Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

BACKGROUND: VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization. CASES: We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described. CONCLUSIONS: This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

Neurogenic orthostatic hypotension in Parkinson's disease: is there a role for locus coeruleus magnetic resonance imaging?

Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and degenerates early in Parkinson's disease (PD). The objective of this study is to test whether degeneration of the LC is associated with orthostatic hypotension (OH) in PD. A total of 22 cognitively intact PD patients and 52 age-matched healthy volunteers underwent 3 T magnetic resonance (MRI) with neuromelanin-sensitive T1-weighted sequences (LC-MRI). For each subject, a template space-based LC-MRI was used to calculate LC signal intensity (LC contrast ratio-LCCR) and the estimated number of voxels (LCVOX) belonging to LC. Then, we compared the LC-MRI parameters in PD patients with OH (PDOH+) versus without OH (PDOH-) (matched for sex, age, and disease duration) using one-way analysis of variance followed by multiple comparison tests. We also tested for correlations between subject's LC-MRI features and orthostatic drop in systolic blood pressure (SBP). PDOH- and PDOH+ did not differ significantly (p > 0.05) based on demographics and clinical characteristics, except for blood pressure measurements and SCOPA-AUT cardiovascular domain (p < 0.05). LCCR and LCVOX measures were significantly lower in PD compared to HC, while no differences were observed between PDOH- and PDOH+. Additionally, no correlation was found between the LC-MRI parameters and the orthostatic drop in SBP or the clinical severity of autonomic symptoms (p > 0.05). Conversely, RBD symptom severity negatively correlated with several LC-MRI parameters. Our results failed to indicate a link between the LC-MRI features and the presence of OH in PD but confirmed a marked alteration of LC signal in PD patients.

Different Patterns of Locus Coeruleus MRI Alteration in Alzheimer's and Dementia with Lewy Bodies.

BACKGROUND: The integrity of Locus Coeruleus can be evaluated in vivo using specific Magnetic Resonance Imaging sequences. While this nucleus has been shown to be degenerated both in post-mortem and in vivo studies in Alzheimer's Disease, for other neurodegenerative dementias such as Dementia with Lewy Bodies this has only been shown ex-vivo. OBJECTIVE: To evaluate the integrity of the Locus Coeruleus through Magnetic Resonance Imaging in patients suffering from Dementia with Lewy Bodies and explore the possible differences with the Locus Coeruleus alterations occurring in Alzheimer's Dementia. METHODS: Eleven patients with Dementia with Lewy Bodies and 35 with Alzheimer's Dementia were recruited and underwent Locus Coeruleus Magnetic Resonance Imaging, along with 52 cognitively intact, age-matched controls. Images were analyzed applying an already developed template-based approach; Locus Coeruleus signal was expressed through the Locus Coeruleus Contrast Ratio parameter, and a locoregional analysis was performed. RESULTS: Both groups of patients showed significantly lower values of Locus Coeruleus Contrast Ratio when compared to controls. A different pattern of spatial involvement was found; patients affected by Dementia with Lewy bodies showed global and bilateral involvement of the Locus Coeruleus, whereas the alterations in Alzheimer's Dementia patients were more likely to be localized in the rostral part of the left nucleus. CONCLUSIONS: Magnetic Resonance Imaging successfully detects widespread Locus Coeruleus degeneration in patients suffering from Dementia with Lewy Bodies. Further studies, in larger cohorts and in earlier stages of the disease, are needed to better disclose the potential diagnostic and prognostic role of this neuroradiological tool.

Perampanel as a novel treatment for subcortical myoclonus in myoclonus-dystonia syndrome.

BACKGROUND: Myoclonus-dystonia (MD) is a syndrome characterized by subcortical myoclonus and milder dystonia. The main causative gene is the epsilon sarcoglycan gene (SGCE), but other genes may be involved. Response to medications is variable, with poor tolerability limiting their use. CASE PRESENTATION: We present the case of a patient with severe myoclonic jerks and mild dystonia since childhood. At first neurological visit at the age of 46 years old, she presented brief myoclonic jerks predominating in the upper limbs and neck, mild at rest and elicited by action, posture and tactile stimulus. Myoclonus was accompanied by mild neck and right arm dystonia. Neurophysiological tests suggested subcortical origin of myoclonus, brain MRI was unremarkable. Myoclonus-dystonia was diagnosed, and genetic testing identified a novel mutation in SGCE gene (c.907delC) in heterozygosis. Over time she assumed a large variety of anti-epileptics without beneficial effect on myoclonus and low tolerability. Add-on treatment with Perampanel was started, with a beneficial effect. No adverse events were reported. Perampanel is the first selective non-competitive AMPA receptor antagonist approved in add-on for focal and generalized tonic-clonic seizures. To our knowledge, this is the first trial of Perampanel in MD. CONCLUSIONS: We presented the case of a patient with MD due to SGCE mutation who was treated with Perampanel with beneficial effects. We propose Perampanel as a novel treatment for myoclonus in MD.

Intestinal histomorphological and molecular alterations in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: Changes in gut microbiota composition, enteric inflammation, impairments of the intestinal epithelial barrier and neuroplastic changes in the enteric nervous system have been reported in Parkinson's disease (PD) patients and could contribute to the onset of both neurological and gastrointestinal symptoms. However, their mutual interplay has rarely been investigated. This study evaluated, in an integrated manner, changes in faecal microbiota composition, morphofunctional alterations of colonic mucosal barrier and changes of inflammatory markers in blood and stools of PD patients. METHODS: Nineteen PD patients and nineteen asymptomatic subjects were enrolled. Blood lipopolysaccharide binding protein (LBP, marker of altered intestinal permeability) and interleukin-1ß (IL-1ß) levels, as well as stool IL-1ß and tumour necrosis factor (TNF) levels, were evaluated. Gut microbiota analysis was performed. Epithelial mucins, collagen fibres, claudin-1 and S100-positive glial cells as markers of an impairment of the intestinal barrier, mucosal remodelling and enteric glial activation were evaluated on colonic mucosal specimens collected during colonoscopy. RESULTS: Faecal microbiota analysis revealed a significant difference in the α-diversity in PD patients compared to controls, while no differences were found in the ß-diversity. Compared to controls, PD patients showed significant chenags in plasma LBP levels, as well as faecal TNF and IL-1ß levels. The histological analysis showed a decrease in epithelial neutral mucins and claudin-1 expression and an increased expression of acidic mucins, collagen fibres and S100-positive glial cells. CONCLUSIONS: Parkinson's disease patients are characterized by enteric inflammation and increased intestinal epithelial barrier permeability, as well as colonic mucosal barrier remodelling, associated with changes in gut microbiota composition.

Negative DAT-SPECT in Old Onset Parkinson's Disease: An Additional Pitfall?

Background: Scans without evidence of dopaminergic deficit (SWEDDs) refer to patients clinically diagnosed with Parkinson's disease (PD), but showing normal findings on dopamine transporter single-photon emission computed tomography (DAT-SPECT). This entity remains highly debated, but recent findings suggesting that DAT-SPECT does not reflect either nigral cell bodies or striatal fibers of dopaminergic nigrostriatal neurons could improve our understanding of SWEDDs. Notably, compensatory downregulation of DAT in the early stages of PD seems to be less efficient in older-onset than in young-onset patients. Cases: We report eight patients with old-onset clinical parkinsonism and a positive response to levodopa in which DAT-SPECT was normal both visually and semiquantitatively. Two subjects demonstrated an abnormal scan when repeated later. Conclusions: We suggest that old-onset patients may truly have dopaminergic degeneration despite normal imaging results, presumably because they are diagnosed in the early stages confirming less efficient striatal compensatory strategies in old-age onset PD.

Fluid Biomarkers in Alzheimer's Disease and Other Neurodegenerative Disorders: Toward Integrative Diagnostic Frameworks and Tailored Treatments.

The diagnosis of neurodegenerative diseases (NDDs) represents an increasing social burden, with the unsolved issue of disease-modifying therapies (DMTs). The failure of clinical trials treating Alzheimer's Disease (AD) so far highlighted the need for a different approach in drug design and patient selection. Identifying subjects in the prodromal or early symptomatic phase is critical to slow down neurodegeneration, but the implementation of screening programs with this aim will have an ethical and social aftermath. Novel minimally invasive candidate biomarkers (derived from blood, saliva, olfactory brush) or classical cerebrospinal fluid (CSF) biomarkers have been developed in research settings to stratify patients with NDDs. Misfolded protein accumulation, neuroinflammation, and synaptic loss are the pathophysiological hallmarks detected by these biomarkers to refine diagnosis, prognosis, and target engagement of drugs in clinical trials. We reviewed fluid biomarkers of NDDs, considering their potential role as screening, diagnostic, or prognostic tool, and their present-day use in clinical trials (phase II and III). A special focus will be dedicated to novel techniques for the detection of misfolded proteins. Eventually, an applicative diagnostic algorithm will be proposed to translate the research data in clinical practice and select prodromal or early patients to be enrolled in the appropriate DMTs trials for NDDs.

Essential tremor and cognitive impairment: who, how, and why.

BACKGROUND AND AIMS: Recent years have witnessed the switch from considering essential tremor (ET) a monosymptomatic disorder to consider it as part of a spectrum, including other neurological signs, such as mild cognitive impairment and dementia, thus defining it as "ET plus." There are few data on cognitive impairment in ET patients. The aim of this review is to analyze the clinical characteristics of ET patients developing cognitive impairment, their neuropsychological profile, the underpinning mechanisms, and the possible biomarkers. METHODS: The authors performed a narrative review on cognitive decline in essential tremor, including articles written in English since the year 2000. DISCUSSION: The most recent pathogenetic theories of cognitive impairment in ET rely on the cerebellar dysfunction, being part of the Cerebellar Cognitive Affective Syndrome spectrum. Cognitive impairment in ET patients could be assessed through many tests that demonstrate the involvement of different domains, such as attention, executive functions, and language. There are some clinical characteristics of ET that may indicate a greater risk of developing cognitive impairment, namely, cerebellar symptoms, falls, age at onset, and family history. However, there are no established clinical, neurophysiological, neuropathological, and fluid biomarkers of cognitive impairment in ET. CONCLUSIONS: Increasing data are showing in ET the presence of cerebellar symptoms and cognitive impairment. Further studies are needed to better understand cognition in ET patients, and to define the boundary between ET and ET plus, since deeper phenotyping might have important clinical and therapeutic implications.

Dopamine Transporter Imaging, Current Status of a Potential Biomarker: A Comprehensive Review.

A major goal of current clinical research in Parkinson's disease (PD) is the validation and standardization of biomarkers enabling early diagnosis, predicting outcomes, understanding PD pathophysiology, and demonstrating target engagement in clinical trials. Molecular imaging with specific dopamine-related tracers offers a practical indirect imaging biomarker of PD, serving as a powerful tool to assess the status of presynaptic nigrostriatal terminals. In this review we provide an update on the dopamine transporter (DAT) imaging in PD and translate recent findings to potentially valuable clinical practice applications. The role of DAT imaging as diagnostic, preclinical and predictive biomarker is discussed, especially in view of recent evidence questioning the incontrovertible correlation between striatal DAT binding and nigral cell or axon counts.

Dissecting the Interplay Between Time of Dementia and Cognitive Profiles in Lewy Body Dementias.

BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are differentiated by the time of onset of cognitive and motor symptoms ('1-year rule'). We explored the neuropsychological continuum of DLB and PDD subjects with different timing of dementia onset. OBJECTIVE: Our aim was to compare the neuropsychological profile of DLB and PDD patients with different timing of dementia onset. METHODS: Neuropsychological findings at the diagnosis of dementia of 66 PDD and 42 DLB patients were retrospectively compared. Patients with PDD were divided into three tertile subgroups according to the time interval between the onset of parkinsonism and dementia (N = 24, 2-4 years; N = 17, 5-7 years; N = 25 ≥8 years, respectively). RESULTS: DLB patients performed worse on the Stroop and semantic fluency tests than PDD, even in comparison to PD with early dementia onset. No significant differences among PDD subgroups were reported. CONCLUSION: Executive and semantic language tests could differentiate DLB and PD patients with earlier development of dementia relative to parkinsonism.

Statins in Parkinson's Disease: Influence on Motor Progression.

BACKGROUND: It has been speculated that stains are neuroprotective and are associated with a reduced risk of Parkinson's disease (PD), but only a few studies have investigated the influence of statins on the progression of PD. OBJECTIVE: To evaluate whether long-term statin use may affect motor progression in a large cohort of de novo patients with PD. METHODS: We conducted a 4-year retrospective observational cohort study to assess patients with PD. The patients were consecutively recruited from a single tertiary center between January 2015 and January 2017. Information on motor function was obtained using the MDS-Unified Parkinson Disease Rating Scale (UPDRS)-III and all subjects were extensively characterized, including information about lifestyle habits, cardiovascular risk factors and cholesterol blood levels. RESULTS: Of the 181 participants included in the study, 104 patients were evaluated for eligibility (42 patients were exposed to statin therapies and 62 were not treated with statins). They presented similar scores in UPDRS III at baseline but the statin users had a lower motor impairment at 4 years compared to non-user PD patients. Additionally, statin treatment resulted in slower progression of the rigidity score of UPDRS over 4 years. No other significant differences were observed between PD patients with and without statins. CONCLUSION: Early PD patients with long-term statin usage showed lower motor deterioration after 4 years of disease duration compared with patients not taking statins at diagnosis, suggesting a possible influence of statins on disease progression in PD. Further investigation is warranted to understand the potential beneficial effects of statin treatment on clinical symptoms in PD.

Prevalence and Clinical Correlates of Comorbid Anxiety and Panic Disorders in Patients with Parkinson's Disease.

Mood and anxiety disorders are the most common neuropsychiatric syndromes associated with Parkinson's disease (PD). The aim of our study was to estimate the prevalence of lifetime and current anxiety disorders in patients with Parkinson's Disease (PD), to explore possible distinctive neurological and psychiatric features associated with such comorbidity. One hundred patients were consecutively recruited at the Movement Disorders Section of the Neurological Outpatient Clinic of the University of Pisa. According to the MINI-Plus 5.0.0, 41 subjects were diagnosed with lifetime anxiety disorder (22 with panic disorder) and 26 were diagnosed with current anxiety disorders. Patients with anxiety disorders were more frequently characterized by psychiatric symptoms preceding PD, lifetime major depression and antidepressant treatments. They showed more anxious temperamental traits and scored higher at Parkinson Anxiety Scale (PAS) and persistent anxiety subscale. Current anxiety disorders were associated with more severe psychopathology, depressive symptomatology, and avoidant behavior. Among anxiety subtypes, patients with lifetime panic disorder showed higher rates of psychiatric symptoms before PD, lifetime unipolar depression, current psychiatric treatment, and a more severe psychopathology. Given the overall high impact of anxiety on patients' quality of life, clinicians should not underestimate the extent of different anxiety dimensions in PD.

Understanding the Multiple Role of Mitochondria in Parkinson's Disease and Related Disorders: Lesson From Genetics and Protein-Interaction Network.

As neurons are highly energy-demanding cell, increasing evidence suggests that mitochondria play a large role in several age-related neurodegenerative diseases. Synaptic damage and mitochondrial dysfunction have been associated with early events in the pathogenesis of major neurodegenerative diseases, including Parkinson's disease, atypical parkinsonisms, and Huntington disease. Disruption of mitochondrial structure and dynamic is linked to increased levels of reactive oxygen species production, abnormal intracellular calcium levels, and reduced mitochondrial ATP production. However, recent research has uncovered a much more complex involvement of mitochondria in such disorders than has previously been appreciated, and a remarkable number of genes and proteins that contribute to the neurodegeneration cascade interact with mitochondria or affect mitochondrial function. In this review, we aim to summarize and discuss the deep interconnections between mitochondrial dysfunction and basal ganglia disorders, with an emphasis into the molecular triggers to the disease process. Understanding the regulation of mitochondrial pathways may be beneficial in finding pharmacological or non-pharmacological interventions to delay the onset of neurodegenerative diseases.

Mild Cognitive Impairment in de novo Parkinson's Disease: Selective Attention Deficit as Early Sign of Neurocognitive Decay.

Background: In the present study, we aimed to better investigate attention system profile of Parkinson's disease-Mild Cognitive Impairment (PD-MCI) patients and to determine if specific attentional deficits are associated with 123I-FP-CIT SPECT. Methods: A total of 44 de novo drug-naïve PD patients [(27) with normal cognition (PD-NC) and 17 with MCI (PD-MCI)], 23 MCI patients and 23 individuals with subjective cognitive impairment (SCI) were recruited at the Clinical Neurology Unit of Santa Chiara hospital (Pisa University Medical School, Italy). They were assessed by a wide neuropsychological battery, including Visual Search Test (VST) measuring selective attention. Performances among groups were compared by non-parametric tests (i.e., Kruskal-Wallis and Mann-Whitney, Bonferroni corrected). Further, Spearman's rank correlations were performed to explore the association between neuropsychological variables and 123I-FP-CIT SPECT data in PD subgroup. Results: PD-MCI patients performed worse on VST than patients with PD-NC (p = 0.002), patients with MCI and individuals with SCI (p < 0.001). The performance of PD-MCI patients on VST significantly correlated with caudate nucleus 123I-FP-CIT SPECT uptake (rho = 0.582, p < 0.05), whereas a negative correlation between such test and 123I-FP-CIT SPECT uptake in the left putamen (rho = -0.529, p < 0.05) was found in PD-NC patients. Conclusions: We suggest that selective attention deficit might be a trigger of cognitive decay in de novo PD-MCI patients. The VST should be routinely used to detect attentional deficits in hospital clinical practice, in the light of its closely association with dopamine depletion of basal ganglia in mildly impaired PD patients.

Progress regarding the context-of-use of tau as biomarker of Alzheimer's disease and other neurodegenerative diseases.

Introduction: Tau protein misfolding and accumulation in toxic species is a critical pathophysiological process of Alzheimer's disease (AD) and other neurodegenerative disorders (NDDs). Tau biomarkers, namely cerebrospinal fluid (CSF) total-tau (t-tau), 181-phosphorylated tau (p-tau), and tau-PET tracers, have been recently embedded in the diagnostic criteria for AD. Nevertheless, the role of tau as a diagnostic and prognostic biomarker for other NDDs remains controversial.Areas covered: We performed a systematical PubMed-based review of the most recent advances in tau-related biomarkers for NDDs. We focused on papers published from 2015 to 2020 assessing the diagnostic or prognostic value of each biomarker.Expert opinion: The assessment of tau biomarkers in alternative easily accessible matrices, through the development of ultrasensitive techniques, represents the most significant perspective for AD-biomarker research. In NDDs, novel tau isoforms (e.g. p-tau217) or proteolytic fragments (e.g. N-terminal fragments) may represent candidate diagnostic and prognostic biomarkers and may help monitoring disease progression. Protein misfolding amplification assays, allowing the identification of different tau strains (e.g. 3 R- vs. 4 R-tau) in CSF, may constitute a breakthrough for the in vivo stratification of NDDs. Tau-PET may help tracking the spatial-temporal evolution of tau pathophysiology in AD but its application outside the AD-spectrum deserves further studies.

α-Synuclein Heteromers in Red Blood Cells of Alzheimer's Disease and Lewy Body Dementia Patients.

BACKGROUND: Red blood cells (RBCs) contain the majority of α-synuclein (α-syn) in blood, representing an interesting model for studying the peripheral pathological alterations proved in neurodegeneration. OBJECTIVE: The current study aimed to investigate the diagnostic value of total α-syn, amyloid-ß (Aß1-42), tau, and their heteroaggregates in RBCs of Lewy body dementia (LBD) and Alzheimer's disease (AD) patients compared to healthy controls (HC). METHODS: By the use of enzyme-linked immunosorbent assays, RBCs concentrations of total α-syn, Aß1-42, tau, and their heteroaggregates (α-syn/Aß1-42 and α-syn/tau) were measured in 27 individuals with LBD (Parkinson's disease dementia, n = 17; dementia with Lewy bodies, n = 10), 51 individuals with AD (AD dementia, n = 37; prodromal AD, n = 14), and HC (n = 60). RESULTS: The total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in the LBD group and the AD group compared with HC, whereas α-syn/Aß1-42 concentrations were significantly lower in the AD dementia group only. RBC α-syn/tau heterodimers had a higher diagnostic accuracy for differentiating patients with LBD versus HC (AUROC = 0.80). CONCLUSION: RBC α-syn heteromers may be useful for differentiating between neurodegenerative dementias (LBD and AD) and HC. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBD from HC. However, they are not consistently different between LBD and AD. Our findings also suggest that α-syn, Aß1-42, and tau interact in vivo to promote the aggregation and accumulation of each other.

Connected speech in progressive supranuclear palsy: a possible role in differential diagnosis.

BACKGROUND: Progressive supranuclear palsy (PSP) is an atypical Parkinsonism characterized by motor and neuropsycological disorders. Language could be impaired in PSP patients, also in Richardson variant (PSP-RS). The analysis of connected speech is used in neurodegenerative disorder to investigate different levels of language organization, including phonetic, phonological, lexico-semantic, morpho-syntactic, and pragmatic processing. OBJECTIVE: In our study, we aimed to investigate the language profile, especially connected speech, in early-stage PSP-RS and Parkinson's disease (PD) patients without predominant speech or language disorders. METHODS: Language was assessed using the Screening for Aphasia in NeuroDegeneration (SAND); connected speech analysis was conducted from the picture description subtest. RESULTS: We enrolled 48 patients, 22 PD and 26 PSP (18 PSP-RS and 8 non-RS). PSP-RS patients presented an impairment in language domain, particularly regarding connected speech. PSP-RS patients presented worse performances than PD in different scores. The output of PSP-RS patients was characterized by a reduction in number of sentences and subordinates with respect to PD; PSP presented also more repaired sequences and phonological and lexico-semantic errors than PD. Number of sentences and number of subordinates of the picture description task were identified as predictors of PSP diagnosis. CONCLUSION: In summary, the SAND scale is able to identify language impairment in PSP patients. The analysis of connected speech could highlight some important aspects of language impairment in PSP-RS patients, and it could be helpful in the differential diagnosis with PD.