Parkinson's disease and vitamins: a focus on vitamin B12.

Parkinson's disease (PD) has been linked to a vast array of vitamins among which vitamin B12 (Vit B12) is the most relevant and often investigated specially in the context of intrajejunal levodopa infusion therapy. Vit B12 deficiency, itself, has been reported to cause acute parkinsonism. Nevertheless, concrete mechanisms through which B12 deficiency interacts with PD in terms of pathophysiology, clinical manifestation and progression remains unclear. Recent studies have suggested that Vit B12 deficiency along with the induced hyperhomocysteinemia are correlated with specific PD phenotypes characterized with early postural instability and falls and more rapid motor progression, cognitive impairment, visual hallucinations and autonomic dysfunction. Specific clinical features such as polyneuropathy have also been linked to Vit B12 deficiency specifically in context of intrajejunal levodopa therapy. In this review, we explore the link between Vit B12 and PD in terms of physiopathology regarding dysfunctional neural pathways, neuropathological processes as well as reviewing the major clinical traits of Vit B12 deficiency in PD and Levodopa-mediated neuropathy. Finally, we provide an overview of the therapeutic effect of Vit B12 supplementation in PD and posit a practical guideline for Vit B12 testing and supplementation.

Addressing ethnic disparities in neurological research in the United Kingdom: An example from the prospective multicentre COVID-19 Clinical Neuroscience Study.

BACKGROUND: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection. METHODS: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment. RESULTS: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups. CONCLUSIONS: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here.

Musculoskeletal pain in Parkinson's disease: Association with dopaminergic deficiency in the caudate nucleus.

BACKGROUND: Musculoskeletal (MSK) pain affects over 80% of People with Parkinson's (PD, PwP) and may, in part, be dopaminergic in origin, as dopaminergic medication often leads to its relief. METHODS: PwP who underwent striatal dopamine transporter visualization with a radiopharmaceutical DaTscan™ (123 I-Ioflupane Injection) using a single-photon emission computed tomography (SPECT) as a part of their clinical-diagnostic work up were enrolled in the "Non-motor International Longitudinal Study" (NILS; UK National Institute for Health Research Clinical Research Network Number 10084) and included in this cross-sectional analysis. The association between specific DaTscan binding ratios for each striatum, the caudate nucleus and putamen and clinical ratings for MSK pain (assessed using the King's Parkinson's Disease Pain Scale (KPPS)) were analysed. RESULTS: 53 PwP (30.2% female; age: 63.79 ± 11.31 years; disease duration (DD): 3.32 (0.31-14.41) years; Hoehn & Yahr stage (H&Y): 2 (1-4); Levodopa Equivalent Daily Dose (LEDD): 543.08 ± 308.94 mg) were assessed and included in this analysis. MSK pain was highly prevalent (71.7% of all participants, mean KPPS Item 1 score 5.34 ± 4.76) and did not correlate with the motor symptoms burden (SCOPA-Motor total score; p = 0.783) but showed a significant correlation with quality of life (PDQ-8, rs = 0.290, p = 0.035). z-scores for the caudate nucleus (Exp (B) = 0.367, 95% CI for Exp (B) 0.148-0.910, p = 0.031) and striatum (Exp (B) = 0.338, 95% CI for Exp (B) 0.123-0.931, p = 0.036), adjusted for DD, H&Y and LEDD, were significant determinants of MSK pain. CONCLUSIONS: Our findings suggest an association between MSK pain in PwP and the severity of dopaminergic deficiency in the caudate nucleus. SIGNIFICANCE: In People with Parkinson's, musculoskeletal pain does not arise simply as a direct sequel to motor symptoms-instead, it is linked to the severity of dopaminergic depletion in the caudate nucleus.

Chaudhuri's Dashboard of Vitals in Parkinson's syndrome: an unmet need underpinned by real life clinical tests.

We have recently published the notion of the "vitals" of Parkinson's, a conglomeration of signs and symptoms, largely nonmotor, that must not be missed and yet often not considered in neurological consultations, with considerable societal and personal detrimental consequences. This "dashboard," termed the Chaudhuri's vitals of Parkinson's, are summarized as 5 key vital symptoms or signs and comprise of (a) motor, (b) nonmotor, (c) visual, gut, and oral health, (d) bone health and falls, and finally (e) comorbidities, comedication, and dopamine agonist side effects, such as impulse control disorders. Additionally, not addressing the vitals also may reflect inadequate management strategies, leading to worsening quality of life and diminished wellness, a new concept for people with Parkinson's. In this paper, we discuss possible, simple to use, and clinically relevant tests that can be used to monitor the status of these vitals, so that these can be incorporated into clinical practice. We also use the term Parkinson's syndrome to describe Parkinson's disease, as the term "disease" is now abandoned in many countries, such as the U.K., reflecting the heterogeneity of Parkinson's, which is now considered by many as a syndrome.

Non-motor symptoms in amyotrophic lateral sclerosis: lessons from Parkinson's disease.

Amyotrophic lateral sclerosis and Parkinson's disease are neurodegenerative diseases of the motor system which are now recognized also to affect non-motor pathways. Non-motor symptoms have been acknowledged as important determinants of quality of life in Parkinson's disease, and there is increasing interest in understanding the extent and role of non-motor symptoms in amyotrophic lateral sclerosis. We therefore reviewed what is known about non-motor symptoms in amyotrophic lateral sclerosis, using lessons from Parkinson's disease.

Revisiting Alpha-Synuclein Pathways to Inflammation.

Alpha-synuclein (α-Syn) is a short presynaptic protein with an active role on synaptic vesicle traffic and the neurotransmitter release and reuptake cycle. The α-Syn pathology intertwines with the formation of Lewy Bodies (multiprotein intraneuronal aggregations), which, combined with inflammatory events, define various α-synucleinopathies, such as Parkinson's Disease (PD). In this review, we summarize the current knowledge on α-Syn mechanistic pathways to inflammation, as well as the eventual role of microbial dysbiosis on α-Syn. Furthermore, we explore the possible influence of inflammatory mitigation on α-Syn. In conclusion, and given the rising burden of neurodegenerative disorders, it is pressing to clarify the pathophysiological processes underlying α-synucleinopathies, in order to consider the mitigation of existing low-grade chronic inflammatory states as a potential pathway toward the management and prevention of such conditions, with the aim of starting to search for concrete clinical recommendations in this particular population.

NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease.

OBJECTIVE: N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoantibody-mediated neurological syndrome with prominent cognitive and neuropsychiatric symptoms. The clinical relevance of NMDAR antibodies outside the context of encephalitis was assessed in this study. METHODS: Plasma from patients with Parkinson's disease (PD) (N=108) and healthy control subjects (N=89) was screened at baseline for immunoglobulin A (IgA), IgM, and IgG NMDAR antibodies, phosphorylated tau 181 (p-tau181), and the neuroaxonal injury marker neurofilament light (NfL). Clinical assessment of the patients included measures of cognition (Mini-Mental State Examination [MMSE]) and neuropsychiatric symptoms (Hospital Anxiety and Depression Scale; Non-Motor Symptoms Scale for Parkinson's Disease). A subgroup of patients (N=61) was followed annually for up to 6 years. RESULTS: Ten (9%) patients with PD tested positive for NMDAR antibodies (IgA, N=5; IgM, N=6; IgG, N=0), and three (3%) healthy control subjects had IgM NMDAR antibodies; IgA NMDAR antibodies were detected significantly more commonly among patients with PD than healthy control subjects (χ2=4.23, df=1, p=0.04). Age, gender, and disease duration were not associated with NMDAR antibody positivity. Longitudinally, antibody-positive patients had significantly greater decline in annual MMSE scores when the analyses were adjusted for education, age, disease duration, p-tau181, NfL, and follow-up duration (adjusted R2=0.26, p=0.01). Neuropsychiatric symptoms were not associated with antibody status, and no associations were seen between NMDAR antibodies and p-tau181 or NfL levels. CONCLUSIONS: NMDAR antibodies were associated with greater cognitive impairment over time in patients with PD, independent of other pathological biomarkers, suggesting a potential contribution of these antibodies to cognitive decline in PD.

Plasma p-tau181, neurofilament light chain and association with cognition in Parkinson's disease.

Early identification of cognitive impairment in Parkinson's disease (PD) has important clinical and research implications. The aim of our study was to investigate the role of plasma tau phosphorylated at amino acid 181 (p-tau181) and plasma neurofilament light chain (NfL) as biomarkers of cognition in PD. Baseline concentrations of plasma p-tau181 and NfL were measured in a cohort of 136 patients with PD and 63 healthy controls (HC). Forty-seven PD patients were followed up for up to 2 years. Cross-sectional and longitudinal associations between baseline plasma biomarkers and cognitive progression were investigated using linear regression and linear mixed effects models. At baseline, plasma p-tau181 concentration was significantly higher in PD subjects compared with HC (p = 0.026). In PD patients, higher plasma NfL was associated with lower MMSE score at baseline, after adjusting for age, sex and education (p = 0.027). Baseline plasma NfL also predicted MMSE decline over time in the PD group (p = 0.020). No significant association between plasma p-tau181 concentration and baseline or longitudinal cognitive performance was found. While the role of p-tau181 as a diagnostic biomarker for PD and its relationship with cognition need further elucidation, plasma NfL may serve as a feasible, non-invasive biomarker of cognitive progression in PD.

Why do 'OFF' periods still occur during continuous drug delivery in Parkinson's disease?

Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of 'OFF' periods. However, data suggest that despite their efficacy in reducing the number and duration of 'OFF' periods, these strategies still do not prevent 'OFF' periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent 'OFF' periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent 'OFF' periods unresponsive to dopaminergic therapy delivered via CDD.

Spotlight on non-motor symptoms and Covid-19.

The Coronavirus Disease 2019 (Covid-19) pandemic has profoundly affected the quality of life (QoL) and health of the general population globally over the past 2 years, with a clear impact on people with Parkinson's Disease (PwP, PD). Non-motor symptoms have been widely acknowledged to hold a vital part in the clinical spectrum of PD, and, although often underrecognized, they significantly contribute to patients' and their caregivers' QoL. Up to now, there have been numerous reports of newly emerging or acutely deteriorating non-motor symptoms in PwP who had been infected by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), while some of these symptoms, like fatigue, pain, depression, anxiety and cognitive impairment, have also been identified as part of the long-COVID syndrome due to their persistent nature. The subjacent mechanisms, mediating the appearance or progression of non-motor symptoms in the context of Covid-19, although probably multifactorial in origin, remain largely unknown. Such mechanisms might be, at least partly, related solely to the viral infection per se or the lifestyle changes imposed during the pandemic, as many of the non-motor symptoms seem to be prevalent even among Covid-19 patients without PD. Here, we summarize the available evidence and implications of Covid-19 in non-motor PD symptoms in the acute and chronic, if applicable, phase of the infection, with a special reference on studies of PwP.

Impact of Covid-19 on research and training in Parkinson's disease.

The Coronavirus Disease 2019 (Covid-19) pandemic and the consequent restrictions imposed worldwide have posed an unprecedented challenge to research and training in Parkinson's disease (PD). The pandemic has caused loss of productivity, reduced access to funding, an oft-acute switch to digital platforms, and changes in daily work protocols, or even redeployment. Frequently, clinical and research appointments were suspended or changed as a solution to limit the risk of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spread and infection, but since the care and research in the field of movement disorders had traditionally been performed at in-person settings, the repercussions of the pandemic have even been more keenly felt in these areas. In this chapter, we review the implications of this impact on neurological research and training, with an emphasis on PD, as well as highlight lessons that can be learnt from how the Covid-19 pandemic has been managed in terms of restrictions in these crucial aspects of the neurosciences. One of the solutions brought to the fore has been to replace the traditional way of performing research and training with remote, and therefore socially distanced, alternatives. However, this has introduced fresh challenges in international collaboration, contingency planning, study prioritization, safety precautions, artificial intelligence, and various forms of digital technology. Nonetheless, in the long-term, these strategies will allow us to mitigate the adverse impact on PD research and training in future crises.

Characterization of Non-Motor Fluctuations Using the Movement Disorder Society Non-Motor Rating Scale.

Background: Non-motor fluctuations (NMF) in people with Parkinson's disease (PwP) are clinically important yet understudied. Objective: To study NMF in PwP using both the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) NMF subscale and wearable sensors. Methods: We evaluated differences in overall burden of NMF and of specific NMF across disease durations: <2 years (n = 33), 2-5 years (n = 35), 5-10 years (n = 33), and > 10 years (n = 31). In addition, wearable triaxial sensor output was used as an exploratory outcome for early morning "off" periods. Results: Significant between-group differences were observed for MDS-NMS NMF total scores (P < 0.001), and specifically for depression, anxiety, fatigue and cognition, with both NMF prevalence and burden increasing in those with longer disease duration. Whereas only 9.1% with a short disease duration had NMF (none of whom had dyskinesia), in PwP with a disease duration of >10 years this was 71.0% (P < 0.001). From a motor perspective, dyskinesia severity increased evenly with increasing disease duration, while NMF scores in affected individuals showed an initial increase with largest differences between 2-5 years disease duration (P < 0.001), with plateauing afterwards. Finally, we observed that the most common NMF symptoms in patients with sensor-confirmed early morning "off" periods were fluctuations in cognitive capabilities, restlessness, and excessive sweating. Conclusions: Non-motor fluctuations prevalence in PwP increases with disease duration, but in a pattern different from motor fluctuations. Moreover, NMF can occur in PwP without dyskinesia, and in those with NMF the severity of NMF increases most during years 2-5 after diagnosis.

Plasma Neurofilament Light and p-tau181 and Risk of Psychosis in Parkinson's Disease.

BACKGROUND: Neuropsychiatric symptoms are common and important to people with Parkinson's disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively, which have yet to be explored in association with the affective and psychotic symptoms in PD. OBJECTIVE: To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD. METHODS: We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n = 63) were assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using the Non-Motor Symptom Scale and affective symptoms were measured in the Hospital Anxiety and Depression Scale. RESULTS: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40-47.4], p = 0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms. CONCLUSION: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD.

Self-reported periodontitis and C-reactive protein in Parkinson's disease: a cross-sectional study of two American cohorts.

Periodontitis triggers systemic repercussions, such as elevated levels of high-sensitive C-reactive protein (hs-CRP). This has never been studied within Parkinson's Disease (PD). The aim of this study is to compare hs-CRP levels of self-reported periodontitis cases versus cases without periodontitis in PD patients. Data from the National Health and Nutrition Examination Survey (2015-2016 and 2017-2018 waves) were analyzed. PD cases were identified through medication regimens and periodontitis cases through a validated self-report questionnaire. 51 participants were included (24 females, 27 males, with mean age of 62.96 (14.71)). While the self-reported periodontitis group presented elevated levels of circulating hs-CRP (5.36 vs. 1.99 mg/L, p = 0.031), the self-reported without periodontitis group presented higher lymphocyte levels (29.35 vs. 28.03%, p = 0.007). Blood levels of hs-CRP were significantly higher in PD cases with self-reported periodontitis. Apart from the lymphocyte levels, there were no other significant differences according to the self-reported periodontal status. Future studies shall explore this association using clinical measures.

Bergamo Field Hospital Confronting COVID-19: Operating Instructions.

The coronavirus disease (COVID-19) pandemic represented an unprecedented challenge for health care facilities, and innovative solutions were urgently required to overcome the high volume of critically ill infectious patients, limit in-hospital outbreaks, and limit the risk of occupational infection for health care workers (HCWs). Bergamo was the hardest-hit Italian province by COVID-19, and the local health care system had to undergo a profound and prompt reorganization. A COVID-19-only field hospital was rapidly set up meeting the standards for severe acute respiratory infection (SARI) treatment centers (https://apps.who.int/iris/handle/10665/331603). A zones partition, dedicated in-hospital pathways for HCWs, strict infection prevention and control (IPC) measures, and constant staff supervision were key components of our strategy to limit the risk of occupational infection for HCWs. Herein, we present the Bergamo field hospital layout enlightening fundamental IPC measures adopted as a valuable example of a SARI treatment center confronting COVID-19.

'Dopamine agonist Phobia' in Parkinson's disease: when does it matter? Implications for non-motor symptoms and personalized medicine.

INTRODUCTION: Dopamine agonists have been widely used to treat patients with Parkinson's disease, but concerns related to their well-known side effects might prevent their use even when indicated. In this review, the authors describe for the first time the concept of 'Dopamine Agonist Phobia', a pharmacophobia that the authors believe might affect clinicians, and they provide evidence of the benefits of dopamine agonists, focusing on non-motor symptoms. AREAS COVERED: The authors performed an extensive literature research, including studies exploring the use of dopamine agonists for the treatment of non-motor symptoms. The authors indicate the highest level of evidence in each section. EXPERT OPINION: 'Dopamine Agonist Phobia' may preclude valid therapeutic options in selected cases, specifically for the treatment of non-motor symptoms. Thus, the authors propose a personalized approach in Parkinson's disease treatment, and encourage a thoughtful use of dopamine agonists, rather than an overall nihilism.

Costs and effectiveness of influenza vaccination: a systematic review.

BACKGROUND: Seasonal influenza can cause a significant public health burden. Vaccination is proposed as the most effective measure to prevent influenza and related undesired outcomes. OBJECTIVE: To estimate the efficiency of influenza vaccination. METHODS: A literature review of economic evaluations of influenza vaccinations, published over the last 5 years, was performed using MEDLINE (through PubMed), Web of Science and Scopus. RESULTS: 935 papers were identified and 30 were selected, including studies performed in different population subgroups: general population, children, adults, elderly, pregnant women and high risk patients. Twenty-one studies were performed in Europe and in US. The majority of the studies were carried out on elderly patients and children. All except one were cost-effectiveness analyses and reported influenza vaccination as a cost-saving or cost-effective intervention. CONCLUSIONS: Vaccination strategies are economically favourable in a range of countries and sub-groups of patients.

Becker muscular dystrophy due to an intronic splicing mutation inducing a dual dystrophin transcript.

We describe a 29-year-old patient who complained of left thigh muscle weakness since he was 23 and of moderate proximal weakness of both lower limbs with difficulty in climbing stairs and running since he was 27. Mild weakness of iliopsoas and quadriceps muscles and muscle atrophy of both the distal forearm and thigh were observed upon clinical examination. He harboured a novel c.1150-3C>G substitution in the DMD gene, affecting the intron 10 acceptor splice site and causing exon 11 skipping and an out-of-frame transcript. However, protein of normal molecular weight but in reduced amounts was observed on Western Blot analysis. Reverse transcription analysis on muscle RNA showed production, via alternative splicing, of a transcript missing exon 11 as well as a low abundant full-length transcript which is enough to avoid the severe Duchenne phenotype. Our study showed that a reduced amount of full length dystrophin leads to a mild form of Becker muscular dystrophy. These results confirm earlier findings that low amounts of dystrophin can be associated with a milder phenotype, which is promising for therapies aiming at dystrophin restoration.

ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study.

ASAH1 gene encodes for acid ceramidase that is involved in the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 variants cause both the severe and early-onset Farber disease and rare cases of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by childhood onset of proximal muscle weakness and atrophy due to spinal motor neuron degeneration followed by occurrence of severe and intractable myoclonic seizures and death in the teenage years. We studied two subjects, a 30-year-old pregnant woman and her 17-year-old sister, affected with a very slowly progressive non-5q SMA since childhood. No history of seizures or myoclonus has been reported and EEG was unremarkable. The molecular study of ASAH1 gene showed the presence of the homozygote nucleotide variation c.124A>G (r.124a>g) that causes the amino acid substitution p.Thr42Ala. Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. This study describes for the first time the association between ASAH1 variants and an adult SMA phenotype with no myoclonic epilepsy nor death in early age, thus expanding the phenotypic spectrum of ASAH1-related SMA. ASAH1 molecular analysis should be considered in the diagnostic testing of non-5q adult SMA patients.