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Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE‐ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)‐ℰ4 isoform. Post‐mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non‐HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies. Assessment of neuropathological findings in individuals affected by pathological expansion of CAG HTT.

Idiopathic Parkinson’s disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies. Idiopathic Parkinson’s disease can be stratified according to the severity of neuronal respiratory complex I deficiency. The emerging disease subtypes show distinct molecular and clinical profiles.

Background/aimsTo assess the prevalence of non-motor symptoms (NMS) in Huntington’s disease (HD) and compare it with a cohort of patients with Parkinson’s disease (PD)Materials and MethodsPatients were consecutively recruited from the outpatient clinic. They were assessed through the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS-III), the motor part of the Unified Huntington’s Disease Rating Scale (UHDRS-motor) and the Total Functional Capacity (TFC). Non-motor symptoms were evaluated using the PD non-motor symptoms quest (NMSQuest) in both HD and PD patients.ResultsWe enrolled 123 participants: 53 HD, 45 PD and 25 healthy controls (HC). NMS were significantly more prevalent in HD patients than in HC. The most frequent NMS in HD were attentional deficits (73.58%), apathy (64.15%), dysphagia (62.26%), memory complaints (62.26%), depression (56.60%) and falls, insomnia and urinary urgency (50.94%). There was not statistical difference in the total score of NMS between early (1–2) vs. advanced stages (>3). Only dysphagia and memory complaints were more prevalent in the latter. The total score of the NMS was higher in HD than in PD (p=0.025) even though the duration of the disease was similar in both groups. HD scored significantly more than PD in 11 items (dysphagia, constipation, fecal incontinence, fecal tenesmus, weight loss, memory, apathy, attention, falls, nightmares, illusions).ConclusionsPatients with HD have a high prevalence of non-motor symptoms compared with HC. There is little difference between initial and advanced stages. The prevalence of non-motor symptoms is higher in HD than in PD.

Chronic inflammatory demyelinating polyradiculoneuropathy with NF155 antibodies (anti‐NF155+) constitutes a specific chronic inflammatory demyelinating polyradiculoneuropathy subset with a high incidence of limb's tremor and poor response to conventional therapies. We report a patient with chronic inflammatory demyelinating polyradiculoneuropathy anti‐NF155+ with a severe tremor involving limbs, head and voice that responded very well to rituximab. This response correlated with a sharp decrease in the anti‐NF155 titers. This case is the first report associating head and voice tremor to chronic inflammatory demyelinating polyradiculoneuropathy, reinforces the hypothesis of the cerebellar origin of this tremor and provides indirect evidence that the antibodies may be the cause of the tremor in these patients.

The accurate diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is hampered by imperfect clinical-pathological correlations. To assess and compare the diagnostic value of the magnetic resonance parkinsonism index (MRPI) and other magnetic resonance imaging-based measures of cerebral atrophy to differentiate between PSP, CBD, and other neurodegenerative diseases. This prospective diagnostic study included participants with 4-repeat tauopathies (4RT), PSP, CBD, other neurodegenerative diseases and available MRI who appeared in the University of California, San Francisco, Memory and Aging Center database. Data were collected from October 27, 1994, to September 29, 2019. Data were analyzed from March 1 to September 14, 2021. The main outcome of this study was the neuropathological diagnosis of PSP or CBD. The clinical diagnosis at the time of the MRI acquisition was noted. The imaging measures included the MRPI, cortical thickness, subcortical volumes, including the midbrain, pons, and superior cerebellar peduncle volumes. Multinomial logistic regression models (MLRM) combining different cortical and subcortical regions were defined to discriminate between PSP, CBD, and other pathologies. The areas under the receiver operating characteristic curves (AUROC) and cutoffs were calculated to differentiate between PSP, CBD, and other diseases. Of the 326 included participants, 176 (54%) were male, and the mean (SD) age at MRI was 64.1 (8.0) years. The MRPI showed good diagnostic accuracy for the differentiation between PSP and all other pathologies (accuracy, 87%; AUROC, 0.90; 95% CI, 0.86-0.95) and between 4RT and other pathologies (accuracy, 80%; AUROC, 0.82; 95% CI, 0.76-0.87), but did not allow the discrimination of participants with CBD. Its diagnostic accuracy was lower in the subgroup of patients without the canonical PSP-Richardson syndrome (PSP-RS) or probable corticobasal syndrome (CBS) at MRI. MLRM combining cortical and subcortical measurements showed the highest accuracy for the differentiation between PSP and other pathologies (accuracy, 95%; AUROC, 0.98; 95% CI, 0.97-0.99), CBD and other pathologies (accuracy, 83%; AUROC, 0.86; 95% CI, 0.81-0.91), 4RT and other pathologies (accuracy, 89%; AUROC, 0.94; 95% CI, 0.92-0.97), and PSP and CBD (accuracy, 91%; AUROC, 0.95; 95% CI, 0.91-0.99), even in participants without PSP-RS or CBS at MRI. In this study, the combination of widely available cortical and subcortical measures of atrophy on MRI discriminated between PSP, CBD, and other pathologies and could be used to support the diagnosis of 4RT in clinical practice.

The pathological hallmarks of multiple system atrophy and Parkinson's disease are, respectively, misfolded-α-synuclein-laden glial cytoplasmic inclusions and Lewy bodies. CSF-soluble misfolded α-synuclein aggregates (seeds) are readily detected in people with Parkinson's disease by α-synuclein seed amplification assay (synSAA), but identification of seeds associated with multiple system atrophy for diagnostic purposes has proven elusive. We aimed to assess whether a novel synSAA could reliably distinguish seeds from Lewy bodies and glial cytoplasmic inclusions. In this multicentre cohort study, a novel synSAA that multiplies and detects seeds by fluorescence was used to analyse masked CSF and brain samples from participants with either clinically diagnosed or pathology-confirmed multiple system atrophy, Parkinson's disease, dementia with Lewy bodies, isolated rapid eye movement sleep behaviour disorder (IRBD), disorders that were not synucleinopathies, or healthy controls. Participants were from eight available cohorts from seven medical centres in four countries: New York Brain Bank, New York, USA (NYBB); University of Pennsylvania, Philadelphia, PA, USA (UPENN); Paracelsus-Elena-Klinik, Kassel, Germany (DeNoPa and KAMSA); Hospital Clinic Barcelona, Spain (BARMSA); Universität Tübingen, Tübingen, Germany (EKUT); Göteborgs Universitet, Göteborgs, Sweden (UGOT); and Karolinska Institutet, Stockholm, Sweden (KIMSA). Clinical cohorts were classified for expected diagnostic accuracy as either research (longitudinal follow-up visits) or real-life (single visit). Sensitivity and specificity were estimated according to pathological (gold standard) and clinical (reference standard) diagnoses. In 23 brain samples (from the NYBB cohort), those containing Lewy bodies were synSAA-positive and produced high fluorescence amplification patterns (defined as type 1); those containing glial cytoplasmic inclusions were synSAA-positive and produced intermediate fluorescence (defined as type 2); and those without α-synuclein pathology produced below-threshold fluorescence and were synSAA-negative. In 21 pathology-confirmed CSF samples (from the UPENN cohort), those with Lewy bodies were synSAA-positive type 1; those with glial cytoplasmic inclusions were synSAA-positive type 2; and those with four-repeat tauopathy were synSAA-negative. In the DeNoPa research cohort (which had no samples from people with multiple system atrophy), the novel synSAA had sensitivities of 95% (95% CI 88–99) for 80 participants with Parkinson's disease and 95% (76–100) for 21 participants with IRBD, and a specificity of 95% (86–99) for 60 healthy controls. Overall (combining BARMSA, EKUT, KAMSA, UGOT, and KIMSA cohorts that were enriched for cases of multiple system atrophy), the novel synSAA had 87% sensitivity for multiple system atrophy (95% CI 80–93) and specificity for type 2 seeds was 77% (67–85). For participants with multiple system atrophy just in research cohorts (BARMSA and EKUT), the novel synSAA had a sensitivity of 84% (95% CI 71–92) and a specificity for type 2 seeds of 87% (74–95), whereas cases from real-life cohorts (KAMSA, KIMSA, and UGOT) had a sensitivity of 91% (95% CI 80–97) but a decreased specificity for type 2 seeds of 68% (53–81). The novel synSAA produced amplification patterns that enabled the identification of underlying α-synuclein pathology, showing two levels of fluorescence that corresponded with different pathological hallmarks of synucleinopathy. The synSAA might be useful for early diagnosis of synucleinopathies in clinical trials, and potentially for clinical use, but additional formal validation work is needed. Michael J Fox Foundation for Parkinson's Research, Amprion.

Background/aimsThe presence of non-motor symptoms in Huntington’s disease (HD) has not been systematically assessed so far. Our objective was to know their prevalence and to compare it with a cohort of patients with Parkinson’s disease (PD).Materials and methodsParticipants were consecutively recruited from our outpatient clinic. They were assessed through the motor part of the Unified Huntington’s Disease Rating Scale, the motor part of the Unified Parkinson’s Disease Rating Scale, the total functional capacity scale and the PD non-motor symptoms questionnaire.ResultsWe enrolled 123 participants: 53 HD, 45 PD and 25 healthy controls (HC). Non-motor symptoms were significantly more prevalent in HD patients than in HC. The most frequent non-motor symptoms in HD, involving more than 50% of patients, were attentional deficits, apathy, dysphagia, memory complaints, depression falls, insomnia and urinary urgency. The total score of non-motor symptoms correlated with disease duration, total functional capacity and disease stage. HD scored significantly higher than PD in 11 items (dysphagia, constipation, bowel incontinence, faecal tenesmus, weight loss, memory, apathy, attention, falls, nightmares, delusions) and in four domains (cognitive, hallucinations and delusions, digestive and cardiovascular). PD did not score significantly higher than HD in any domain.ConclusionsHD patients have a high prevalence of non-motor symptoms, which is even higher than in PD, and correlates with disease progression.

Over recent decades, the search for sensitive and specific biomarkers of degenerative parkinsonisms has intensified. So also has the number of clinical trials aimed at disease modification and the subsequent need for improved recruitment of participants in the earliest possible stages and with the highest diagnostic certainty. Also increasing in number have been searches for ways to determine target engagement and biological effect, along with tracking of disease progression or its modification. With post mortem neuropathological confirmation remaining the most definite diagnostic category for most conditions, the updated diagnostic criteria are slowly introducing some routine biomarkers as supportive tools, mostly related to symptoms such as loss of smell in Parkinson's Disease (PD) or demonstration of REM sleep behaviour disorders in both PD and multiple system atrophy (MSA), or structural or functional (chiefly dopaminergic) imaging, which sometimes lacks either sensitivity or specificity [specific MRI signs for MSA or progressive supranuclear palsy (PSP)]. However, potential new tools such as seed amplification assays (SAAs) and PET imaging of underlying alpha-synuclein and 4R-tau pathologies, while not without their own challenges, are being increasingly seen as the next generation of diagnostic tools. In this setting, proposals to biologically define these conditions, primarily for research purposes (which might eventually include clinical trials) are emerging. In this review, we aimed to overview of the current use of routine biomarkers and any future promise of biological definition by molecular markers tracking underlying pathology.

One of the most impactful non-motor manifestations of Parkinson’s disease (PD) is cognitive impairment. Cognitive decline in PD exists as a continuum, with symptoms ranging from normal cognition to mild cognitive impairment (MCI) and finally dementia (PDD). MCI is clinically heterogeneous and its progression varies with cases reverting to normal cognition. On the contrary, when dementia occurs, the decline is usually rapid and stereotyped. The combination of Lewy and Alzheimer’s disease pathology is the most robust pathological correlate of PDD. There are no approved drugs for PD-MCI and the benefit from the only approved symptomatic treatment for PDD is modest. This review aims to present the aspects in which greater evidence exists and summarize the epidemiology, pathogenesis, clinical features, diagnostic approach, and treatment of cognitive dysfunction and dementia in PD.

ObjectiveTo describe an adult patient with Rasmussen’s disease with focal dystonia as the most disabling symptom and the good response to unilateral globus pallidus internus (GPi) deep brain stimulation (DBS).MethodsRetrospective review of clinical records and diagnostic tests.ResultsThe patient had displayedmild focal seizures with sensory and motor symptoms on the left arm and hemiface since the age of 22. Ten years later she experienced abrupt onset of focal left dystonia involving mainly the leg. Brain MRI showed progressive right hemisphere atrophy, and  18 fluorodeoxyglucose-positron emission tomography (18FDG-PET) showed right hypometabolism mainly over the frontal and insular regions. Brain biopsy confirmed chronic encephalitis. The dystonia became very severe and made walking extremely difficult. Different treatments including dopaminergic, anticholinergic, immunomodulatory drugs and botulinum toxin were ineffective. Finally the patient was treated with unilateral GPi DBS. Shortly after the onset of the stimulation, the dystonia started to improve. Parameters have been adjusted, and 18 months after surgery the patient is able to walk and run unaided, although a mild left leg dystonia persists.ConclusionRasmussen’s disease may be difficult to diagnose in adult patients. Associated movement disorders may be more disabling than seizures. Focal dystonia may be treated successfully with DBS.