Pain is among the most prevalent, disabling, and underrecognized non-motor symptoms of Parkinson’s disease (PD), affecting approximately 40–85

Background:Leukodystrophies are inherited heterogeneous diseases that are predominantly characterized by degenerative changes in the white matter of the central nervous system. These disorders begin both in childhood and in adulthood and have a complex phenotype that includes involuntary movements specifically chorea. Methods:This paper describes two female patients for whom generalized chorea was the primary clinical manifestation of leukodystrophy. Literature search was done through PubMed database with aim to included articles that described case reports of patients (both adult and childhood-onset) with leukodystrophy presenting with chorea in patients with metachromatic leukodystrophy (MLD) or L-2-hydroxiglutaric aciduria (L2HGA). Results:The first case presents MLD with adult-onset chorea combined with cognitive-behavioral changes mimicking Huntington's disease, while the second case is caused by L2HGA and the diagnosis had been established in the adulthood. The search resulted in 163 articles, but only one in the end described phenotype suggestive of dyskinetic movement disorder. Discussion:Leukodystrophies, though primarily white matter disorders, can present with involuntary movements. Our cases with MLD and L2HGA highlight adult patients with chorea as a key manifestations, so metabolic and genetic testing is crucial in unexplained chorea. Highlights:Leukodystrophies cause white matter degeneration and involuntary movements. We present two cases: one with MLD mimicking Huntington's disease and one with L2HGA diagnosed in the adulthood. These clinical manifestations have not yet been precisely reported in the literature. This manuscript present rare adult-onset chorea in leukodystrophies and expands phenotypic diversity.

The GBA1 related Parkinson’s disease (PD) is associated with more severe non-motor symptoms. To date, studies of the role of GBA1 mutations in the occurrence of impulse control behaviours (ICBs) in PD have yielded controversial results. Our aim was to investigate the frequency and characteristics of ICBs in PD patients with GBA1 mutations. 213 consecutive PD patients were included. Clinical data were gathered via interviews and using the standard set of questionnaires. Genetic analysis of exons 8–11 of the GBA1 gene was performed for all participants. GBA1 variants were detected in 32 out of 213 patients (GBA-PD). ICBs were more frequent in GBA-PD (31.2

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with a high genetic and clinical heterogeneity. Numerous HSP patients remain genetically undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel variants and genes is needed. Our previous study analyzed 74 adult Serbian HSP patients from 65 families using panel of the 13 most common HSP genes in combination with a copy number variation analysis. Conclusive genetic findings were established in 23 patients from 19 families (29%). In the present study, nine patients from nine families previously negative on the HSP gene panel were selected for the whole exome sequencing (WES). Further, 44 newly diagnosed adult HSP patients from 44 families were sent to WES directly, since many studies showed WES may be used as the first step in HSP diagnosis. WES analysis of cohort 1 revealed a likely genetic cause in five (56%) of nine HSP families, including variants in the ETHE1 , ZFYVE26 , RNF170 , CAPN1 , and WASHC5 genes. In cohort 2, possible causative variants were found in seven (16%) of 44 patients (later updated to 27% when other diagnosis were excluded), comprising six different genes: SPAST , SPG11 , WASCH5 , KIF1A , KIF5A , and ABCD1 . These results expand the genetic spectrum of HSP patients in Serbia and the region with implications for molecular genetic diagnosis and future causative therapies. Wide HSP panel can be the first step in diagnosis, alongside with the copy number variation (CNV) analysis, while WES should be performed after.

Background Whether connectome mapping of structural and functional connectivity across the brain could be used to predict patterns of atrophy progression in patients with mild Parkinson disease (PD) has not been well studied. Purpose To assess the structural and functional connectivity of brain regions in healthy controls and its relationship with the spread of gray matter (GM) atrophy in patients with mild PD. Materials and Methods This prospective study included participants with mild PD and controls recruited from a single center between January 2012 and December 2023. Participants with PD underwent three-dimensional T1-weighted brain MRI, and the extent of regional GM atrophy was determined at baseline and every year for 3 years. The structural and functional brain connectome was constructed using diffusion tensor imaging and resting-state functional MRI in healthy controls. Disease exposure (DE) indexes-indexes of the pathology of each brain region-were defined as a function of the structural or functional connectivity of all the connected regions in the healthy connectome and the severity of atrophy of the connected regions in participants with PD. Partial correlations were tested between structural and functional DE indexes of each GM region at 1- or 2-year follow-up and atrophy progression at 2- or 3-year follow-up. Prediction models of atrophy at 2- or 3-year follow-up were constructed using exhaustive feature selection. Results A total of 86 participants with mild PD (mean age at MRI, 60 years ± 8 [SD]; 48 male) and 60 healthy controls (mean age at MRI, 62 years ± 9; 31 female) were included. DE indexes at 1 and 2 years were correlated with atrophy at 2 and 3 years (r range, 0.22-0.33; P value range, .002-.04). Models including DE indexes predicted GM atrophy accumulation over 3 years in the right caudate nucleus and some frontal, parietal, and temporal brain regions (R2 range, 0.40-0.61; all P < .001). Conclusion The structural and functional organization of the brain connectome plays a role in atrophy progression in the early stages of PD. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Yamada in this issue.

Wilson’s disease (WD) is an autosomal recessive inherited disorder of copper metabolism caused by mutations in the ATP7B gene, which is located on chromosome 13q14.3. The global genetic prevalence of WD at birth is approximately 13.9–15.4 per 100,000 population. Although WD is a rare condition associated with treatment efficacy, mortality rates in patients with WD (5–6.1%) are higher than healthy controls. Prevalent features of WD include hepatic, neurologic, and psychiatric syndromes, even though various signs and symptoms of the disease have been depicted to this point. If diagnosed and treated at an early stage, WD patients would likely improve and be often largely asymptomatic for the rest of their lives. Prompt diagnosis and lifelong treatment substantially affect outcome. We aimed to summarize current knowledge about WD epidemiology, genetics, clinical manifestations, diagnostic workup, and current WD management.

Parkinson’s disease (PD) progresses with motor fluctuations emerging several years after treatment initiation. Initially managed with oral medications, these fluctuations may later necessitate device-aided therapy (DATs). Globally, various DATs options are available, including continuous subcutaneous apomorphine infusion, deep brain stimulation, levodopa-carbidopa intestinal gel, levodopa-entacapone-carbidopa intestinal gel, and subcutaneous foslevodopa/foscarbidopa infusion, each with its complexities. Hence, matching complex patients with suitable therapy is critical. This review offers practical insights for physicians managing complex PD cases. Balancing evidence and experience is vital to select the most suitable DATs, considering factors like disease stage and patient preferences. Comparative analysis of DATs benefits and risks provides essential insights for clinicians and patients. Treatment sequences vary based on availability, patient needs, and disease progression. Less invasive options like apomorphine are often preferred initially, followed by other DATs if needed. Patient selection requires comprehensive evaluations, including motor function and cognitive status. Follow-up care involves symptom monitoring and adjusting medications. Customized treatment plans are essential for optimizing PD management with DATs.

The etiology of PD remains unclear, with aging identified as the primary risk factor. Epidemiological data show an increasing prevalence of PD with age, affecting 1 - 2% of persons over 65. The incidence of PD rises rapidly with age, peaking in the eighth decade of life. Motor symptoms in older PD patients are characterized by severe hypokinetic syndrome, axial features, and postural and gait difficulties. Non-motor symptoms, including cognitive impairment, sleep disorders, and dysautonomia, significantly impact quality of life. The prevalence of dementia and frailty increases with age and PD duration. This age group faces a higher risk of side effects from antiparkinsonian therapies, thus therapeutic adjustments are necessary to address the progression of both motor and non-motor symptoms. The differential diagnosis of PD involves distinguishing it from other Parkinsonian syndromes, which can be challenging due to overlapping symptoms and the absence of specific diagnostic tools. The presence of mild Parkinsonian signs in the aged population predicts worse outcomes, including dementia, disability, and mortality. This review provides a comprehensive overview of the clinical manifestations, therapeutic considerations, and differential diagnosis of PD in older adults, highlighting the importance of individualized treatment approaches.

INTRODUCTION:Motor imagery (MI) involves recreating a movement mentally without physically performing the movement itself. MI has a positive impact on motor performance, motor learning and neural plasticity. We analysed the connection between motor imagination and altered movement execution in individuals with dystonia, a complex sensorimotor disorder. The aim of our study was to examine MI ability in patients with functional dystonia (FD) in comparison to organic dystonia (OD). METHODS:Our case-control study involved 46 patients, 22 with FD and 24 with OD. The assessment consisted of specific questionnaire and standardized motor, cognitive and psychiatric scales. The KVIQ-20 was used to test MI in each patient. RESULTS:Patients with FD scored lower on both global visual and kinaesthetic scales of the KVIQ-20 exam compared to patients with OD (63.1 ± 18.5 vs. 73.7 ± 13.2, and 54.9 ± 21.9 vs. 68.8 ± 18.2, respectively). Patients with FD also exhibited visual and/or kinaesthetic MI impairment in different body segments. The internal perspective when imagining movements was preferred in both patients with FD and OD. CONCLUSION:FD patients showed global dysfunction of visual and kinaesthetic MI abilities. Techniques for MI improvements might have a potential role in dystonia rehabilitation.

Introduction/Aims: Understanding the differences in neuropsychiatric symptoms (NPSs) across tauopathies, particularly in the early stages of the disease, may aid in differential diagnosis. The aims of the research are as follows: a) to examine the patterns of NPSs in primary (frontotemporal dementia - FTD and progressive supranuclear palsy - PSP) and secondary (Alzheimer's disease - AD) tauopathies; b) to examine the differences in NPSs reported by patients and caregivers. Methods: The study included 312 patients, 176 of whom had a disease duration of ≤3 years. The presence of NPSs based on caregiver's report was assessed by neuropsychiatric questionnaire (NPI). Patient's assessment of NPSs was examined by Hamilton's Depression and Anxiety Scales and the Apathy Scale. Results: In AD, the most common and severe neuropsychiatric symptoms are mood disorders and apathy. In contrast, agitation-related symptoms are also prominent in FTD and PSP. The profile of NPSs in FTD and PSP is similar, but irritability and aberrant motor behavior are more pronounced in FTD, while sleep disturbances are dominant in PSP. The prevalence of NPSs reported by caregivers on NPI was higher than that reported by patients. Conclusions: FTD and PSP are characterized by more frequent and more severe NPSs and have distinct psychiatric patterns compared to AD, even in the early disease course. Caregiver's observations of the patient's behavior could be of key importance in distinguishing these tauopathies, particularly in the absence of hard motor and cognitive symptoms in early disease course. Assessments of depression, anxiety, and apathy by patients themselves and their caregivers differ significantly, and data from these two sources cannot be considered interchangeable and comparable.

IntroductionPU.1-mutated agammaglobulinemia (PU.MA) represents a recently described autosomal-dominant form of agammaglobulinemia caused by mutation of the SPI1 gene. This gene codes for PU.1 pioneer transcription factor important for the maturation of monocytes, B lymphocytes, and conventional dendritic cells. Only six cases with PU.MA, presenting with chronic sinopulmonary and systemic enteroviral infections, have been previously described. Accumulating literature evidence suggests a possible relationship between SPI1 mutation, microglial phagocytic dysfunction, and the development of Alzheimer’s disease (AD).Case descriptionWe present a Caucasian female patient born from a non-consanguineous marriage, who was diagnosed with agammaglobulinemia at the age of 15 years when the immunoglobulin replacement therapy was started. During the following seventeen years, she was treated for recurrent respiratory and intestinal infections. At the age of 33 years, the diagnosis of celiac-like disease was established. Five years later progressive cognitive deterioration, unstable gait, speech disturbances, and behavioral changes developed. Comprehensive microbiological investigations were negative, excluding possible infective etiology. Brain MRI, 18FDG-PET-CT, and neuropsychological testing were suggestive for a diagnosis of a frontal variant of AD. Clinical exome sequencing revealed the presence of a novel frameshift heterozygous variant c.441dup in exon 4 of the SPI1 gene. Despite intensive therapy, the patient passed away a few months after the onset of the first neurological symptoms.ConclusionWe describe the first case of PU.MA patient presenting with a rapidly progressive neurocognitive deterioration. The possible role of microglial dysfunction in patients with SPI1 mutation could explain their susceptibility to neurodegenerative diseases thus highlighting the importance of genetic testing in patients with inborn errors of immunity. Since PU.MA represents a newly described form of agammaglobulinemia, our case expands the spectrum of manifestations associated with SPI1 mutation.

Background: In older age, walking ability gradually decreases due to factors including impaired balance, reduced muscle strength, and impaired vision and proprioception. Further, cognitive functions play a key role during walking and gradually decline with age. There is greater variability in gait parameters when the demands during walking increase, in dual- and multiple-task situations. The aim of this study was to analyze gait parameters while performing a demanding cognitive and motor dual task in three different age-related healthy elderly subject groups. Method: A total of 132 healthy individuals (54 males, 78 females) were divided into three groups—55 to 65, 66 to 75, and 76 to 85 years. The subjects performed a basic walking task, dual motor task, dual mental task, and combined motor and mental task while walking. The gait parameters cycle time, stride length, swing time, and double support time were noted, as well as the variability of those parameters. Results: Cycle time was longer and stride length was shorter in the >76-year-old group than in the 51–65-year-old group in all test conditions. A comparison of all three groups did not show a significant difference in swing time, while double support time was increased in the same group. Conclusions: Changes are observed when gait is performed simultaneously with an additional motor or cognitive task. Early detection of gait disorders can help identify elderly people at increased risk of falls. Employing a dual-task paradigm during gait assessment in healthy elderly subjects may help identify cognitive impairment early in the course of the disturbance.

To decipher the mechanisms of network-based neurodegeneration in Parkinson's disease (PD) investigating the relationship between functional connectivity (FC) in healthy connectome and grey matter (GM) atrophy accumulation in mild PD patients, and to develop a predictive model for atrophy spreading in PD.

Wilson?s disease (WD) is an autosomal recessive inherited disorder of copper metabolism caused by mutations in the ATP7B gene, which is located on chromosome 13q14.3. The global genetic prevalence of WD at birth is approximately 13.9?15.4 per 100,000 population. Although WD is a rare condition associated with treatment efficacy, mortality rates in patients with WD (5?6.1%) are higher than healthy controls. Prevalent features of WD include hepatic, neurologic, and psychiatric syndromes, even though various signs and symptoms of the disease have been depicted to this point. If diagnosed and treated at an early stage, WD patients would likely improve and be often largely asymptomatic for the rest of their lives. Prompt diagnosis and lifelong treatment substantially affect outcome. We aimed to summarize current knowledge about WD epidemiology, genetics, clinical manifestations, diagnostic workup, and current WD management.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

BACKGROUND:The hypothesis that the effectiveness of deep brain stimulation (DBS) in Parkinson's disease (PD) would be related to connectivity dysfunctions between the site of stimulation and other brain regions is growing.OBJECTIVE:To investigate how the subthalamic nucleus (STN), the most frequently used DBS target for PD, is functionally linked to other brain regions in PD patients according to DBS eligibility.METHODS:Clinical data and resting-state functional MRI were acquired from 60 PD patients and 60 age- and sex-matched healthy subjects within an ongoing longitudinal project. PD patients were divided into 19 patients eligible for DBS and 41 non-candidates. Bilateral STN were selected as regions of interest and a seed-based functional MRI connectivity analysis was performed.RESULTS:A decreased functional connectivity between STN and sensorimotor cortex in both PD patient groups compared to controls was found. Whereas an increased functional connectivity between STN and thalamus was found in PD patient groups relative to controls. Candidates for DBS showed a decreased functional connectivity between bilateral STN and bilateral sensorimotor areas relative to non-candidates. In patients eligible for DBS, a weaker STN functional connectivity with left supramarginal and angular gyri was related with a more severe rigidity and bradykinesia whereas a higher connectivity between STN and cerebellum/pons was related to poorer tremor score.CONCLUSION:Our results suggest that functional connectivity of STN varies among PD patients eligible or not for DBS. Future studies would confirm whether DBS modulates and restores functional connectivity between STN and sensorimotor areas in treated patients.