Parkinson's disease (PD) is typically managed by dopaminergic supplementation. As the disease progresses, most patients receiving levodopa treatment develop motor and non-motor symptoms that may be managed with therapy modifications. However, in time, they become refractory to conventional medical treatment and require device-aided therapies (DATs). The characterization of "on-off" periods and therapeutic efficacy variables in DATs have received ample attention in the literature, but only limited information is available on variables that affect the well-being of patients during "on" periods unrelated to their duration. In this Point of View article, therefore, we reflected on the concept of the quality of "on" periods - that is to say, the motor and non-motor fluctuating symptoms experienced during "on" time by patients with advanced PD (APD) treated with DATs that must be addressed and defined by acknowledging those issues raised by the patients as essential to their well-being. To explore this definition, a panel of experts in movement disorders met to discuss and subsequently conducted an exhaustive literature search. By this approach, we offer an analysis of symptoms that impact the quality of "on" periods in patients undergoing DATs which may be modifiable with therapy and propose a definition and initial approach to consider the quality of "on" as a therapeutic goal in treating persons with APD.

Objective Although Huntington's disease is characterized by motor onset, psychiatric disturbances may present years prior and affect functioning. However, there is inter-individual variability in psychiatric expression and progression. This study therefore strives to stratify longitudinal psychiatric signatures that may inform Huntington's disease prognosis, with potential clinical applications.Methods Forty-six Huntington's disease gene carriers (21 premanifest, 25 manifest; 31 female; age range 25-69) underwent short-Problem Behavior Assessment for depression, irritability, apathy, and dysexecutive behaviors for up to six longitudinal visits. The Disease Trajectories software, a machine-learning approach, was employed to perform unsupervised clustering of psychiatric trajectories. Linear fits were calculated for each cluster. Lastly, the main clusters of shared trajectories were assessed for group differences in demographic and clinical characteristics.Results The Disease Trajectories analysis software identified two main psychiatric patterns comprising premanifest and manifest patients that explained 54% of the sample. These two clusters evinced a dissociation in the development of depression and irritability; the first cluster was defined by increasing irritability with no depression and the second by a rise-and-fall in depression with no irritability. Both clusters showed a longitudinal increase in clinically relevant apathy and dysexecutive behaviors.Conclusions Ultimately, through the detection of individual-level psychiatric trajectories with machine-learning, this exploratory study reveals that a dissociation of depression and irritability is apparent even in premanifest stages. These findings underscore individual differences in the severity of longitudinal multivariate clinical characteristics for real-world patient stratification, with implications for precision medicine.

Huntington's disease (HD) is characterized by progressive neurodegeneration, often accompanied by disrupted iron regulation and altered white matter (WM) integrity. This study investigates iron content and microstructural changes in the anterior thalamic radiations (ATR) across different HD stages. Thirty-one gene carriers and twenty-four controls underwent neuropsychological assessment and 3 T-MRI scanning, including relaxometry and diffusion tensor imaging (DTI) sequences to assess iron content and WM microstructure. ATR changes were examined using average and along-the-tract analyses, with ANOVA and post-hoc Tukey tests to identify group differences and Spearman correlations to evaluate clinical associations. Machine-learning models were applied to assess the potential of MRI metrics as diagnostic biomarkers for HD, focusing on disease stage differentiation and presymptomatic detection. Premanifest individuals exhibited increased iron content and enhanced WM integrity bilaterally, while manifest patients maintained elevated left ATR iron levels alongside bilateral WM degeneration. Both ATRs contribute to the clinical manifestations of HD, including cognitive impairment and neuropsychiatric disturbances. Both along-the-tract relaxometry and DTI metrics emerged as promising biomarkers for distinguishing HD subgroups and identifying presymptomatic individuals. These findings highlight the interplay between iron dysregulation and WM disruption in HD, offering potential pathways for early diagnosis and targeted therapeutic strategies.

Background: Huntington’s disease is an inherited neurodegenerative disorder affecting striato-cortical circuits, with significant heterogeneity in the severity and progression of symptoms and neurodegenerative patterns. Objectives: To identify how distinct functional striato-cortical connectivity signatures may predict clinical profiles in Huntington’s disease. Methods: Thirty-eight Huntington’s disease gene expansion carriers underwent cross-sectional motor, cognitive, and behavioral assessments and multimodal MRI. Principal component analysis was employed to characterize Huntington’s disease clinical profiles. Next, seed-based whole-brain functional connectivity maps were derived for three basal ganglia seeds (caudate nucleus, putamen, nucleus accumbens) to delineate cortico-striatal connections. Multiple linear regressions assessed relationships between resulting clinical profiles and seed-based resting-state functional connectivity maps. Finally, basal ganglia gray matter volumes were examined in relation to clinical profiles and connectivity. Results: Principal component analysis identified two main clinical profiles in Huntington’s disease: motor-cognitive and behavioral. Multiple linear regression models revealed distinct functional neural signatures associated with each profile. Motor-cognitive symptoms related with a divergent connectivity pattern, specifically decreased connectivity between the caudate and putamen with executive and premotor areas, in contrast to increased connectivity between the ventral nucleus accumbens and executive network regions. Meanwhile, the behavioral profile was linked to decreased connectivity in limbic networks. Basal ganglia atrophy was associated with increased nucleus accumbens-cortical connectivity as well as motor-cognitive symptom severity. Conclusions: Distinct Huntington’s disease clinical profiles can be characterized by predominantly motor-cognitive or behavioral disturbances, each related with unique functional and structural brain signatures. This substantiates that striato-cortical circuits exhibit functional interaction and potential reorganization.

Huntington's disease (HD) is an inherited neurodegenerative condition characterized by motor, cognitive, and behavioral impairments. Apathy, marked by reduced motivation and goal-directed behavior, is the most prevalent psychiatric symptom in HD, impacting both patients and caregivers. Traditionally linked to executive dysfunction within the dorsolateral prefrontal cortex (dlPFC)-dorsal striatum loop in HD, the role of limbic regions in the basal ganglia and their impact on reward processing deficits remains poorly understood. This study sought to dissociate the functional correlates that are altered in reward valuation and may underlie apathy in HD. We aimed to tease apart whether apathy is associated with insensitivity to processing rewards, hypersensitivity to losses, or both, leading to the observed lack of motivation in apathetic individuals. Thirty-nine HD gene-expansion carriers (HDGEC) and 26 non-apathetic control participants underwent functional magnetic resonance imaging during a gambling task. The goal was to identify disrupted reward-related regions in HDGEC and their association with apathetic symptoms. Whole-brain analysis of gains and losses separately showed a significant reduction in activity, when HD group was compered to controls, within the left ventral striatum (VS), including the nucleus accumbens. The effect observed in the VS remained when clinically apathetic HDGEC were compared with controls. Conversely, non-apathetic HDGEC did not show any significant differences from controls. Interestingly, these group differences appeared exclusively during the processing of the reward. Additionally, higher levels of apathy were associated with especially decreased activity related with the processing of gains in this region. Our findings highlight the vulnerability of the left VS in HD and its association with the altered processing of gains, particularly in apathetic individuals, while preserving the valuation of losses. This suggests that reward insensitivity associated with VS dysfunction may be an important component of apathy in HD. Understanding the underlying mechanisms of reward processing and apathy in HD may help elucidate the implications of limbic regions as opposed to frontal executive dysfunction in apathy.

Lifelong cognitive engagement conveys benefits in Huntington's disease (HD) and may positively affect non-cognitive domains in other populations. However, the effect of lifelong cognitive engagement on the progression of motor and psychiatric domains in HD remains unknown, as is its neurobiological basis. Forty-five HD individuals completed the Cognitive Reserve Questionnaire (CRQ) and longitudinal clinical evaluation (maximum total of six visits, mean inter-assessment duration of 13.53 +/- 4.1 months). Of these, thirty-three underwent longitudinal neuroimaging (18 +/- 6 months follow-up). Generalized linear mixed-effects models were executed to predict the effect of individual differences in lifelong cognitive engagement on HD clinical progression and voxel-based morphometry to explore the impact of lifelong cognitive engagement on whole-brain gray matter volume atrophy. Controlling for age, disease stage, and sex, higher CRQ scores were associated with reduced overall severity and longitudinal progression across cognitive, motor, and psychiatric domains. Those with higher CRQ scores demonstrated reduced gray matter volume loss in the middle frontal gyrus, supplementary motor area, and middle cingulate. This putative impact on HD clinical progression may be conferred by preservation of brain volume in neural hubs that integrate executive function with action initiation and behavioral regulation, providing support for early cognitive engagement, even prior to diagnosis.

AbstractBackgroundDespite its impact on daily life, impulsivity in Huntington's disease (HD) is understudied as a neuropsychiatric symptom. Our aim is to characterize temporal impulsivity in HD and to disentangle the white matter correlate associated with impulsivity.MethodsForty‐seven HD individuals and 36 healthy controls were scanned and evaluated for temporal impulsivity using a delay‐discounting (DD) task and complementary Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Diffusion tensor imaging was employed to characterize the structural connectivity of three limbic tracts: the uncinate fasciculus (UF), the accumbofrontal tract (NAcc‐OFC), and the dorsolateral prefrontal cortex connectig the caudate nucleus (DLPFC‐cn). Multiple linear regression analyses were applied to analyze the relationship between impulsive behavior and white matter microstructural integrity.ResultsOur results revealed altered structural connectivity in the DLPC‐cn, the NAcc‐OFC and the UF in HD individuals. At the same time, the variability in structural connectivity of these tracts was associated with the individual differences in temporal impulsivity. Specifically, increased structural connectivity in the right NAcc‐OFC and reduced connectivity in the left UF were associated with higher temporal impulsivity scores.ConclusionsThe present findings highlight the importance of investigating the spectrum of temporal impulsivity in HD. As, while less prevalent than other psychiatric features, this symptom is still reported to significantly impact the quality of life of patients and caregivers. This study provides evidence that individual differences observed in temporal impulsivity may be explained by variability in limbic frontostriatal tracts, while shedding light on the role of sensitivity to reward in modulating impulsive behavior through the selection of immediate rewards.

AimsThe study's aim is to investigate the efficacy and safety of SOM3355 (bevantolol hydrochloride), a beta(1)-adrenoreceptor antagonist with recently identified vesicular monoamine transporter type 2 inhibitory properties, as a repositioned treatment to reduce chorea in Huntington's disease (HD). MethodsA randomized, placebo-controlled proof-of-concept study was performed in 32 HD patients allocated to 2 arms of 4 sequential 6-week periods each. Patients received placebo and SOM3355 at 100 and 200 mg twice daily in a crossover design. The primary endpoint was improvement by at least 2 points in the total maximal chorea score in any active drug period compared with the placebo period. ResultsThe primary endpoint was met in 57.1% of the patients. Improvements >= 3, >= 4, >= 5 and >= 6 points vs. placebo treatment were observed in 28.6, 25.0, 17.9 and 10.7% of the patients, respectively. A mixed-model analysis found a significant improvement in the total maximal chorea score of -1.14 (95% confidence interval, -2.11 to -0.16; P = .0224) with 200 mg twice daily SOM3355 treatment compared with placebo treatment. These results were paralleled by Clinical and Patient Global Impression of Change ratings (secondary endpoints). An elevation in plasma prolactin levels by 1.7-1.9-fold was recorded (P < .005), probably reflecting the effect on the dopamine pathway, consistent with vesicular monoamine transporter type 2 inhibition. The most frequent adverse events during SOM3355 administration were mild to moderate. ConclusionWithin the limits of this study, the results suggest that SOM3355 reduces chorea in patients with HD and is well-tolerated. Larger studies are necessary to confirm its therapeutic utility as an antichoreic drug.EudraCT number: 2018-000203-16 and Identifier: NCT03575676.

INTRODUCTION:Apathy, a prevalent feature in neurological disorders including Huntington's disease (HD), is characterized by a reduction in goal-directed behavior across cognitive, auto-activation (i.e., self-activating thoughts/behavior), and emotional domains. Nonetheless, current diagnostic criteria are incapable of distinguishing multidimensional apathy profiles. Meanwhile, the short-Lille Apathy Rating Scale (LARS-s) bears potential as an operative diagnostic tool to disentangle apathy dimensions in clinical practice. The present study thereby examines the psychometric properties and factor structure of the LARS-s to tap into apathy profiles and their underlying neural correlates in HD.METHODS:Forty HD individuals were scanned and evaluated for apathy using the LARS-s, assessed for reliability and validity in HD, and the short-Problem Behavior Assessment (PBA-s). To study the dimensional structure of apathy, principal component analysis (PCA) of the LARS-s was implemented. Resulting factors were associated with gray matter volume through whole-brain voxel-based morphometry.RESULTS:The LARS-s demonstrated satisfactory psychometric properties, sharing convergent validity with PBA-s apathy and discriminant validity against depression. PCA resulted in three factors representative of apathy profiles across cognitive, auto-activation, and emotional domains. Anatomically, global apathy was significantly related with large-scale motor, cognitive, and limbic networks. Exploratory analyses of apathy profiles revealed correspondence between each factor and distinct cortical and subcortical nodes.CONCLUSION:The LARS-s is capable of capturing the multidimensional spectrum of apathy. At the same time, apathy profiles in HD are underpinned by functionally diverse neural networks. Such findings promote the continued study of apathy domains to pinpoint personalized therapeutic targets in neurologic disorders in addition to HD.

Background Although white matter (WM) abnormalities and subcortical iron accumulation are causal factors of neurodegeneration in Huntington’s disease (HD), their specific role is not clear yet. Aims: To understand the dynamics of the physiopathology process underlying in HD by using a multimodal temporo-spatial characterization of WM tracts (microstructural integrity and iron content). Methods Thirty-one HD gene-expansion carriers (12 premanifest, 19 manifest) and 24 healthy controls participated in this study. DTI and T2*-relaxometry were employed to characterize the structural connectivity and the iron distribution of eighteen main WM tracts. Three approaches have been used for the statistical analysis: average measure, segmental measures based on anatomic division of the tracts, and measures along the tract considering multiple points. Results Striatal medium spiny neurons are the most affected entailing basal ganglia atrophy with disruption of cortico-basal ganglia-thalamocortical circuits. Consequently, different WM tracts included in these circuits are presumed to be affected in presymptomatic stages as demonstrated in our study: motor function depending on putamino-pallidal connections (CST), limbic system depending on ventral striatum (cingulate), and executive function depending on caudate (ATR, forceps minor and forceps major). Associative tracts (uncinate, inferior longitudinal, superior longitudinal fronto-parietal and fronto-temporal fasciculus) are also altered in symptomatic stages, most probably as a consequence of transaxonal degeneration when the brain breaks down globally. Conclusion This study has allowed to depict the temporo-spatial dynamics of WM tracts disintegration in HD. In particular, while all tracts showed widespread disintegration as the disease progress, motor-related tracts present higher iron levels than non-motor-related tracts.

Background:Nonmotor symptoms (NMS) are common in advanced Parkinson's disease (APD) and reduce health-related quality of life.Objective:The aim of the study was to evaluate levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) on NMS in APD.Methods:INSIGHTS was a phase 3b, open-label, randomized, multicenter study in patients with APD (LCIG or OMT, 26 weeks) (NCT02549092). Primary outcomes assessed were total NMS (NMS scale (NMSS) and PD sleep scale (PDSS-2)). Key secondary outcomes included the Unified PD Rating Scale (UPDRS) Part II, Clinical Global Impression of Change (CGI-C), and PD Questionnaire-8 (PDQ-8). Additional secondary measures of Patient Global Impression of Change (PGIC), King's PD Pain Scale (KPPS), and Parkinson Anxiety Scale (PAS) also were evaluated. Finally, safety was assessed.Results:Out of 89 patients randomized, 87 were included in the analysis (LCIG, n = 43; OMT, n = 44). There were no significant differences in NMSS or PDSS-2 total score changes (baseline to Week 26) between LCIG and OMT; within-group changes were significant for NMSS (LCIG, p < 0.001; OMT, p = 0.005) and PDSS-2 (LCIG, p < 0.001; OMT, p < 0.001). Between-group treatment differences were nominally significant for UPDRS Part II (p = 0.006) and CGI-C (p < 0.001) at Week 26 in favor of LCIG; however, statistical significance could not be claimed in light of primary efficacy outcomes. PGIC (Week 26) and KPPS (Week 12) scores were nominally significantly reduced with LCIG versus OMT (p < 0.001; p < 0.05). There were no significant differences in PDQ-8 or PAS. Adverse events (AEs) were mostly mild to moderate; common serious AEs were pneumoperitoneum (n = 2) and stoma-site infection (n = 2) (LCIG).Conclusions:There were no significant differences between LCIG versus OMT in NMSS or PDSS-2; both LCIG and OMT groups significantly improved from baseline. AEs were consistent with the known safety profile.

Levodopa-carbidopa intestinal gel (LCIG) has shown to be efficacious in motor and non-motor symptoms (NMS). Nevertheless, studies with patient Quality of Life (QoL) as a primary endpoint are scarce. To assess the effect of LCIG on Advanced Parkinson’s Disease (APD) patients QoL. Secondarily, the impact on motor symptoms and NMS, emotional well-being, treatment satisfaction, and caregiver QoL, stress, disease burden, anxiety, depression, and work impairment were also investigated. In this prospective, 6-month multicenter postmarketing observational study, LCIG was administered to 59 patients with APD. Endpoints were assessed using validated scales and questionnaires. LCIG significantly improved patient QoL (PDQ-39 mean change ± standard deviation from baseline, −12.8 ± 14.6; P < 0.0001), motor symptoms (UPDRS-III in “On,” −6.5 ± 11.8; P = 0.0002), NMS (NMSS, −35.7 ± 31.1; P < 0.0001), mood (Norris/Bond-Lader VAS, −6.6 ± 21.1; P = 0.0297), fatigue (PFS-16, −0.6 ± 1.0; P = 0.0003), depression (BDI-II, −5.1 ± 9.4; P = 0.0002), anxiety (BAI, −6.2 ± 9.6; P < 0.0001), and patient treatment satisfaction (SATMED-Q, 16.1 ± 16.8; P < 0.0001). There were significant correlations between the change from baseline to 6 months between PDQ-39 and UPDRS-IV, NMSS, BAI, BDI-II, AS, and PFS-16 scores, and Norris/Bond-Lader alertness/sedation factor. Caregiver anxiety also improved (Goldberg anxiety scale, −1.1 ± 1.0; P = 0.0234), but the clinical relevance of this finding is questionable. The serious adverse events reported were similar to those previously described for LCIG. In patients with APD, LCIG improves QoL, motor symptoms and NMS, emotional well-being, and satisfaction with the treatment. Improvement in patient QoL is associated with improvements in motor complications, NMS, anxiety, depression, apathy and fatigue. Improvements in patients’ QoL does not correspond with improvements in caregivers’ QoL or burden.

Background While Huntington’s disease (HD) is diagnosed by motor onset, psychiatric disturbances may present years prior to formal diagnosis, bearing a significant burden on daily functioning. However, there is great inter-individual heterogeneity in psychiatric expression and evolution over time. As such, the present study strives to discern longitudinal psychiatric signatures that may inform patterns of HD progression. Methods Forty-seven HD gene-expansion carriers (23 premanifest, 24 manifest) underwent psychiatric evaluation with the short-Problem Behavior Assessment (PBA-s) for a maximum total of six longitudinal visits. Unsupervised clustering of weighted PBA-s scores was performed with the Disease Trajectories (DT) analysis software based on dynamic time warping, which allows the non-linear alignment of sequences that may vary in speed, but conceal similar temporal characteristics. Next, clusters with shared psychiatric evolution were assessed for group differences in diagnostic status and severity of psychiatric features. Results DT analysis identified eleven clusters, of which two psychiatric patterns (N≥5) of mixed diagnostic status were further analyzed. Clusters were defined by non-depressive and non-irritable temporal signatures, respectively. Meanwhile, both clusters increased in clinically-relevant apathy and executive dysfunction over time. Conclusion The present study underscores the inherent heterogeneity in HD, where psychiatric signatures may predict common disease trajectories, even in prodromal stages. Through the incipient detection of shared patterns of symptom evolution, these findings model the applicability of the DT analysis software in the clinical context, lending itself to the identification of specific profiles. A stratification of the patients could allow increasing both the likelihood of successful personalized therapeutic approaches and the sensitivity in the detection of biomarkers in clinical trials.

Parkinson’s disease (PD) is a chronic progressive and irreversible disease and the second most common neurodegenerative disease worldwide. In Spain, it affects around 120.000–150.000 individuals, and its prevalence is estimated to increase in the future. PD has a great impact on patients’ and caregivers’ lives and also entails a substantial socioeconomic burden. The aim of the present study was to examine the current situation and the 10-year PD forecast for Spain in order to optimize and design future management strategies. This study was performed using the modified Delphi method to try to obtain a consensus among a panel of movement disorders experts. According to the panel, future PD management will improve diagnostic capacity and follow-up, it will include multidisciplinary teams, and innovative treatments will be developed. The expansion of new technologies and studies on biomarkers will have an impact on future PD management, leading to more accurate diagnoses, prognoses, and individualized therapies. However, the socio-economic impact of the disease will continue to be significant by 2030, especially for patients in advanced stages. This study highlighted the unmet needs in diagnosis and treatment and how crucial it is to establish recommendations for future diagnostic and therapeutic management of PD.

Urinary tract infections (UTIs) are the most common infections in renal transplant recipients (RTR). Klebsiella spp is a well-recognized source of nosocomial infections in immunocompromised patients and is also the most common pathogen capable of producing extended-spectrum β-lactamases (ESBLs).We performed a retrospective cohort study reviewing medical records of patients followed-up at Gdańsk Transplantation Centre. We analyzed urine cultures performed within the first 12 months after renal transplantation (RT) with reference to clinical data. We recorded all Klebsiella spp UTIs.We studied urine cultures and clinical data from 335 RTRs. We observed 59 Klebsiella spp episodes in 24 RT patients, including 10 cases of acute graft pyelonephritis and 8 of urosepsis. More than half were caused by ESBL+, whereas there were no carbapenemase-producing strains. Almost 80% of episodes were diagnosed beginning from the second month post-transplantation. More than 60% of upper Klebsiella spp UTIs were due to ESBL+ strains, although we did not identify any host risk factors including vesico-ureteral reflux, strictures at the uretero-vesical junction, history of recurrent UTIs before RT, comorbidity measured by Charlson Comorbidity Index, history of acute rejection, use of induction, and type of immunosuppression used. Upper Klebsiella spp UTIs were slightly more prevalent in males with urinary flow impairment due to various reasons.Klebsiella spp virulence factors, not the host factors, seem to be mostly responsible for developing upper UTIs in RT patients.

Background Apathy, a common neuropsychiatric disturbance in Huntington's disease (HD), is subserved by a complex neurobiological network. However, no study has yet employed a whole-brain approach to examine underlying regional vulnerabilities that may precipitate apathy changes over time. Objectives To identify whole-brain gray matter volume (GMV) vulnerabilities that may predict longitudinal apathy development in HD. Methods Forty-five HD individuals (31 female) were scanned and evaluated for apathy and other neuropsychiatric features using the short-Problem Behavior Assessment for a maximum total of six longitudinal visits (including baseline). In order to identify regions where changes in GMV may describe changes in apathy, we performed longitudinal voxel-based morphometry (VBM) on those 33 participants with a magnetic resonance imaging (MRI) scan on their second visit at 18 +/- 6 months follow-up (78 MRI datasets). We next employed a generalized linear mixed-effects model (N = 45) to elucidate whether initial and specific GMV may predict apathy development over time. Results Utilizing longitudinal VBM, we revealed a relationship between increases in apathy and specific GMV atrophy in the right middle cingulate cortex (MCC). Furthermore, vulnerability in the right MCC volume at baseline successfully predicted the severity and progression of apathy over time. Conclusions This study highlights that individual differences in apathy in HD may be explained by variability in atrophy and initial vulnerabilities in the right MCC, a region implicated in action-initiation. These findings thus serve to facilitate the prediction of an apathetic profile, permitting targeted, time-sensitive interventions in neurodegenerative disease with potential implications in otherwise healthy populations. (c) 2021 International Parkinson and Movement Disorder Society