Parkinsonism in SCA19/22: Dopamine Transporter Imaging in an Italian Family Harboring a Novel Mutation.

Spinocerebellar ataxia (SCA)19/22 is a channelopathy caused by mutations in the KCND3 gene encoding for the voltage-gated potassium channel Kv4.3. In the present work, we report an Italian family harboring a novel KCND3 missense mutation characterized by ataxia and mild parkinsonism. Patients underwent dopamine transporter single-photon emission computed tomography to assess dopaminergic degeneration. Normal findings were observed, and treatment with levodopa did not yield any benefit, thus suggesting the involvement of other mechanisms to explain parkinsonian symptoms in SCA19/22. Our cases expand the genetic and imaging spectrum of this rare disease and emphasize a cautious approach in managing parkinsonism in these patients.

Electrophysiological and neuropsychological assessment of cognition in spinocerebellar ataxia type 1 patients: a pilot study.

BACKGROUND: Event-related potentials (ERPs) reflect cognitive processing: negative early components (N100, N200) are involved in the sensory and perceptual processing of a stimulus, whereas late positive component P300 requires conscious attention. Both neuropsychological and affective disorders are present in patients with spinocerebellar ataxia type 1 (SCA1), but the underlying mechanisms need further clarification. MATERIALS AND METHODS: In this pilot study, we assessed cognitive processing by recording auditory ERPs in 16 consecutive SCA1 patients and 16 healthy controls (HC) matched for age and sex. Motor and nonmotor symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) and an extensive neuropsychological battery. ERPs were recorded using an oddball paradigm, and peak latency and amplitude of N100, N200, and P300 were measured in the averaged responses to target tones. RESULTS: We found in SCA1 significantly increased latencies of N200 and P300 (p=0.033, p=0.007) and decreased amplitudes of N100 and P300 (p=0.024, p=0.038) compared with HC. Furthermore, P300 latency had the highest AUC in the discrimination of SCA1 in ROC analysis. The expansion of trinucleotide repeats correlated with P300 latency (r=-0.607, p=0.048), whereas both P300 and N100 amplitudes correlated with the severity of motor symptoms (r=-0.692, p=0.003; r=-0.621; p=0.010). Significant correlations between P300 latency and the scores of Emotion Attribution Task (r=-0.633, p=0.027), as well as between N200 latency and the scores of Frontal Assessment Battery and Stroop test (r=-0.520, p=0.047; r=0.538, p=0.039), were observed. CONCLUSIONS: This research provides for the first time an extensive characterization of ERPs as useful electrophysiological markers to identify early cognitive dysfunction in SCA1.

Striatal dopamine transporter imaging in Parkinson's disease drug-naïve patients: focus on sexual dysfunction.

INTRODUCTION: Dopamine is involved in sexual behavior, but dopaminergic imaging studies establishing the relationship between nigrostriatal dopaminergic degeneration and sexual dysfunction (SD) in Parkinson's disease (PD) are lacking. METHODS: We retrospectively analyzed clinical and 123I-FP-CIT SPECT data of 43 drug-naïve PD patients. Based on the sexual function domain of the Non-Motor Symptoms Scale (NMSS), we identified 23 patients with sexual concerns (WSC), reporting a score ≥ 2 due to hyposexuality, and 20 patients without sexual concerns (NoSC). Dopamine transporter (DAT) uptake was assessed through semi-quantitative analysis in the most and least affected putamen (maP, laP), and most and least affected caudate (maC, laC). Total putamen-to-caudate ratio and total striatal binding ratio (tSBR) were also quantified. RESULTS: WSC and NoSC had similar demographic and disease-related characteristics. WSC displayed lower uptake values in maC (p = 0.016), maP (p = 0.004), laC (p = 0.019), laP (p = 0.009), and tSBR (p = 0.006). Pearson correlation analysis revealed, in the WSC group, moderate inverse correlations between the log-transformed SD scores and the uptake in maP (r = - 0.473, p = 0.023), maC (r = - 0.428, p = 0.042), laP (r = -0.437, p = 0.037), and tSBR (r = - 0.460, p = 0.027). After controlling in a two-way ANCOVA model for age and sex, between-group differences,between WSC and NoSC remained statistically significant only for dopaminergic denervation in maP [F(1,38) = 7.478, p = 0.009)], laP [F(1,38) = 4.684, p = 0.037)], and tSBR [F(1,38) = 5.069, p = 0.030]. CONCLUSION: To the best of our knowledge, this is the first study reporting the relationship between the severity of SD and specific patterns of nigrostriatal dopaminergic denervation (especially involving both putamina) in newly diagnosed drug-naïve PD patients.

Beyond canvas: behavioral onset of rfc1-expansion disease in an Italian family-causal or casual?

INTRODUCTION: Biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene was recently identified in two/third of patients with cerebellar ataxia, sensory neuropathy, and bilateral vestibular areflexia syndrome (CANVAS). The phenotypic spectrum has expanded since (i.e., parkinsonism, motor neuron involvement, cognitive decline); no behavioral symptoms have been reported yet. CASE REPORT: We report an Italian family that met the diagnostic criteria for CANVAS, and RFC1-expansion was detected in five of seven. All the affected members presented behavioral-psychiatric symptoms (anxiety, panic attacks, alcohol abuse) before the multisystemic RFC1-expansion manifestation. The disease course was progressive, with ataxia and behavioral-cognitive aspects as the most disabling symptoms. CONCLUSION: These behavioral-cognitive observations may broaden the RFC1-expansion phenotypic spectrum and highlight the importance of investigating the whole non-motor symptoms in ataxic patients.

The Italian tremor Network (TITAN): rationale, design and preliminary findings.

INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research.

The prevention of falls in patients with Parkinson's disease with in-home monitoring using a wearable system: a pilot study protocol.

BACKGROUND: Parkinson's disease (PD) is a chronic, progressive neurodegenerative condition that gradually worsens motor function and leads to postural instability and, eventually, falls. Several factors may influence the frequency of future falls, such as slowness, freezing of gait, loss of balance, and mobility problems, cognitive impairments, and the number of previous falls. The TED bracelet is an advanced technological wearable device able to predict falls. AIMS: This principal aim is to investigate the feasibility of a full-scale research project that uses the TED bracelet to identify whether individuals with PD are at risk of falling. METHODS: This study will involve a pilot prospective observational study design; the subjects will include 26 patients suffering from mild PD and 26 others with no PD and no gait problems. Data will be collected from the TED bracelet and then compared to a paper-based fall diary. The enrolled participants will have a scheduled outpatient evaluation to collect both clinical and instrumental data as well as biological samples. DISCUSSION: This pilot study could then be implemented in a larger form to further evaluate the effectiveness of the TED device. Finally, it will help further develop gait monitoring systems for people with Parkinson's disease and other neurodegenerative diseases that can affect physical function and mobility, such as dementia and Alzheimer's. CONCLUSIONS: Preventing falls and their complications could lead to major advancements in the quality of home care for patients with PD, which would significantly impact the quality of life of both these patients and their caregivers.

Immune Response Modifications in the Genetic Forms of Parkinson's Disease: What Do We Know?

Parkinson's disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons in the pars compacta of the midbrain substantia nigra. PD pathophysiology is complex, multifactorial, and not fully understood yet. Nonetheless, recent data show that immune system hyperactivation with concomitant production of pro-inflammatory cytokines, both in the central nervous system (CNS) and the periphery, is a signature of idiopathic PD. About 5% of PD patients present an early onset with a determined genetic cause, with either autosomal dominant or recessive inheritance. The involvement of immunity in the genetic forms of PD has been a matter of interest in several recent studies. In this review, we will summarize the main findings of this new and promising field of research.

Polymorphisms of Dopamine Receptor Genes and Parkinson's Disease: Clinical Relevance and Future Perspectives.

Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD.

Relationship between circulating CD4+ T lymphocytes and cognitive impairment in patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is characterized by loss of dopaminergic neurons. Neuroinflammation may represent an important factor in the pathophysiology of PD and recent findings indicate that PD patients present a pro-inflammatory peripheral profile of CD4+ T lymphocytes, which may correlate with motor disability. However, no data are currently available on the relationship between CD4+ T lymphocytes and cognitive function in PD. The aim of our study is to evaluate the relationship between cognitive profile and circulating CD4+ T lymphocyte subsets in PD patients. METHODS: PD patients underwent blood withdrawal and CD4+ T lymphocyte subpopulations, including CD4+ T naïve and memory cells, Th1, Th2, Th17, Th1/17 and T regulatory (Treg) cells were evaluated by flow cytometry. Cognitive evaluation was performed using Addenbrooke Cognitive Examination (ACE-R). RESULTS: 43 consecutive PD patients (31 males; age [mean ± SD]: 68.9 ± 8.4 years) were enrolled. 14/43 (32.6%) were drug naïve. Based on the ACE-R score, patients were divided in two groups using defined cutoff values. In comparison to patients with normal cognitive profile, patients with cognitive impairment had a higher number of circulating lymphocytes. Moreover, drug naïve patients with a worse cognitive outcome had a lower number of resting Treg and higher number of activated Treg. Furthermore, we found a correlation between pro-inflammatory peripheral immune phenotype and worse cognitive outcome in the ACE-R total and sub-items scores. CONCLUSIONS: In our cohort of PD patients, cognitive impairment was associated with higher number of circulating lymphocytes, and - at least in drug naïve patients - with dysregulation of the Treg compartment. Further studies are needed to assess whether and to what extent peripheral immunity mechanistically contributes to cognitive decline in PD.

Cognition in Patients with Spinocerebellar Ataxia 1 (SCA1) and 2 (SCA2): A Neurophysiological and Neuropsychological Approach.

Background/Objectives: Cognitive impairment in spinocerebellar ataxia patients has been reported since the early-disease stage. We aimed to assess cognitive differences in SCA1 and SCA2 patients. Methods: We performed neuropsychological (NPS) and neurophysiological (auditory event-related potentials, aERPs) assessments in 16 SCA1 and 18 SCA2 consecutive patients. Furthermore, clinical information (age at onset, disease duration, motor disability) was collected. Results: NPS tests yielded scores in the normal range in both groups but with lower scores in the Frontal Assessment Battery (p < 0.05) and Visual Analogue Test for Anosognosia for motor impairment (p < 0.05) in SCA1, and the Trail Making Test (p < 0.01), Raven's progressive matrices (p < 0.01), Stroop (p < 0.05), and emotion attribution tests (p < 0.05) in SCA2. aERPs showed lower N100 amplitude (p < 0.01) and prolonged N200 latency (p < 0.01) in SCA1 compared with SCA2. Clinically, SCA2 had more severe motor disability than SCA1 in the Assessment and Rating of Ataxia Scale. Conclusions: SCA2 showed more significant difficulties in attentional, visuospatial, and emotional function, and greater motor impairment. In contrast, SCA1 showed less cognitive flexibility/phasic ability, probably affected by a more severe degree of dysarthria. The same group revealed less neural activity during nonconscious attentional processing (N100-N200 data), suggesting greater involvement of sensory pathways in discriminating auditory stimuli. NFS did not correlate with NPS findings, implying an independent relationship. However, the specific role of the cerebellum and cerebellar symptoms in NPS test results deserves more focus.

Comparing GBA1-Parkinson's disease and idiopathic Parkinson's disease: α-Synuclein oligomers and synaptic density as biomarkers in the skin biopsy.

The main genetic risk factors for Parkinson's disease (PD) are presently represented by variants in GBA1 gene encoding for the ß-glucocerebrosidase (GCase). Searching for a peripheral biomarker that can be used for selecting and monitoring patients in clinical trials targeting GBA1-associated PD (GBA1-PD) is a current challenge. We previously demonstrated that α-synuclein oligomers expressed as proximity ligation assay (PLA) score in synaptic terminals of skin biopsy are a reliable biomarker for distinguishing idiopathic PD (iPD) from healthy controls (HC). This cross-sectional study investigates an unexplored cohort of GBA1-PD (n = 27) compared to 28 HC, and 36 iPD cases to (i) analyze α-synuclein oligomers and quantify them throughout PLA score, (ii) investigate GCase expression in brain and synaptic terminals targeting the sweat gland, (iii) unravel indicators that could differentiate patients with specific GBA1 mutations. PLA score discriminates GBA1-PD from HC with sensitivity = 88.9% (95% CI 70.84-97.65), specificity = 88.5% (95% CI 69.85-97.55), and PPV = 88.9% (95% CI 73.24-95.90), AUC value = 0.927 (95% CI 0.859-0.996). No difference was found between GBA1-PD patients and iPD, suggesting a common pathological pathway based on α-synuclein oligomers. GCase score did not differ in GBA1-PD, iPD, and HC in the synaptic terminals, whereas a positive correlation was found between PLA score and GCase score. Moreover, a significant increase in synaptic density was observed in GBA1-PD compared to iPD and HC (P < 0.0001). Employing ROC curve to discriminate GBA1-PD from iPD, we found an AUC value for synaptic density = 0.855 (95% CI 0.749-0.961) with sensitivity = 85.2% (95% CI 66.27%-95.81%), specificity = 77.1% (95% CI 59.86%-89.58%), and PPV = 74.19% (60.53%-84.35%). The highest synaptic density values were observed in p.N409S patients. This work points out to the value of both PLA score and synaptic density in distinguishing GBA1-PD from iPD and to their potential to stratify and monitor patients in the context of new pathway-specific therapeutic options.

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

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

Disease mechanisms as subtypes: Immune dysfunction in Parkinson's disease.

In recent years, the contraposition between inflammatory and neurodegenerative processes has been increasingly challenged. Inflammation has been emphasized as a key player in the onset and progression of Parkinson disease (PD) and other neurodegenerative disorders. The strongest indicators of the involvement of the immune system derived from evidence of microglial activation, profound imbalance in phenotype and composition of peripheral immune cells, and impaired humoral immune responses. Moreover, peripheral inflammatory mechanisms (e.g., involving the gut-brain axis) and immunogenetic factors are likely to be implicated. Even though several lines of preclinical and clinical studies are supporting and defining the complex relationship between the immune system and PD, the exact mechanisms are currently unknown. Similarly, the temporal and causal connections between innate and adaptive immune responses and neurodegeneration are unsettled, challenging our ambition to define an integrated and holistic model of the disease. Despite these difficulties, current evidence is providing the unique opportunity to develop immune-targeted approaches for PD, thus enriching our therapeutic armamentarium. This chapter aims to provide an extensive overview of past and present studies that explored the implication of the immune system in neurodegeneration, thus paving the road for the concept of disease modification in PD.

The Immune System as a Therapeutic Target for Old and New Drugs in Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons and intraneuronal accumulation of protein aggregates. The exact mechanisms leading to neuronal death in PD are not fully understood, but several different molecular pathways are involved, leading to the concept that molecular subtypes may coexist in the nosological spectrum of PD. To this respect, immune system activation, both in the periphery and inside the central nervous system, was detected as a common trait of several pathogenic pathways of PD. The current working hypothesis implies that immune cells shift towards a proinflammatory phenotype and trigger the production of neurotoxic cytokines, ultimately contributing to neurodegeneration. While it is very important to understand how commonly used antiparkinson drugs interact with such changes, the search for treatments that may directly or indirectly modulate immune function is a great opportunity for disease modification.

Relationship between [123I]FP-CIT SPECT data and peripheral CD4 + T cell profile in newly-diagnosed drug-naïve Parkinson's disease patients.

BACKGROUND: Dysregulation of the CD4 + T cell compartment occurs in Parkinson's Disease (PD). Nonetheless, the exact relationship with dopamine transporter (DAT) SPECT denervation patterns is currently unknown. METHODS: Expression of transcription factors and levels of circulating CD4 + T cell subsets were assessed in peripheral blood mononuclear cells (PBMC) from 23 newly diagnosed drug-naïve PD patients. Semi-quantitative [123I]-FP-CIT SPECT data, i.e. uptake in the most and least affected putamen (maP, laP) and caudate (maC, laC), total striatal binding ratio (tSBR), and total putamen-to-caudate ratio (tP/C) were obtained. RESULTS: FOXP3 mRNA levels correlated with the uptake in maC (r = - 0.542, P = 0.011), laP (r = - 0.467, P = 0.033), and tSBR (r = - 0.483, P = 0.027). Concerning flow cytometry analysis of circulating CD4 + T cell subsets, a significant relationship between tP/C, caudate uptake, and the levels of both T helper (Th)1 and 2, was detected. Furthermore, we found significant correlations between the uptake in maP and the total count of naïve and activated T regulatory cells (Treg) (r = - 0.717, P = 0.001; r = - 0.691, P = 0.002), which were confirmed after the Benjamini-Hochberg correction for multiple comparisons using a false discovery rate at level q = 0.10. Levels of circulating naïve Treg were higher (P = 0.014) in patients with more extensive dopaminergic denervation, suggesting a compensatory phenomenon. CONCLUSIONS: Peripheral CD4 + T cell immunity is involved in early-stage PD and novel correlations with striatal DAT loss were observed.

The PROB-PD trial: a pilot, randomised, placebo-controlled study protocol to evaluate the feasibility and potential efficacy of probiotics in modulating peripheral immunity in subjects with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease. No disease-modifying treatment is available, and therapy is symptomatic. The histopathologic hallmark is the loss of dopaminergic neurons and accumulation of α-synuclein (α-syn) in surviving neurons, but the underlying pathophysiology is unclear. Inflammatory mechanisms seem to play a prominent role, with an imbalance of immune functions and neurotoxicity caused by reactive oxygen species (ROS). Involvement of peripheral adaptive immunity, with an imbalance in T cell subpopulations and in the expression of transcriptional factors in CD4+ T cells, has also been reported. Although clinical presentation is defined by motor symptoms, patients also report non-motor symptoms, often before the onset of a clinically established disease. Etiopathogenesis of PD is unknown, but an initial aggregation of α-syn in the gut, with subsequent propagation along the vagus nerve to the brain has been hypothesised. Interestingly, in an α-syn overexpressing murine model, the absence of gut microbiota prevented both microglia activation and motor impairment, thus pointing to a fundamental role of microbiota in the development of PD. Magistrelli et al. showed that in peripheral blood mononuclear cells of PD patients, probiotics modulate the in vitro production of cytokines toward an anti-inflammatory profile and reduce the production of ROS. METHODS: This is a pilot randomised placebo-controlled clinical trial protocol for a 12-week treatment with probiotics. At least 80 patients affected by PD will be recruited and randomly allocated to either the treatment or placebo group in a 1:1 ratio. General inclusion criteria will be the onset of PD 2 to 5 years before the trial and absence of autoimmune comorbidities or immunomodulating therapy. Our primary endpoint is the assessment of changes in extracellular cytokine levels (Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10) and ROS production. Secondary outcomes include changes in lymphocyte subpopulations and transcriptional factors mRNA levels. DISCUSSION: This study is designed to highlight the potential beneficial role of probiotics administration on peripheral immunity through the modulation of gut microbiota. Explorative outcomes will be evaluated to assess variations in motor and non-motor symptoms and the possible correlation with probiotics administration. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05173701. Registered 08 November 2021.

Clinical correlates of "pure" essential tremor: the TITAN study.

Background: To date, there are no large studies delineating the clinical correlates of "pure" essential tremor (ET) according to its new definition. Methods: From the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of "pure" ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum. Results: Out of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) "pure" ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options. Discussion: The findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of "pure" ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of "pure" ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies.