PEG-J replacement for duodenal levodopa infusion in Parkinson's disease patients: a retrospective study.

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.

Changes of olfactory tract in Parkinson's disease: a DTI tractography study.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Fiber tracking diffusion tensor imaging analysis of olfactory tract was feasible, and it could be helpful for characterizing hyposmia in Parkinson's disease.

Small-expanded allele spinocerebellar ataxia 17: imaging and phenotypic variability.

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.

Levodopa-responsive breathing discomfort in Parkinson's disease patients.

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.

CSF neurochemical profile and cognitive changes in Parkinson's disease with mild cognitive impairment.

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 (Aß42/40 ratio, sAPPα, sAPPß), 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.

Cerebrospinal fluid lipoproteins inhibit α-synuclein aggregation by interacting with oligomeric species in seed amplification assays.

BACKGROUND: Aggregation of α-synuclein (α-syn) is a prominent feature of Parkinson's disease (PD) and other synucleinopathies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially undermining unoptimized α-syn SAAs and preventing seed quantification. METHODS: In this study, we characterized the inhibitory effect of CSF milieu on detection of α-syn aggregates by means of CSF fractionation, mass spectrometry, immunoassays, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn. RESULTS: We found the high-molecular weight fraction of CSF (> 100,000 Da) to be highly inhibitory on α-syn aggregation and identified lipoproteins to be the main drivers of this effect. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, on the other hand we observed lipoprotein-α-syn complexes by transmission electron microscopy. These observations are compatible with hypothesizing an interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates. We observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of diagnostic SAA. Additionally, we observed a decreased inhibition capacity of CSF on α-syn aggregation after immunodepleting ApoA1 and ApoE. Finally, we observed that CSF ApoA1 and ApoE levels significantly correlated with SAA kinetic parameters in n = 31 SAA-negative control CSF samples spiked with preformed α-syn aggregates. CONCLUSIONS: Our results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results from analysis of SAA-derived kinetic parameters to date. Furthermore, our data show that lipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts.

Botulinum Toxin for the Treatment of Hemifacial Spasm: An Update on Clinical Studies.

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.

Impulse Control Disorders and Levodopa-Induced Dyskinesias in Parkinson's Disease: Pulsatile versus Continuous Dopaminergic Stimulation.

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.

T2*-weighted MRI values correlate with motor and cognitive dysfunction in Parkinson's disease.

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.