Non-Surgical Periodontal Therapy's Influence on Alpha-Synuclein and Inflammatory Marker Levels: A Pilot Study.

Background: Microbial dysbiosis may contribute to alpha-synuclein (α-Syn) homeostasis disruption, yet the burden of inflammatory periodontal infection and its treatment have never been studied in this regard. We aimed to compare the cytokine and α-Syn levels in the saliva and blood of patients with periodontitis who underwent non-surgical periodontal therapy (NSPT) and those of their healthy counterparts. Methods: Periodontal examination and saliva and blood sample collection were carried out in incoming patients at a university clinic. The periodontitis group (PG) received NSPT. The sample collection and periodontal observation were repeated 30 days after. IL-6, IL1-ß and total α-Syn were quantified using immunoassay methods. The periodontal inflamed surface area (PISA) was calculated as a proxy for periodontal inflammation. Results: Eleven participants formed the PG, and there were fifteen healthy controls (HC). At baseline, no correlation between salivary and plasma α-Syn was found. The salivary α-Syn levels revealed a tendency to decrease 30 days after, particularly in the PD cases. The variation in PISA and α-Syn showed significant correlation. Salivary α-Syn correlated negatively with salivary IL-6 levels at both timepoints in the total sample (rho = -0.394 and rho = -0.451) and in the HC (rho = -0.632 and rho = -0.561). Variations in plasma IL-6 and α-Syn were negatively correlated (rho = -0.518) in the healthy participants. Baseline plasma IL1-ß negatively correlated with plasmatic α-Syn at 30 days in the HC (rho = -0.581). Conclusions: Salivary and plasma α-Syn bioavailability operate independently, and periodontal diagnosis was not a confounding factor. Salivary α-Syn levels were significantly affected by NSPT, contrary to plasma levels. These results should be confirmed in future larger and prospective studies.

Dietary Caffeine and Brain Dopaminergic Function in Parkinson Disease.

OBJECTIVE: This study was undertaken to investigate the effects of dietary caffeine intake on striatal dopamine function and clinical symptoms in Parkinson disease in a cross-sectional and longitudinal setting. METHODS: One hundred sixty-three early Parkinson disease patients and 40 healthy controls were investigated with [123I]FP-CIT single photon emission computed tomography, and striatal dopamine transporter binding was evaluated in association with the level of daily coffee consumption and clinical measures. After a median interval of 6.1 years, 44 patients with various caffeine consumption levels underwent clinical and imaging reexamination including blood caffeine metabolite profiling. RESULTS: Unmedicated early Parkinson disease patients with high coffee consumption had 8.3 to 15.4% lower dopamine transporter binding in all studied striatal regions than low consumers, after accounting for age, sex, and motor symptom severity. Higher caffeine consumption was further associated with a progressive decline in striatal binding over time. No significant effects of caffeine on motor function were observed. Blood analyses demonstrated a positive correlation between caffeine metabolites after recent caffeine intake and dopamine transporter binding in the ipsilateral putamen. INTERPRETATION: Chronic caffeine intake prompts compensatory and cumulative dopamine transporter downregulation, consistent with caffeine's reported risk reduction in Parkinson disease. However, this decline does not manifest in symptom changes. Transiently increased dopamine transporter binding after recent caffeine intake has implications for dopaminergic imaging guidelines. ANN NEUROL 2024;96:262-275.

Parkinson's Kinetigraph for Wearable Sensor Detection of Clinically Unrecognized Early-Morning Akinesia in Parkinson's Disease: A Case Report-Based Observation.

Early-morning off periods, causing early-morning akinesia, can lead to significant motor and nonmotor morbidity in levodopa-treated fluctuating Parkinson's disease (PD) cases. Despite validated bedside scales in clinical practice, such early-morning off periods may remain undetected unless specific wearable technologies, such as the Parkinson's KinetiGraph™ (PKG) watch, are used. We report five PD cases for whom the PKG detected early-morning off periods that were initially clinically undetected and as such, untreated. These five cases serve as exemplars of this clinical gap in care. Post-PKG assessment, clinicians were alerted and targeted therapies helped abolish the early-morning off periods.

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 Comorbidities in People with Parkinson's Disease: Considerations From An Expert Panel.

In the UK, guidance exists to aid clinicians and patients deciding when treatment for Parkinson's disease (PD) should be initiated and which therapies to consider. National Institute for Health and Care Excellence (NICE) guidance recommends that before starting PD treatment clinicians should discuss the following: the patient's individual clinical circumstances; lifestyle; preferences; needs and goals; as well as the potential benefits and harms of the different drug classes. Individualization of medicines and management in PD significantly improves patients' outcomes and quality of life. This article aims to provide simple and practical guidance to help clinicians address common, but often overlooked, co-morbidities. A multi-disciplinary group of PD experts discussed areas where clinical care can be improved by addressing commonly found co-morbidities in people with Parkinson's (PwP) based on clinical experience and existing literature, in a roundtable meeting organized and funded by Bial Pharma UK Ltd. The experts identified four core areas (bone health, cardiovascular risk, anticholinergic burden, and sleep quality) that, if further standardized may improve treatment outcomes for PwP patients. Focusing on anticholinergic burden, cardiac risk, sleep, and bone health could offer a significant contribution to personalizing regimes for PwP and improving overall patient outcomes. Within this opinion-based paper, the experts offer a list of guiding factors to help practitioners in the management of PwP.

Safety and tolerability of long-term apomorphine infusion in advanced Parkinson's disease: an Indian multi-center (APO-IND) experience.

Advanced Parkinson's Disease (APD) is complicated by the emergence of motor and non-motor fluctuations, which are initially predictable and eventually become unpredictable, in part due to erratic gastric absorption and short half of oral levodopa. Attempts to manage such fluctuations with oral dopaminergic drugs often lead to disabling dyskinesias. Continuous Subcutaneous Apomorphine Infusion (CSAI), despite being approved for the treatment of APD since 1993, was approved in India only in 2019. We studied the safety, tolerability and efficacy of CSAI in Indian patients with APD in a registry design to raise local awareness of this important treatment. We conducted a prospective registry-based observational audit at 10 centers across different states of India. Patients with APD, not responding to or with significant side effects from oral dopaminergic therapy, were assessed at baseline and at month 6 and 12 following CSAI infusion. Fifty-one patients completed the study, CSAI significantly reduced the functional impact of dyskinesia (p < 0.01 at 6 months and p < 0.001 at 12 months). There was a significant improvement in the OFF-state from baseline (p < 0.01 at 6 months and p < 0.001 at 12 months) No discernible side effects were observed apart from mild site reaction (n = 7), nausea (n = 7) skin nodules (n = 2). CSAI demonstrated safety, efficacy, tolerability and improved quality of life in patients with APD, as shown in previous studies. Our study highlighted current existing inequalities in treatment availability, lack of awareness, knowledge gap, affordability and cost remains a concern regarding apomorphine use in Indian PD population.

The Park Sleep subtype in Parkinson's disease: from concept to clinic.

INTRODUCTION: The heterogeneity of Parkinson's disease (PD) is evident from descriptions of non-motor (NMS) subtypes and Park Sleep, originally identified by Sauerbier et al. 2016, is one such clinical subtype associated with the predominant clinical presentation of sleep dysfunctions including excessive daytime sleepiness (EDS), along with insomnia. AREAS COVERED: A literature search was conducted using the PubMed, Medline, Embase, and Web of Science databases, accessed between 1 February 2023 and 28 March 2023. In this review, we describe the clinical subtype of Park Sleep and related 'tests' ranging from polysomnography to investigational neuromelanin MRI brain scans and some tissue-based biological markers. EXPERT OPINION: Cholinergic, noradrenergic, and serotonergic systems are dominantly affected in PD. Park Sleep subtype is hypothesized to be associated primarily with serotonergic deficit, clinically manifesting as somnolence and narcoleptic events (sleep attacks), with or without rapid eye movement behavior disorder (RBD). In clinic, Park Sleep recognition may drive lifestyle changes (e.g. driving) along with therapy adjustments as Park Sleep patients may be sensitive to dopamine D3 active agonists, such as ropinirole and pramipexole. Specific dashboard scores based personalized management options need to be implemented and include pharmacological, non-pharmacological, and lifestyle linked advice.

Pain in Parkinson disease: mechanistic substrates, main classification systems, and how to make sense out of them.

ABSTRACT: Parkinson disease (PD) affects up to 2% of the general population older than 65 years and is a major cause of functional loss. Chronic pain is a common nonmotor symptom that affects up to 80% of patients with (Pw) PD both in prodromal phases and during the subsequent stages of the disease, negatively affecting patient's quality of life and function. Pain in PwPD is rather heterogeneous and may occur because of different mechanisms. Targeting motor symptoms by dopamine replacement or with neuromodulatory approaches may only partially control PD-related pain. Pain in general has been classified in PwPD according to the motor signs, pain dimensions, or pain subtypes. Recently, a new classification framework focusing on chronic pain was introduced to group different types of PD pains according to mechanistic descriptors: nociceptive, neuropathic, or neither nociceptive nor neuropathic. This is also in line with the International Classification of Disease-11 , which acknowledges the possibility of chronic secondary musculoskeletal or nociceptive pain due to disease of the CNS. In this narrative review and opinion article, a group of basic and clinical scientists revise the mechanism of pain in PD and the challenges faced when classifying it as a stepping stone to discuss an integrative view of the current classification approaches and how clinical practice can be influenced by them. Knowledge gaps to be tackled by coming classification and therapeutic efforts are presented, as well as a potential framework to address them in a patient-oriented manner.

Hiccups, Hypersalivation, Hallucinations in Parkinson's Disease: New Insights, Mechanisms, Pathophysiology, and Management.

Parkinson's disease (PD) is a chronic, progressive neurological disorder and the second most common neurodegenerative condition. We report three common but overlooked symptoms in PD-hiccups, hypersalivation, and hallucinations-in terms of their prevalence, pathophysiology, and up-to-date evidence-based treatment strategies. Whilst all these three symptoms do occur in many other neurological and non-neurological conditions, early recognition and treatment are paramount. Whilst hiccups affect 3% of healthy people, their rate of occurrence is higher (20%) in patients with PD. Hypersalivation (Sialorrhea) is another common neurological manifestation of many neurological and other neurodegenerative conditions such as motor neuron disease (MND), with a median prevalence rate of 56% (range: 32-74%). A 42% prevalence of sialorrhea is also reported in sub-optimally treated patients with PD. Hallucinations, especially visual hallucinations, are commonly reported, with a prevalence of 32-63% in PD, and a 55-78% prevalence is noted in patients with dementia with Lewy bodies (DLB), followed by tactile hallucinations, which are indicated by a sensation of crawling bugs or imaginary creatures across the skin surface. Whilst mainstay and primary management strategies for all these three symptoms are carried out through history taking, it is also essential to identify and treat possible potential triggers such as infection, minimise or avoid causative (such as drug-induced) factors, and especially carry out patient education before considering more definitive treatment strategies, such as botulinum toxin therapies for hypersalivation, to improve the quality of life of patients. This original review paper aims to provide a comprehensive overview of the disease mechanisms, pathophysiology, and management of hiccups, hypersalivation, and hallucinations in 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.

A scoping review of neurodegenerative manifestations in explainable digital phenotyping.

Neurologists nowadays no longer view neurodegenerative diseases, like Parkinson's and Alzheimer's disease, as single entities, but rather as a spectrum of multifaceted symptoms with heterogeneous progression courses and treatment responses. The definition of the naturalistic behavioral repertoire of early neurodegenerative manifestations is still elusive, impeding early diagnosis and intervention. Central to this view is the role of artificial intelligence (AI) in reinforcing the depth of phenotypic information, thereby supporting the paradigm shift to precision medicine and personalized healthcare. This suggestion advocates the definition of disease subtypes in a new biomarker-supported nosology framework, yet without empirical consensus on standardization, reliability and interpretability. Although the well-defined neurodegenerative processes, linked to a triad of motor and non-motor preclinical symptoms, are detected by clinical intuition, we undertake an unbiased data-driven approach to identify different patterns of neuropathology distribution based on the naturalistic behavior data inherent to populations in-the-wild. We appraise the role of remote technologies in the definition of digital phenotyping specific to brain-, body- and social-level neurodegenerative subtle symptoms, emphasizing inter- and intra-patient variability powered by deep learning. As such, the present review endeavors to exploit digital technologies and AI to create disease-specific phenotypic explanations, facilitating the understanding of neurodegenerative diseases as "bio-psycho-social" conditions. Not only does this translational effort within explainable digital phenotyping foster the understanding of disease-induced traits, but it also enhances diagnostic and, eventually, treatment personalization.

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.

The Dashboard Vitals of Parkinson's: Not to Be Missed Yet an Unmet Need.

The vitals of Parkinson's disease (PD) address the often-ignored symptoms, which are considered either peripheral to the central core of motor symptoms of PD or secondary symptoms, which, nevertheless, have a key role in the quality of life (QoL) and wellness of people with Parkinson's (PwP) [...].

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.

Covid-19 and Parkinson's disease: Acute clinical implications, long-COVID and post-COVID-19 parkinsonism.

The Coronavirus Disease 2019 (Covid-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to unprecedented challenges for the delivery of healthcare and has had a clear impact on people with chronic neurological conditions such as Parkinson's disease (PD). Acute worsening of motor and non-motor symptoms and long-term sequalae have been described during and after SARS-CoV-2 infections in people with Parkinson's (PwP), which are likely to be multifactorial in their origin. On the one hand, it is likely that worsening of symptoms has been related to the viral infection itself, whereas social restrictions imposed over the course of the Covid-19 pandemic might also have had such an effect. Twenty cases of post-Covid-19 para-infectious or post-infectious parkinsonism have been described so far where a variety of pathophysiological mechanisms seem to be involved; however, a Covid-19-induced wave of post-viral parkinsonism seems rather unlikely at the moment. Here, we describe the interaction between SARS-CoV-2 and PD in the short- and long-term and summarize the clinical features of post-Covid-19 cases of parkinsonism observed so far.

Neuroimaging Biomarkers in a Patient with Probable Psychiatric-Onset Prodromal Dementia with Lewy Bodies.

OBJECTIVES: Psychiatric-onset prodromal Dementia with Lewy Bodies (DLB) is a recently proposed clinical entity characterized by psychiatric presentation that may predate clinical dementia by many years. It is not yet clear how to identify patients with prominent late-onset psychiatric symptoms who may have underlying Lewy Bodies disease. Here, we describe how neuroimaging can assist the identification of this condition. METHODS: A 77-year-old man presented with late-onset psychosis. He underwent an extensive clinical and neuropsychological evaluation. These included Brain MRI with Arterial Spin labeling (ASL) which quantifies perfusion. [123I] FP-CIT SPECT and I-Metaiodobenzylguanidine (mIBG) scintigraphy assessed striatal dopaminergic and cardiac adrenergic integrity, respectively. RESULTS: Clinical evaluation revealed a history of REM sleep behavior disorder and parkinsonism induced by antipsychotics. The patient's cognitive function was normal. Conventional MRI showed parieto-occipital atrophy, and posterior hypoperfusion was revealed by ASL-MRI. Of note, the "cingulate island sign" was present. FP-CIT SPECT and I-Metaiodobenzylguanidine endorsed the suspicion of α-synucleinopathy. The patient fulfils the recently proposed key features of psychiatric-onset Prodromal DLB. DISCUSSION: Prodromal DLB is an emerging concept. Biomarkers have not been yet established. We propose that nuclear imaging and advanced MRI technics showing posterior hypoperfusion and the presence of the "cingulate island sign" could be promising biomarkers candidates.

Coronavirus Disease 2019 and Related Parkinsonism: The Clinical Evidence Thus Far.

Background: The Coronavirus disease 2019 (Covid-19) pandemic has fueled both research and speculation, as to whether it could be a "perfect storm" for a post-Covid emergence of parkinsonism in some susceptible individuals, analogous to the post-encephalitic parkinsonism reported after the 1918 influenza epidemic. This theory is further augmented by reports of a pathogenic effect of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) on the central nervous system with specific impact on the dopaminergic pathway, as well as the possibility of the virus to selectively bind to Angiotensin-Converting Enzyme-2 (ACE-2); these molecules are expressed abundantly in the midbrain dopamine neurons and, are likely involved in several cellular mechanisms cited in Parkinson's Disease (PD) pathophysiology. Objectives­Methods: Therefore, we performed a review of the literature up to February 2022 to explore the current landscape considering published cases of new-onset parkinsonism after a SARS-CoV-2 infection in otherwise healthy individuals. We summarized their clinical features, diagnostic and treatment approaches, discussing potential underlying mechanisms in light of PD pathogenesis theories. Results: Twenty cases that developed parkinsonian features simultaneously or shortly after a reported SARS-CoV-2 infection were reviewed. In 11 of them, parkinsonism appeared in the context of encephalopathy, while four patients developed post-infectious parkinsonism without encephalopathy, and four bore similarities to idiopathic PD. Nine patients exhibited a good response to dopaminergic therapy, while four responded to immunomodulatory treatment. Conclusions: Available data does not yet justify a clear association between the Covid-19 pandemic and a parkinsonism wave. However, vigilance is necessary, as long-term effects might have not been revealed.

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.

The neuropsychiatry of Parkinson's disease: advances and challenges.

In people with Parkinson's disease, neuropsychiatric signs and symptoms are common throughout the disease course. These symptoms can be disabling and as clinically relevant as motor symptoms, and their presentation can be similar to, or distinct from, their counterparts in the general population. Correlates and risk factors for developing neuropsychiatric signs and symptoms include demographic, clinical, and psychosocial characteristics. The underlying neurobiology of these presentations is complex and not well understood, with the strongest evidence for neuropathological changes associated with Parkinson's disease, mechanisms linked to dopaminergic therapy, and effects not specific to Parkinson's disease. Assessment instruments and formal diagnostic criteria exist, but there is little routine screening of these signs and symptoms in clinical practice. Mounting evidence supports a range of pharmacological and non-pharmacological interventions, but relatively few efficacious treatment options exist. Optimising the management of neuropsychiatric presentations in people with Parkinson's disease will require additional research, raised awareness, specialised training, and development of innovative models of care.