal resting potential. This technique has previously been applied as adjunct treatment in Alzheimer's disease, while data for frontotemporal dementia are controversial. In this scoped review, we summarize and critically appraise the currently available evidence regarding the use of tDCS for improving performance in naming and/or matching tasks in patients with svPPA. Clinical trials addressing this topic were identified through MEDLINE (accessed by PubMed) and Web of Science, as of November 2022, week 3. Clinical trials have been unable to show a significant benefit of tDCS in enhancing semantic performance in svPPA patients. The heterogeneity of the studies available in the literature might be a possible explanation. Nevertheless, the results of these studies are promising and may offer valuable insights into methodological differences and overlaps, raising interest among researchers in identifying new non-pharmacological strategies for treating svPPA patients. Further studies are therefore warranted to investigate the potential therapeutic role of tDCS in svPPA.

A smart devices based secondary prevention program for cerebrovascular disease patients.

Background: Commercially available health devices are gaining momentum and represent a great opportunity for monitoring patients for prolonged periods. This study aimed at testing the feasibility of a smart device-based secondary prevention program in a cohort of patients with cryptogenic stroke. Methods: In this proof-of-principle study, patients with non-disabling ischemic stroke and transient ischemic attacks (TIA) in the subacute phase were provided with a smartwatch and smart devices to monitor several parameters - i.e., oxygen saturation, blood pressure, steps a day, heart rate and heart rate variability - for a 4-week period (watch group). This group was compared with a standard-of-care group. Our primary endpoint was the compliance with the use of smart devices that was evaluated as the number of measures performed during the observation period. Results: In total, 161 patients were recruited, 87 in the WATCH group and 74 in the control group. In the WATCH group, more than 90% of patients recorded the ECG at least once a day. In total, 5,335 ECGs were recorded during the study. The median blood pressure value was 132/78 mmHg and the median oxygen saturation value was 97%. From a clinical standpoint, although not statistically significant, nine atrial fibrillation episodes (10.3%) in the WATCH group vs. 3 (4%) in the control group were detected. Conclusion: Our study suggests that prevention programs for cerebrovascular disease may benefit from the implementation of new technologies.

Circadian profile, daytime activity, and the Parkinson's phenotype: A motion sensor pilot study with neurobiological underpinnings.

Circadian rhythm impairment may play a role in Parkinson's disease (PD) pathophysiology. Recent literature associated circadian rhythm features to the risk of developing Parkinson and to its progression through stages. The association between the chronotype and the phenotype should be verified on a clinical and biological point of view. Herein we investigate the chronotype of a sample of 50 PD patients with the Morningness Eveningness Questionnaire and monitor their daily activity with a motion sensor embedded in a smartphone. Fibroblasts were collected from PD patients (n = 5) and from sex/age matched controls (n = 3) and tested for the circadian expression of clock genes (CLOCK, BMAL1, PER1, CRY1), and for cell morphology, proliferation, and death. Our results show an association between the chronotype and the PD phenotype. The most representative clinical chronotypes were "moderate morning" (56%), the "intermediate" (24%) and, in a minor part, the "definite morning" (16%). They differed for axial motor impairment, presence of motor fluctuations and quality of life (p < 0.05). Patients with visuospatial dysfunction and patients with a higher PIGD score had a blunted motor daily activity (p = 0.006 and p = 0.001, respectively), independently by the influence of age and other motor scores. Fibroblasts obtained by PD patients (n = 5) had an impaired BMAL1 cycle compared to controls (n = 3, p = 0.01). Moreover, a PD flat BMAL1 profile was associated with the lowest cell proliferation and the largest cell morphology. This study contributes to the growing literature on CR abnormalities in the pathophysiology of Parkinson's disease providing a link between the clinical and biological patient chronotype and the disease phenomenology.

Leg restlessness and hyperparathyroidism in Parkinson's disease, a further clue to RLS pathogenesis?

Background: Non-motor manifestations are the main features of Parkinson's disease (PD). These have been associated with vitamin D abnormalities, but the role of parathormone (PTH) is still obscure. Among the non-motor symptoms of PD, the pathogenesis of restless leg syndrome (RLS) is still debated, but it has been associated with the vitamin D/PTH axis in other disease models. Our study deepens the association between vitamin D and PTH with the prevalence of non-motor symptoms of PD and explores such a relationship in patients reporting leg restlessness. Methods: Fifty patients with PD were extensively investigated with motor and non-motor scales. Data on serum levels of vitamin D, PTH, and related metabolites were obtained, and patients were stratified as having vitamin D deficiency or hyperparathyroidism according to standardized criteria. Results: Overall, 80% of patients with PD exhibited low vitamin D levels, and hyperparathyroidism was diagnosed in 45%. The analysis of the non-motor symptoms profile using the non-motor symptom questionnaire (NMSQ) revealed 36% of leg restlessness, a main feature of RLS. This was significantly associated with worse motor symptoms, quality of sleep, and quality of life. Moreover, it was associated with hyperparathyroidism (OR: 3.48) and with PTH levels, independent of vitamin D, calcium/phosphate levels, and motor status. Conclusion: Our results suggest a significant association between the vitamin D/PTH axis and leg restlessness in PD. PTH has a putative role in nociceptive modulation, and previous evidence on hyperparathyroidism has suggested a possible interrelation with RLS. Further investigations are necessary to add PTH to the non-dopaminergic non-motor landscape of PD.

Deep brain stimulation of the dentato-rubro-thalamic tract in a case of Holmes tremor: a constrained spherical deconvolution (CSD)-guided procedure.

Deep brain stimulation (DBS) is an established treatment for movement disorders, including Holmes tremor (HT). HT is a rest and action tremor that occurs as a late symptom of brainstem lesions such as stroke. Unfortunately, it is frequently refractory to medical treatment, hence DBS surgery may be a good option. Due to variable results, the ideal target for DBS in HT still remains to be established, ranging from the thalamus to the globus pallidus internus, to the subthalamic nucleus. Pre-operative imaging also is very challenging, as the complexity of brain fiber architecture may prevent the correct positioning of the directional lead. Herein, we describe the case of a patient affected by a rubral tremor secondary to a brain hemorrhage, who had advanced pre-operative neuroimaging with constrained spherical deconvolution (CSD)-based tractography obtained from diffusion-weighted imaging (DWI) to identify the dentato-rubro-thalamic tract, involved in the pathophysiology of HT. The patient was then addressed to an awake DBS surgery, and with the help of intraoperative microelectrode recordings, a tailored DRTT-targeted procedure was performed. The stimulation determined an almost complete tremor suppression, with no significant side effects at a follow-up of 6 months, paving the way towards new effective techniques for the planning, i.e., CSD-based tractography and the treatment of refractory tremors.

Oligomeric α-synuclein and tau aggregates in NDEVs differentiate Parkinson's disease from atypical parkinsonisms.

The early differential diagnosis of Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), is challenging because of an overlap of clinical features and the lack of reliable biomarkers. Neural-derived extracellular vesicles (NDEVs) isolated from blood provide a window into the brain's biochemistry and may assist in distinguishing between PD and APS. We verified in a case-control study whether oligomeric α-Synuclein and Tau aggregates isolated from NDEVs could allow the differential diagnosis of these conditions. Blood sampling and clinical data, including disease duration, motor severity, global cognition, and levodopa equivalent daily dose (LEDD), were collected from patients with a diagnosis of either PD (n = 70), PSP (n = 21), or CBD (n = 19). NDEVs were isolated from serum by immunocapture using an antibody against the neuronal surface marker L1CAM; oligomeric α-Synuclein and aggregated Tau were measured by ELISA. NDEVs analyses showed that oligomeric α-Synuclein is significantly augmented in PD compared to APS, whereas Tau aggregates are significantly increased in APS compared to PD (p < 0.0001). ROC analyses showed that these two biomarkers have a "good" power of classification (p < 0.0001 for both proteins), with high sensitivity and specificity, with NDEVs concentration of Tau aggregates and oligomeric α-Synuclein being respectively the best biomarker for PD/PSP and PD/CBD diagnostic differentiation. Logistic and multiple regression analysis confirmed that NDEVs-derived oligomeric α-Synuclein and Tau aggregates differentiate PD from CBD and PSP (p < 0.001). Notably, a positive correlation between NDEVs oligomeric α-Synuclein and disease severity (disease duration, p = 0.023; Modified H&Y, p = 0.015; UPDRS motor scores, p = 0.004) was found in PD patients and, in these same patients, NDEVs Tau aggregates concentration inversely correlated with global cognitive scores (p = 0.043). A minimally invasive blood test measuring the concentration of α-synuclein and Tau aggregates in NDEVs can represent a promising tool to distinguish with high sensitivity and specificity PD from CBD or PSP patients. Optimization and validation of these data will be needed to confirm the diagnostic value of these biomarkers in distinguishing synucleinopathies from taupathies.

Posterior Reversible Encephalopathy Syndrome and brain haemorrhage as COVID-19 complication: a review of the available literature.

BACKGROUND: SARS-CoV-2 infection has been associated with various neurological manifestations. Since patients affected by SARS-CoV-2 infection present coagulation and immune system dysregulation, ischemic or haemorragic stroke is not uncommon, irrespective of respiratory distress. However, the occurrence of focal neurological deficits together with other symptoms like headache, cortical blindness, seizure and altered mental status should prompt the diagnosis of Posterior Reversible Encephalopathy Syndrome (PRES). Antithrombotic treatment, the alteration of endothelial function, and coagulopathy due to COVID-19 and PRES leading to the breakdown of blood-brain barrier may then contribute to the occurrence of a brain haemorrhage. METHODS: We describe the case of a COVID-19 patient who developed bilateral occipital lobe haemorrhages suggestive of haemorrhagic PRES. We then reviewed the available literature about haemorrhagic evolution of PRES in COVID-19. RESULTS: We describe the clinical and radiological features of five COVID-19 patients who developed haemorrhagic PRES. CONCLUSIONS: Coagulopathy and endothelial dysfunction resulting from the massive release of cytokines during the host immune response may be key factors in the pathogenesis of COVID-19-related PRES. Antithrombotic therapy and the leakage of the blood-brain barrier can subsequently increase the risk of haemorrhagic transformation of the lesioned brain tissue. A prompt diagnosis of PRES is mandatory, since the timely interruption/reversal of antithrombotic therapy may be a key determinant for a good prognosis.

The effects of transcutaneous auricular vagal nerve stimulation on pupil size.

OBJECTIVE: Mechanisms of action and optimal stimulation parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are currently unknown. Pupil size has gained attention as a promising biomarker of vagal activation in different studies on animal models. The aim of this study is to investigate the effects of taVNS on pupil diameter in healthy subjects. METHODS: All subjects received taVNS at the left external acoustic meatus and control stimulation at the left earlobe during the same experimental session. Different intensities (0.5 mA; 1.0 mA; 2.0 mA; 3.0 mA) for both conditions were tested. Tonic pupil size was recorded in both eyes at baseline and during each stimulation using an infrared-automated pupillometer in three different illuminance conditions (scotopic, mesopic, photopic). RESULTS: In scotopic illuminance condition, a significant interaction between intensity and condition (real vs control) was found for the left eye. Post-Hoc analysis showed that during real taVNS at 2 mA, pupil size was significantly larger in comparison to baseline and 2 mA control stimulation. CONCLUSIONS: Our study demonstrates that taVNS induces pupil dilation under specific illuminance conditions and at specific stimulation intensity. SIGNIFICANCE: The effects of taVNS are strictly dependent on technical aspects, such as stimulation parameters and experimental set-up.

Temporal Lobe Epilepsy and Alzheimer's Disease: From Preclinical to Clinical Evidence of a Strong Association.

Increasing evidence coming from both experimental and humans' studies strongly suggest the existence of a link between epilepsy, in particular temporal lobe epilepsy (TLE), and Alzheimer's disease (AD). Patients with mild cognitive impairment and AD are more prone to have seizures, and seizures seem to facilitate amyloid-ß and tau deposits, thus promoting neurodegenerative processes. Consistent with this view, long-lasting drug-resistant TLE and AD have been shown to share several pathological and neuroimaging features. Even if studies addressing prevalence of interictal and subclinical epileptiform activity in these patients are not yet conclusive, their findings raise the possibility that epileptiform activity might negatively impact memory and hasten cognitive decline, either directly or by association with unrecognized silent seizures. In addition, data about detrimental effect of network hyperexcitability in temporal regions in the premorbid and early stages ofADopen up newtherapeutic opportunities for antiseizure medications and/or antiepileptic strategies that might complement or enhance existing therapies, and potentially modify disease progression. Here we provide a review of evidence linking epileptiform activity, network hyperexcitability, and AD, and their role promoting and accelerating neurodegenerative process. Finally, the effects of antiseizure medications on cognition and their optimal administration in patients with AD are summarized.

Remote smartphone gait monitoring and fall prediction in Parkinson's disease during the COVID-19 lockdown.

BACKGROUND: Falls could be serious events in Parkinson's disease (PD). Patient remote monitoring strategies are on the raise and may be an additional aid in identifying patients who are at risk of falling. The aim of the study was to evaluate if balance and timed-up-and-go data obtained by a smartphone application during COVID-19 lockdown were able to predict falls in PD patients. METHODS: A cohort of PD patients were monitored for 4 weeks during the COVID-19 lockdown with an application measuring static balance and timed-up-and-go test. The main outcome was the occurrence of falls (UPDRS-II item 13) during the observation period. RESULTS: Thirty-three patients completed the study, and 4 (12%) reported falls in the observation period. The rate of falls was reduced with respect to patient previous falls history (24%). The stand-up time and the mediolateral sway, acquired through the application, differed between "fallers" and "non-fallers" and related to the occurrence of new falls (OR 1.7 and 1.6 respectively, p < 0.05), together with previous falling (OR 7.5, p < 0.01). In a multivariate model, the stand-up time and the history of falling independently related to the outcome (p < 0.01). CONCLUSIONS: Our study provides new data on falls in Parkinson's disease during the lockdown. The reduction of falling events and the relationship with the stand-up time might suggest that a different quality of falls occurs when patient is forced to stay home - hence, clinicians should point their attention also on monitoring patients' sit-to-stand body transition other than more acknowledged features based on step quality.

COVID-19 in teriflunomide-treated patients with multiple sclerosis: A case report and literature review.

BACKGROUND: . Teriflunomide is an immunomodulatory drug approved for Multiple Sclerosis (MS) treatment that inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in the de novo pyrimidine synthesis pathway. This mechanism can produce antiviral effects, thus teriflunomide has gained attention during COVID-19 pandemic. Moreover, in the last months, some case-reports have been published describing MS patients treated with teriflunomide who developed mild and self-limiting forms of COVID-19. METHODS: Here, we describe the case of a 57-year-old man affected by MS, and treated with teriflunomide, who developed a mild form of SARS-CoV-2 infection. Moreover, we provide a detailed literature review about the available cases of COVID-19 in MS patients treated with teriflunomide. We report clinical features, disease course and outcome, and we discuss similarities and differences among patients. RESULTS: Apart from the present report, since February 2020, five papers have been published describing 14 MS patients who developed SARS-CoV-2 infection during teriflunomide treatment. Patients were mostly female (53%), with an average age of 50.5 (±11.3) years. Median EDSS was 2.25 (range 0-6). The average time on treatment with teriflunomide was 3.7 (± 1.6) years. Relevant comorbidities were present in 4 patients (27%). Regarding SARS-CoV-2 infection, the most common symptom was fever (100%) followed by gastrointestinal disturbances (67%), fatigue (55%) and cough (55%). 5 patients were hospitalized and 2 required oxygen support. In patient hospitalized (n=5) compared to the others (n=10), age was significantly higher (59.6 vs 45.9 years, p=0.025) while gender, EDSS, duration of teriflunomide therapy and comorbidities were not significantly different. Outcome was good for all patients with a variable recovery time, ranging from few days to some weeks. Teriflunomide was continued during the entire course of SARS-CoV-2 infection in all patients except for two. Compared to the patients already described, our patient was 7 years older, average time on teriflunomide treatment was about 2.5 years shorter, and median EDSS was 1.5 point lower. Despite significant comorbidities, the outcome was good since our patient was hospitalized but he did not require oxygen supplementation nor intensive care and was able to return at home after only 10 days. Teriflunomide therapy was continued throughout the period. CONCLUSION: Available data suggest that teriflunomide therapy should not be discontinued in MS patients who develop SARS-CoV-2 infection, also in presence of significant comorbidities or clinical conditions requiring hospitalization. Additional studies are necessary to assess if the drug can also have a protective role against SARS-CoV-2.

Parkinson's Disease Remote Patient Monitoring During the COVID-19 Lockdown.

Objective: To evaluate the feasibility of a smartphone remote patient monitoring approach in a real-life Parkinson's disease (PD) cohort during the Italian COVID-19 lockdown. Methods: Fifty-four non-demented PD patients who were supposed to attend the outpatient March clinic were recruited for a prospective study. All patients had a known UPDRS-III and a modified Hoehn and Yahr (H&Y) score and were provided with a smartphone application capable of providing indicators of gait, tapping, tremor, memory and executive functions. Different questionnaires exploring non-motor symptoms and quality of life were administered through phone-calls. Patients were asked to run the app at least twice per week (i.e., full compliance). Subjects were phone-checked weekly throughout a 3-week period for compliance and final satisfaction questionnaires. Results: Forty-five patients (83.3%) ran the app at least once; Twenty-nine (53.7%) subjects were half-compliant, while 16 (29.6%) were fully compliant. Adherence was hindered by technical issues or digital illiteracy (38.7%), demotivation (24%) and health-related issues (7.4%). Ten patients (18.5%) underwent PD therapy changes. The main factors related to lack of compliance included loss of interest, sadness, anxiety, the absence of a caregiver, the presence of falls and higher H&Y. Gait, tapping, tremor and cognitive application outcomes were correlated to disease duration, UPDRS-III and H&Y. Discussion: The majority of patients were compliant and satisfied by the provided monitoring program. Some of the application outcomes were statistically correlated to clinical parameters, but further validation is required. Our pilot study suggested that the available technologies could be readily implemented even with the current population's technical and intellectual resources.