Background Olfactory dysfunction is a non-motor symptom and an important biomarker of Parkinson’s disease (PD) because of its high prevalence (> 90%). Whether hyposmia correlates with motor symptoms is unclear. In the present study, we aim to investigate the relationship between olfactory impairment with both motor and non-motor features and disease variables (disease duration, stage, and severity). Methods One-hundred fifty-four PD patients were evaluated. Odor identification ability was tested using Italian Olfactory Identification Test (IOIT). A comprehensive spectrum of motor and non-motor features was assessed. Cognitive function was investigated through MMSE. Patients were divided into 3 different clinical phenotypes using UPDRS-III: tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT). Results Three of the 33 IOIT items were most frequently misidentified: basil (74.3%), coffee (66.9%), and mushroom (59.6%). Hyposmia was found in 93%. Hyposmic patients were older than controls ( p = 0.01). Hoehn & Yahr (H&Y) score of 2 or greater was associated with higher probability of being hyposmic (OR = 5.2, p = 0.01). IOIT score did not significantly differ between TDT, ART, and MXT of analyzed PD patients. Performance to IOIT inversely correlated with age ( p < 0.01), disease duration ( p = 0.01), and H&Y score of 2 or higher ( p < 0.01). Clinical features that associated with higher IOIT score were freezing of gait (FOG) ( p < 0.001) and camptocormia ( p < 0.05). Conclusions In our cohort, IOIT scores showed a positive correlation with axial motor signs, but not with non-motor symptoms. IOIT may be a useful tool not only for supporting PD diagnosis but also for providing prognostic information about motor function.

Background: This is a retrospective longitudinal study comparing 374 patients with Parkinson’s disease (PD) who were treated in centers offering a specialized program of enhanced rehabilitation therapy in addition to expert outpatient care to 387 patients with PD, who only received expert outpatient care at movement disorders centers in Italy. Methods: The data are from subjects recruited in the Parkinson’s Outcome Project (POP) at six Italian centers that are part of a multicenter collaboration for care quality improvement (the Fresco Network). The effects were measured with a baseline and a follow-up clinical evaluation of the Timed-Up-and-Go test (TUG), Parkinson’s Disease Questionnaire (PDQ-39), and Multidimensional Caregiver Strain Index (MCSI), the number of falls and hospitalizations for any cause. We used a generalized linear mixed model with the dependent variables being the response variable, which included the covariates demographics, evaluation, and treatment variables. Results: We found that the subjects who underwent specialized enhanced rehabilitation had a better motor outcome over time than those who were managed by expert neurologists but had participated in community programs for exercise and other allied health interventions. The greatest effects were seen in patients in the early stages of the disease with a high amount of vigorous exercise per week in the last six months. Similar effects were seen for PDQ39, MCSI, the number of falls, and hospitalization. Conclusions: Long-term benefits to motor function and the quality of life in patients with PD and burden reduction in their caregivers can be achieved through a systematic program of specialized enhanced rehabilitation interventions.

Pathophysiological substrate(s) and progression of Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) are still matter of debate. Baseline cerebrospinal fluid (CSF) neurochemical profile and cognitive changes after 2 years were investigated in a retrospective series of PD-MCI (n = 48), cognitively normal PD (PD-CN, n = 40), prodromal Alzheimer's disease (MCI-AD, n = 25) and cognitively healthy individuals with other neurological diseases (OND, n = 44). CSF biomarkers reflecting amyloidosis (Aβ42/40 ratio, sAPPα, sAPPβ), tauopathy (p-tau), neurodegeneration (t-tau, NfL, p-NfH), synaptic damage (α-syn, neurogranin) and glial activation (sTREM2, YKL-40) were measured. The great majority (88%) of PD-MCI patients was A-/T-/N-. Among all biomarkers considered, only NfL/p-NfH ratio was significantly higher in PD-MCI vs. PD-CN (p = 0.02). After 2 years, one-third of PD-MCI patients worsened; such worsening was associated with higher baseline levels of NfL, p-tau, and sTREM2. PD-MCI is a heterogeneous entity requiring further investigations on larger, longitudinal cohorts with neuropathological verification.

Brain iron load is one of the most important neuropathological hallmarks in movement disorders. Specifically, the iron provides most of the paramagnetic metal signals in the brain and its accumulation seems to play a key role, although not completely explained, in the degeneration of the basal ganglia, as well as other brain structures. Moreover, iron distribution patterns have been implicated in depicting different movement disorders. This work reviewed current literature on Magnetic Resonance Imaging for Brain Iron Detection and Quantification (MRI-BIDQ) in neurodegenerative processes underlying movement disorders.

Abstract Background Reducing percutaneous endoscopic gastrostomies with jejunal extension tubes (PEG-J) related complications is vital to the long-term preservation of duodenal levodopa infusion (DLI) in advanced Parkinson’s disease (APD). Here, we provide data on the frequency of complications for both the standard “pull” and the non-endoscopic, radiologic assisted, “push” replacement PEG-J techniques in APD. Methods We retrospectively identified all patients treated with DLI from October 2009 to January 2020 at the Movement Disorders Center. Patients features and demographics, PEG-J procedures, causes for any discontinuation, reported complications and mortality were collected. In this cohort, PEG-J replacements were performed using the standard “pull” procedure or the radiologic assisted “push” method. Descriptive statistical analysis, t-test and paired t-test with False Discovery Rate correction was performed. Results This retrospective study included 30 APD patients [median age 72 ± 5.6 years; mean disease duration 17.2 + 5.7 years]. Mean treatment duration was 35.6 (30.6) months. Overall, 156 PEG-J procedures were performed, and Nineteen patients (63.3%) had a total of 185 reported complications, 85 of which were peristomal complications. 17 (56.6%) underwent 100 replacement procedures due to complications. The most commonly reported complication for replacement was J-tube dislocation (36%). One patient discontinued treatment after 6 months, due to peripheral neuropathy. Six patients died for causes not related to DLI. PEG-J replacements performed with the “push” method had a higher turnover (5.6 vs. 7.6 mo.), but fewer reported complications (67 vs. 75%). Conclusion The overall rate of complications was lower for “push” technique. This result might have been due to a higher replacement turnover that acted as a protective factor.

Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer's disease (AD) and Parkinson's disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response.

Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer's disease, fronto-temporal dementia, Parkinson's disease, Huntington's disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.

Spinocerebellar ataxia 17 (SCA17) is a rare genetic cause of adult-onset ataxia caused by an abnormal expansion of the CAG/CAA sequence in the TATA-box Binding Protein (TBP) gene. A number of repeats higher than 49 are full penetrance-expanded. The range between 41 and 49 repeats is characterized by decreased penetrance, and it is usually referred to as "small." Here, we describe two patients with the SCA17 phenotype and with 43 and 44 CAG repeats in the TBP gene, and review all the previously reported cases of SCA17 with a small range of expansions. We focus on both clinical features and imaging findings, which, in the case of small-expanded alleles, can resemble those of atypical parkinsonisms. Thus, we suggest to consider the small-expanded allele SCA17 as a possible diagnosis in patients with adult-onset ataxia, even when both clinical and imaging characteristics are suggestive for other non-genetic neurodegenerative diseases.

Mutations in the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene are associated with autosomal dominant lower extremity-predominant spinal muscular atrophy 1, neuromuscular and neurodevelopmental disorders and hereditary spastic paraplegia. We report a case of adult-onset Parkinson's disease associated to a mutation of DYNC1H1 gene.

Hemifacial spasm (HFS) is a movement disorder characterized by involuntary contractions of the facial muscles innervated by the seventh cranial nerve. Generally, it is associated with a poor quality of life due to social embarrassment and can lead to functional blindness. Moreover, it is a chronic condition, and spontaneous recovery is rare. Intramuscular injections of Botulinum Toxin (BoNT) are routinely used as HFS treatment. Methods: We reviewed published articles between 1991 and 2021 regarding the effectiveness and safety of BoNT in HFS as well as any reported differences among BoNT formulations. Results: The efficacy of BoNT for HFS treatment ranged from 73% to 98.4%. The mean duration of the effect was around 12 weeks. Effectiveness did not decrease over time. Adverse effects were usually mild and transient. The efficacy and tolerability of the different preparations appeared to be similar. Among the studies, dosage, injected muscles, intervals of treatment, and rating scales were variable, thus leading to challenges in comparing the results. Conclusions: BoNT was the treatment of choice for HFS due to its efficacy and safety profile. Further studies are needed to investigate the factors that influence the outcome, including the optimal timing of treatment, injection techniques, dosage, and the best selection criteria for formulations.

In synucleinopathies, the presence of an underlying Alzheimer's disease (AD) pathology can be involved in cognitive decline. Cerebrospinal fluid (CSF) profile consistent with amyloidosis, as well as CSF AD signature are sometimes reported in Parkinson's disease (PD) with dementia. Additionally, decreased CSF Aβ42 levels predict earlier appearance of cognitive decline in PD. However, contradictory results are available for CSF AD biomarkers in PD patients with mild cognitive impairment (PD-MCI). Our aim was to assess potential correlation between CSF AD biomarkers and PD-MCI.

Neuroinflammatory and neurodegenerative diseases are characterized by the interplay of a number of molecular pathways that can be assessed through biofluids, especially cerebrospinal fluid and blood. Accordingly, the definition and classification of these disorders will move from clinical and pathological to biological criteria. The consequences of this biomarker-based diagnostic and prognostic approach are highly relevant to the field of drug development. Indeed, in view of the availability of disease-modifying drugs, fluid biomarkers offer a unique opportunity for improving the quality and applicability of results from clinical trials. Herein, we discuss the benefits of using fluid biomarkers for patient stratification, target engagement, and outcome assessment, as well as the most recent developments in neuroinflammatory and neurodegenerative diseases.

BACKGROUND:Dopaminergic medications in Parkinson's disease (PD) are usually associated with the development of both levodopa-induced dyskinesias (LID) and impulse control and repetitive behavior disorders (ICRB). OBJECTIVE:To assess the prevalence and the severity of ICRB in a cohort of moderate and advanced PD patients and to investigate the potential interplay between ICRB, LID and dopaminergic therapies. METHODS:117 PD patients were consecutively recruited. LID were assessed by using the Rush Dyskinesia Rating Scale (RDRS). ICRB were tested by means of Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS). RESULTS:55 patients were affected by LID. Among them, 37 were treated only by oral therapy, OT (LID/OT), while 18 were on treatment with jejunal levodopa infusion, JLI (LID/JLI). 62 patients were not affected by LID (NLID) and all of them were on therapy only with oral drugs. The overall prevalence of clinically significant ICRB was 34% (95% CI = 26% to 43%) and the mean value (±SD) of QUIP-RS total score was 5.4±8.5. Prevalence of clinically significant ICRB, as well as severity of ICRB, was higher in patients with LID compared to NLID patients (p = 0.016 and p < 0.001, respectively). When considering LID/JLI, LID/OT and NLID groups, QUIP-RS total score was significantly higher in LID/OT patients compared to LID/JLI (10.4±11.8 vs. 4.9±6.0, p = 0.019) and NLID (10.4±11.8 vs. 2.5±4.8, p < 0.001) groups. CONCLUSION:PD patients with LID show ICRB more frequently and more severely than patients without LID. Among LID patients, those treated by JLI showed a lower severity of ICRB than those on OT, suggesting a potential protective effect of JLI on ICRB.

Neuropathological investigations report that in synucleinopathies with dementia, namely Parkinson’s disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB), the histopathological hallmarks of Alzheimer’s Disease (AD), in particular amyloid plaques, are frequently observed. In this study, we investigated the cerebrospinal fluid (CSF) AD biomarkers in different clinical phenotypes of synucleinopathies. CSF Aβ42/Aβ40 ratio, phosphorylated tau and total tau were measured as markers of amyloidosis (A), tauopathy (T) and neurodegeneration (N) respectively, in 98 PD (48 with mild cognitive impairment, PD-MCI; 50 cognitively unimpaired, PD-nMCI), 14 PDD and 15 DLB patients, and 48 neurological controls (CTRL). In our study, CSF AD biomarkers did not significantly differ between CTRL, PD-MCI and PD-nMCI patients. In PD-nMCI and PD-MCI groups, A-/T-/N- profile was the most represented. Prevalence of A+ was similar in PD-nMCI and PD-MCI (10% and 13%, respectively), being higher in PDD (64%) and in DLB (73%). DLB showed the lowest values of Aβ42/Aβ40 ratio. Higher total tau at baseline predicted a worse neuropsychological outcome after one year in PD-MCI. A+/T+, i.e., AD-like CSF profile, was most frequent in the DLB group (40% vs 29% in PDD).

Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer's disease (AD) biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.

Impaired olfactory function is one of the main features of Parkinson’s disease. However, how peripheral olfactory structures are involved remains unclear. Using diffusion tensor imaging fiber tracking, we investigated for MRI microstructural changes in the parkinsonian peripheral olfactory system and particularly the olfactory tract, in order to seek a better understanding of the structural alternations underlying hyposmia in Parkinson’s disease. All patients were assessed utilizing by the Italian Olfactory Identification Test for olfactory function and the Unified Parkinson’s Disease Rating Scale-III part as well as Hoehn and Yahr rating scale for motor disability. Imaging was performed on a 3 T Clinical MR scanner. MRI data pre-processing was carried out by DTIPrep, diffusion tensor imaging reconstruction, and fiber tracking using Diffusion Toolkit and tractography analysis by TrackVis. The following parameters were used for groupwise comparison: fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, and tract volume. Overall 23 patients with Parkinson’s disease (mean age 63.6 ± 9.3 years, UPDRS-III 24.5 ± 12.3, H&Y 1.9 ± 0.5) and 18 controls (mean age 56.3 ± 13.7 years) were recruited. All patients had been diagnosed hyposmic. Diffusion tensor imaging analysis of the olfactory tract showed significant fractional anisotropy, and tract volume decreases for the Parkinson’s disease group compared with controls (P < 0.05). Fractional anisotropy and age, in the control group, were significant for multiple correlations (r = − 0.36, P < 0.05, Spearman’s rank correlation). Fiber tracking diffusion tensor imaging analysis of olfactory tract was feasible, and it could be helpful for characterizing hyposmia in Parkinson’s disease.

To create an objective rating tool for hemifacial spasm (HFS) and validate it on a cohort of patients. A panel of movement disorders specialists elaborated, through the Delphi method, the Hemifacial Spasm Grading Scale (HSGS). The validity of the scale was tested in a longitudinal, prospective observational study, with standardized video recording protocol before and after botulinum neurotoxin (BoNT) treatment. The video recordings obtained from each patient were then independently assessed with HSGS by three blinded raters. The scale was compared to patient-reported HFS-7 scale and to the clinical grading of spasm intensity scale. Intra-rater reproducibility ranged between ICC 0.73 (95% CI = 0.54–0.86) and 0.83 (0.68–0.92) and inter-rater reproducibility between 0.62 (95% CI = 0.44–0.77) and 0.82 (0.69–0.90). HSGS scores correlated with clinical grading of spasm intensity scale scores, but not with HFS-7. HSGS confirmed BoNT efficacy, with scores lowering at 1 month from treatment. HSGS represents an objective, quick and reliable scale for the assessment of HFS, and might be useful to monitor BoNT treatment efficacy over time.

Brain iron load is one of the main neuropathologic hallmarks of Parkinson's disease (PD). Previous studies indicated that iron in the substantia nigra (SN) is related to disease duration and motor impairment. We explore, through a cross-sectional study, the association between brain iron distribution, evaluated by T2*-weighted magnetic resonance imaging (T2*), and clinical features in a cohort of patients with PD. Thirty-two patients with PD, compared with 10 control subjects, were evaluated for motor and cognitive features (attention and working memory, executive functions, language, memory, and visuospatial function). They underwent a magnetic resonance imaging protocol including T2* analysis of specific brain regions of interest to measure iron load compared with healthy control subjects. We found that iron content of the SN correlated positively with both disease duration and Unified Parkinson's Disease Rating Scale III off score. Montreal Cognitive Assessment, Spatial Span, and Graded Naming Test scores were inversely associated with iron load of the SN, whereas Wechsler Adult Intelligence Scale-IV Similarities score showed an inverse relationship with iron content in all the regions of interest examined. Our findings suggest a relationship between topographic brain iron distribution and cognitive domain impairment.

In Parkinson’s disease (PD), respiratory disturbances have been reported and the effect of levodopa on respiratory function remains controversial. The objective of this study was to evaluate pulmonary function utilizing spirometric and subjective evaluations in mild to moderated PD. Thirty-four consecutive sporadic PD patients (Hoehn and Yahr scale: 1–3) were prospectively evaluated using clinimetric scales, spirometry and modified Borg scale, all in off- and on-conditions. To check the respiratory function, a follow-up was performed at 4 years in a subgroup of these patients. Spirometric results were normal for all patients in both the on- and off-conditions at baseline. After levodopa administration, in addition to a significant improvement in subjective state of breathing discomfort, the mean forced expiratory volume in 1 s (FEV1), vital capacity (VC), forced vital capacity (FVC) values and their mean percentages predicted values (FEV1%, VC%, FVC%) were significantly increased (p < 0.05). Moreover, residual volume, total lung capacity, and the FEV1/FVC ratio were not significantly different for the ON and OFF conditions. At 4-year follow-up no resulting variations in the baseline values for FEV1%, FVC% or VC% were revealed. The results from this prospective study suggest that PD patients report frequently pulmonary discomfort. Levodopa improves respiratory symptoms. Pulmonary restrictive and obstructive dysfunctions, when not present at baseline, might not be present at 4-year follow-up.