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Functional brain networks have preserved architectures in rest and task; nevertheless, previous work consistently demonstrated task-related brain functional reorganization. Efficient rest-to-task functional network reconfiguration is associated with better cognition in young adults. However, aging and cognitive load effects, as well as contributions of intra- and internetwork reconfiguration, remain unclear. We assessed age-related and load-dependent effects on global and network-specific functional reconfiguration between rest and a spatial working memory (SWM) task in young and older adults, then investigated associations between functional reconfiguration and SWM across loads and age groups. Overall, global and network-level functional reconfiguration between rest and task increased with age and load. Importantly, more efficient functional reconfiguration associated with better performance across age groups. However, older adults relied more on internetwork reconfiguration of higher cognitive and task-relevant networks. These reflect the consistent importance of efficient network updating despite recruitment of additional functional networks to offset reduction in neural resources and a change in brain functional topology in older adults. Our findings generalize the association between efficient functional reconfiguration and cognition to aging and demonstrate distinct brain functional reconfiguration patterns associated with SWM in aging, highlighting the importance of combining rest and task measures to study aging cognition., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2024 Massachusetts Institute of Technology.)

Competing Interests: The authors declared no conflict of interest.

Objectives: Current cognitive screening and diagnostic instruments rely on visually dependent tasks and are, therefore, not suitable to assess cognitive impairment (CI) in visually impaired older adults. We describe the content development of the VISually Independent test battery Of NeuroCOGnition (VISION-Cog)-a new diagnostic tool to evaluate CI in visually impaired older Singaporean adults., Design: The content development phase consisted of two iterative stages: a neuropsychological consultation and literature review (stage 1) and an expert-panel discussion (stage 2). In stage 1, we investigated currently available neuropsychological test batteries for CI to inform constructions of our preliminary test battery. We then deliberated this battery during a consensus meeting using the Modified Nominal Group technique (stage 2) to decide, via agreement of five experts, the content of a pilot neuropsychological battery for the visually impaired., Setting: Singapore Eye Research Institute., Participants: Stakeholders included researchers, psychologists, neurologists, neuro-ophthalmologists, geriatricians and psychiatrists., Outcome Measure: pilot VISION-Cog., Results: The two-stage process resulted in a pilot VISION-Cog consisting of nine vision-independent neuropsychological tests, including the modified spatial memory test, list learning, list recall and list recognition, adapted token test, semantic fluency, modified spatial analysis, verbal subtests of the frontal battery assessment, digit symbol, digit span forwards, and digit span backwards. These tests encompassed five cognitive domains-memory and learning, language, executive function, complex attention, and perceptual-motor abilities. The expert panel suggested improvements to the clarity of test instructions and culturally relevant test content. These suggestions were incorporated and iteratively pilot-tested by the study team until no further issues emerged., Conclusions: We have developed a five-domain and nine-test VISION-Cog pilot instrument capable of replacing vision-dependent diagnostic batteries in aiding the clinician-based diagnosis of CI in visually impaired older adults. Subsequent phases will examine the VISION-Cog's feasibility, comprehensibility and acceptability; and evaluate its diagnostic performance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We pilot-tested the VIS ually I ndependent test battery O f N euro COG nition (VISION-Cog) to determine its feasibility, comprehensibility and acceptability in evaluating cognitive impairment (CI) in visually impaired older Asian adults., Design: The VISION-Cog was iteratively fine-tuned through pilot studies and expert-panel discussion. In the first pilot study (Stage 1), we recruited 15 visually impaired and cognitively normal participants aged ≥60 years to examine the pilot VISION-Cog's feasibility (length of time to administer), comprehensibility (clarity of instructions) and acceptability (participant burden). We then presented the pilot results to the expert panel (Stage 2) who decided via agreement on a revised version of the VISION-Cog. Subsequently, we conducted a second pilot study (Stage 3) on another four participants to ascertain improvement in feasibility, comprehensibility and acceptability of the revised version., Setting: Singapore Eye Research Institute., Participants: Nineteen Asian adults aged ≥60 years with visual impairment (defined as near visual acuity worse than N8) were recruited., Outcome Measure: Revised VISION-Cog., Result: The VISION-Cog was deemed feasible, taking approximately 60 min to complete on average. All participants agreed that the test instructions were clear, and the battery did not cause undue discomfort or frustration. The data collector rated all tests as very user-friendly (score of 5/5). Minor modifications to the pilot VISION-Cog were suggested by the panel to improve its safety, clarity of instructions and content validity, which were incorporated and iteratively tested in the second pilot study until no further issues emerged., Conclusions: Using an iterative mixed-methods process, we have developed a feasible, comprehensible and acceptable 5-domain and 9-item visually independent VISION-Cog test battery suitable to assist CI diagnosis in older adults with visual impairment. We will assess its diagnostic potential against clinician-based assessment of CI in subsequent phases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: White matter hyperintensities, a neuroimaging marker of small-vessel cerebrovascular disease and apolipoprotein ε4 (APOE4) allele, are important dementia risk factors. However, APOE4 as a key effect modifier in the relationship between white matter hyperintensities and grey matter volume needs further exploration., Methods: One hundred ninety-two early-stage dementia (including mild cognitive impairment and mild dementia) and 259 cognitively unimpaired participants from a neurocognitive research cohort with neuroimaging data, APOE genotyping, and neuropsychological assessments were studied. We investigated independent and interactive effects of white matter hyperintensities and APOE4 on whole-brain voxel-wise grey matter volume using voxel-based morphometry (uncorrected p < 0.001; minimum cluster size = 100 voxels). We further assessed interactive effects between APOE4 and white matter hyperintensities on global cognition, memory, and executive function in early-stage dementia and cognitively unimpaired participants., Results: Independent of APOE4 status, higher white matter hyperintensity load was associated with greater grey matter atrophy across frontal, parietal, temporal, and occipital lobes in cognitively unimpaired and early-stage dementia subjects. However, interaction analyses and independent sample analyses revealed that APOE4 non-carriers demonstrated greater white matter hyperintensity-associated grey matter atrophy compared to APOE4 carriers in both cognitively unimpaired and early-stage dementia groups. Additional confirmatory analyses among APOE4 non-carriers demonstrated that white matter hyperintensities resulted in widespread grey matter loss. Analyses of cognitive function demonstrated that higher white matter hyperintensity load was associated with worse global (Mini-Mental State Examination, Montreal Cognitive Assessment) and executive function (Color Trails 2) in APOE4 non-carriers compared to APOE4 carriers in early-stage dementia but not cognitively unimpaired participants., Conclusions: The association between white matter hyperintensities and grey matter loss is more pronounced in APOE4 non-carriers than APOE4 carriers in the cognitively unimpaired and early-stage dementia stages. Furthermore, white matter hyperintensity presence results in poorer executive function in APOE4 non-carriers compared to APOE4 carriers. This finding may have significant impact on the design of clinical trials with disease modifying therapies., (© 2023. The Author(s).)

Objective: Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative disorders, including behavioural variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non-fluent variant PPA (nfvPPA). While a strong genetic component is implicated in FTD, genetic FTD in Asia is less frequently reported. We aimed to investigate the frequency of Southeast Asian FTD patients harbouring known genetic FTD variants., Methods: A total of 60 FTD-spectrum patients (25 familial and 35 sporadic) from Singapore and the Philippines were included. All underwent next-generation sequencing and repeat-primed PCR for C9orf72 expansion testing. Neurofilament light chain (NfL) levels were measured in a subset of patients., Results: Overall, 26.6% (16/60 cases) carried pathogenic or likely pathogenic variants in a FTD-related gene, including: MAPT Gln351Arg (n = 1); GRN Cys92Ter (n = 1), Ser301Ter (n = 2), c.462 + 1G > C (n = 1); C9orf72 expansion (35-70 repeats; n = 8); TREM2 Arg47Cys (n = 1); and OPTN frameshift insertion (n = 2). Genetic mutations accounted for 48% (12/25) of patients with familial FTD, and 11.4% (4/35) of patients with sporadic FTD. C9orf72 repeat expansions were the most common genetic mutation (13.3%, 8/60), followed by GRN (6.7%, 4/60) variants. Within mutation carriers, plasma NfL was highest in a C9orf72 expansion carrier, and CSF NfL was highest in a GRN splice variant carrier., Interpretation: In our cohort, genetic mutations are present in one-quarter of FTD-spectrum cases, and up to half of those with family history. Our findings highlight the importance of wider implementation of genetic testing in FTD patients from Southeast Asia., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common age-related neurodegenerative diseases comprising Lewy body spectrum disorders associated with cortical and subcortical Lewy body pathology. Over 30% of PD patients develop PD dementia (PDD), which describes dementia arising in the context of established idiopathic PD. Furthermore, Lewy bodies frequently accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD), where they are observed in the amygdala of approximately 60% of sporadic and familial AD. While PDD and DLB share similar pathological substrates, they differ in the temporal onset of motor and cognitive symptoms; however, protein markers to distinguish them are still lacking., Methods: Here, we systematically studied a series of AD and PD pathogenesis markers, as well as mitochondria, mitophagy, and neuroinflammation-related indicators, in the substantia nigra (SN), temporal cortex (TC), and caudate and putamen (CP) regions of human post-mortem brain samples from individuals with PDD and DLB and condition-matched controls., Results: We found that p-APP T668 (TC), α-synuclein (CP), and LC3II (CP) are all increased while the tyrosine hydroxylase (TH) (CP) is decreased in both PDD and DLB compared to control. Also, the levels of Aβ42 and DD2R, IBA1, and p-LRRK2 S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-Tau S199/202 in CP and DD2R, DRP1, and VPS35 in TC are all increased in PDD compared to DLB., Conclusions: Together, our comprehensive and systematic study identified a set of signature proteins that will help to understand the pathology and etiology of PDD and DLB at the molecular level., (© 2021. The Author(s).)

Background: Southeast Asia represents 10% of the global population, yet little is known about regional clinical characteristics of dementia and risk factors for dementia progression. This study aims to describe the clinico-demographic profiles of dementia in Southeast Asia and investigate the association of onset-type, education, and cerebrovascular disease (CVD) on dementia progression in a real-world clinic setting., Methods: In this longitudinal study, participants were consecutive series of 1606 patients with dementia from 2010 to 2019 from a tertiary memory clinic from Singapore. The frequency of dementia subtypes stratified into young-onset (YOD; <65 years age-at-onset) and late-onset dementia (LOD; ≥65 years age-at-onset) was studied. Association of onset-type (YOD or LOD), years of lifespan education, and CVD on the trajectory of cognition was evaluated using linear mixed models. The time to significant cognitive decline was investigated using Kaplan-Meier analysis., Results: Dementia of the Alzheimer's type (DAT) was the most common diagnosis (59.8%), followed by vascular dementia (14.9%) and frontotemporal dementia (11.1%). YOD patients accounted for 28.5% of all dementia patients. Patients with higher lifespan education had a steeper decline in global cognition (p<0.001), with this finding being more pronounced in YOD (p=0.0006). Older patients with a moderate-to-severe burden of CVD demonstrated a trend for a faster decline in global cognition compared to those with a mild burden., Conclusions: There is a high frequency of YOD with DAT being most common in our Southeast Asian memory clinic cohort. YOD patients with higher lifespan education and LOD patients with moderate-to-severe CVD experience a steep decline in cognition., (© 2021. The Author(s).)

Background: micro-RNAs (miRNAs) are stable, small, non-coding RNAs enriched in exosomes. Their variation in levels according to different disease etiologies have made them a promising diagnostic biomarker for neurodegenerative diseases such as Alzheimer's disease (AD). Altered expression of miR-320a, miR-328-3p, and miR-204-5p have been reported in AD and frontotemporal dementia (FTD)., Objective: To determine their reliability, we aimed to examine the expression of three exosomal miRNAs isolated from cerebrospinal fluid (CSF) of patients with young-onset AD and FTD (< 65 years), correlating with core AD biomarkers and cognitive scores., Methods: Exosomes were first isolated from CSF samples of 48 subjects (8 controls, 28 AD, and 12 FTD), followed by RNA extraction and quantitative PCR to measure the expression of miR-320a, miR-328-3p, and miR-204-5p., Results: Expression of all three markers (miR-320a ( p  = 0.005), miR-328-3p ( p  = 0.049), and miR-204-5p ( p  = 0.036)) were significantly lower in AD versus controls. miR-320a was reduced in FTD versus controls ( p  = 0.049) and miR-328-3p was lower in AD versus FTD ( p  = 0.054). Notably, lower miR-328-3p levels could differentiate AD from FTD and controls with an AUC of 0.702, 95% CI: 0.534- 0.870, and showed significant correlation with lower CSF Aβ 42 levels ( r  = 0.359, p  = 0.029). Pathway enrichment analysis identified potential targets of miR-328-3p implicated in the AMPK signaling pathway linked to amyloid-β and tau metabolism in AD., Conclusion: Overall, we demonstrated miR-320a and miR-204-5p as reliable biomarkers for AD and FTD and report miR-328-3p as a novel AD biomarker., Competing Interests: The authors have no conflict of interest to report., (© 2021 – The authors. Published by IOS Press.)

Objectives: Medical emergencies in psychiatric inpatients are challenging due to the model of care and limited medical resources. The study aims were to determine the triggers and outcomes of a medical emergency team (MET) call in psychiatric wards, and the risk factors for MET activation and mortality., Design: Retrospective multisite cohort study., Setting: Psychiatry units colocated with acute medical services at three major metropolitan hospitals in Melbourne, Australia., Participants: We studied 487 adult inpatients who experienced a total of 721 MET calls between January 2015 and January 2020. Patients were relatively young (mean age, 45 years) and had few medical comorbidities, but a high prevalence of smoking, excessive alcohol intake and illicit drug use., Outcome Measures: We performed a descriptive analysis of the triggers and outcomes (transfer rates, investigations, final diagnosis) of MET calls. We used logistic regression to determine the factors associated with the primary outcome of inpatient mortality, and the secondary outcome of the need for specific medical treatment compared with simple observation., Results: The most common MET triggers were a reduced Glasgow Coma Scale, tachycardia and hypotension, and 49% of patients required transfer. The most frequent diagnosis was a drug adverse effect or toxidrome, followed by infection and dehydration. There was a strong association between a leave of absence and MET calls, tachycardia and the final diagnosis of drug adverse effects. Mortality occurred in 3% after MET calls. Several baseline and MET clinical variables were associated with mortality but a model with age (per 10 years, OR 1.61, 95% CI 1.29 to 2.01) and hypoxia (OR 3.59, 95% CI 1.43 to 9.04) independently predicted mortality., Conclusion: Vigilance is required in patients returning from day leave, and drug adverse effects remain a challenging problem in psychiatric units. Hypoxic older patients with cardiovascular comorbidity have a higher risk of death., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene ( MAPT ), granulin precursor ( GRN ), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin ( OPTN ) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dominguez, Yu, Tan, Ng, De Guzman, Natividad, Daroy, Cano, Yu, Lian, Zeng, Lim, Foo and Ng.)

The use of antipsychotic medications is associated with side effects, but the occurrence of severe tachycardia (heart rate ≥ 130 per minute) is not well described. The aim of this study was to determine the frequency and strength of the association between antipsychotic use and severe tachycardia in an inpatient population of patients with mental illness, while considering factors which may contribute to tachycardia. We retrospectively analyzed data from 636 Medical Emergency Team (MET) calls occurring in 449 psychiatry inpatients in three metropolitan hospitals co-located with acute medical services, and used mixed-effects logistic regression to model the association between severe tachycardia and antipsychotic use. The median age of patients was 42 years and 39% had a diagnosis of schizophrenia or psychotic disorder. Among patients who experienced MET calls, the use of second-generation (atypical) antipsychotics was commonly encountered (70%), but the use of first-generation (conventional) antipsychotics was less prevalent (10%). Severe tachycardia was noted in 22% of all MET calls, and sinus tachycardia was the commonest cardiac rhythm. After adjusting for age, anticholinergic medication use, temperature >38 °C and hypoglycemia, and excluding patients with infection and venous thromboembolism, the odds ratio for severe tachycardia with antipsychotic medication use was 4.09 (95% CI: 1.64 to 10.2).

Leukodystrophies are a diverse group of genetic disorders that selectively involve the white matter of the brain and are a frequent cause of young-onset cognitive impairment. Genetic diagnosis is challenging. Data on the utility of incorporating brain magnetic resonance imaging (MRI) diagnostic algorithms with next-generation sequencing (NGS) for diagnosis in a real-life clinical setting is limited. We performed sequencing using a custom-designed panel of 200 neurodegeneration-associated genes on 45 patients with young-onset cognitive impairment with leukodystrophy, and classified them based on van der Knaap et al.'s MRI diagnostic algorithm. We found that 20/45 (44.4%) patients carried pathogenic variants or novel variants predicted to be pathogenic (one in CSF1R , two in HTRA1 and 17 in NOTCH3 ). All patients with an established genetic diagnosis had an MRI brain pattern consistent with a specific genetic condition/s. More than half (19/37, 51.4%) of patients with MRI changes consistent with vascular cognitive impairment secondary to small vessel disease (VCI-SVD) had pathogenic variants, including all patients with pathogenic NOTCH3 (17/19, 89.5%) and HTRA1 variants (2/19, 11.5%). Amongst patients harboring pathogenic NOTCH3 variants, 13/17 (76.5%) carried the p.R544C variant seen predominantly in East Asians. Anterior temporal white matter involvement was seen only in patients with pathogenic NOTCH3 variants (6/17, 35.3%). Overall, we demonstrated a high diagnostic utility incorporating a targeted neurodegeneration gene panel and MRI-based diagnostic algorithms in young-onset cognitive impairment patients with leukodystrophy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Tan, Lian, Tandiono, Foo, Lim, Kandiah, Tan and Ng.)

Background: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social-emotional functional deficits., Methods: In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled., Results: Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes., Conclusions: Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5'-untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long-read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92-138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26-380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD., Methods: Plasma NfL was measured in 199 participants (149 PD and 50 healthy controls, HC) using an ultrasensitive single molecule array. Patients were classified into TD or PIGD based on MDS-UPDRS components. After 2 years, 115 patients were reassessed. Association between NfL and clinical measures in PIGD and TD at baseline and at 2-year follow-up were analysed., Results: At baseline, plasma NfL levels were higher in PD than HC (8.8 ± 3.4 vs 16.2 ± 7.6 pg/ml, p < 0.0001), and differentiated PD from HC with a good diagnostic accuracy (AUC = 0.833, p < 0.001). At 2 years, NfL was higher in PIGD than TD (18.4 ± 14.5 vs 12.6 ± 4.4 pg/ml, p = 0.039). Within the PIGD group, higher NfL associated significantly with worse global cognition and UPDRS motor scores at baseline, and was able to predict motor and cognitive decline at a mean follow-up duration of 1.9 years, controlled for age, sex and disease duration., Conclusions: In this longitudinal study, we demonstrated for the first time the potential utility of plasma NfL as a diagnostic and prognostic biomarker in PIGD even at early stages of PD. These important novel findings will require further confirmation in larger, longitudinal PD cohorts.

Objective: The success of clinical research and tissue donation programs are highly dependent on recruitment of willing volunteers. A comprehensive survey of patient preferences and attitudes can help identify and address barriers hindering the recruitment for research., Method: This is a cross-sectional study on 105 Parkinson's disease patients who completed an interviewer-administered questionnaire., Results: Out of 105 respondents, 48% of patients had either already participated in clinical research or were keen to participate. About 80% believed clinical research to be safe for their health and privacy. More than 70% of participants were willing to donate blood, urine, or stool, while 16% were agreeable for cerebrospinal fluid sample donation. Motivating factors for clinical research included altruism (64%) and contribution to advance medical knowledge (64%). Common reasons for unwillingness towards clinical research included the risks involved (43%), time constraints (33%), and mobility challenges (24%)., Conclusion: The attitude of Singaporean Parkinson patients toward clinical research and tissue donation is encouraging with about half of the participants willing to support clinical research. Three-quarters of patients would support tissue donations. Participation in research may be further increased with greater patient and public education to overcome misconceptions and also by limiting the demands of studies., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 Shazma Khan et al.)

Parkinson's disease (PD) is characterized by Lewy bodies containing α-synuclein and ubiquitin aggregates, their co-occurrence possibly linked to a failure of the ubiquitin proteasome system. Ubiquitin C-terminal hydrolase L1 (UCHL1) plays an important role in maintenance of nervous system integrity, and overexpression of UCHL1 has been shown to increase ubiquitin levels within neurons. While cerebrospinal fluid ubiquitin levels were reported to be lower in PD vs controls, plasma UCHL1 levels and their relationship with clinical measures in PD has not been reported. We measured plasma UCHL1 levels using single molecule array (Simoa) in 291 subjects (242 PD and 49 healthy controls, HC). We found that UCHL1 levels were significantly higher in PD patients at moderate stages (Hoehn and Yahr, H&Y stage >2) vs milder PD (H&Y ≤2, p <0.001) and HC ( p =0.001). There was no significant difference in UCHL1 levels between PD patients at H&Y stages ≤2 vs HC. Across all PD patients, UCHL1 correlated significantly with UPDRS Part III motor scores ( β =3.87, 95% CI=0.43-7.31, p =0.028), but not with global cognition. Overall, we found that UCHL1 correlates with motor function in PD, with higher levels seen in later disease stages. These findings will be validated in longitudinal studies.

We utilized ultrasensitive single molecule technology to measure plasma alpha-synuclein in 221 subjects (51 controls, 170 PD). Plasma alpha-synuclein levels were significantly higher in PD than controls (15506.3 vs. 13057.0 pg/mL, P  = 0.037), adjusting for age and gender. In PD, alpha-synuclein levels did not vary by H&Y stage or UPDRS motor scores but were significantly higher in PD patients with poorer cognition (MMSE ≤ 25) than controls ( P  = 0.016, Bonferroni corrected P  = 0.047). Alpha-synuclein levels quantified using ultrasensitive single molecule technology discriminate PD from controls and correlate with cognitive severity. These preliminary findings require independent validation to determine the utility of this assay., Competing Interests: The authors declare no financial disclosures or competing interests.

Normal pressure hydrocephalus (NPH) is a syndrome comprising gait disturbance, cognitive decline and urinary incontinence that is an unique model of reversible brain injury, but it presents as a challenging spectrum of disease cohorts. Diffusion Tensor Imaging (DTI), with its ability to interrogate structural white matter patterns at a microarchitectural level, is a potentially useful tool for the confirmation and characterization of disease cohorts at the clinical-research interface. However, obstacles to its widespread use involve the need for consistent DTI analysis and interpretation tools across collaborator sites. We present the use of DTI profiles, a simplistic methodology to interpret white matter injury patterns based on the morphology of diffusivity parameters. We examined 13 patients with complex NPH, i.e., patients with NPH and overlay from multiple comorbidities, including vascular risk burden and neurodegenerative disease, undergoing extended CSF drainage, clinical assessments, and multi-modal MR imaging. Following appropriate exclusions, we compared the morphology of DTI profiles in such complex NPH patients ( n = 12, comprising 4 responders and 8 non-responders) to exemplar DTI profiles from a cohort of classic NPH patients ( n = 16) demonstrating responsiveness of white matter injury to ventriculo-peritoneal shunting. In the cohort of complex NPH patients, mean age was 71.3 ± 7.6 years (10 males, 2 females) with a mean MMSE score of 21.1. There were 5 age-matched healthy controls, mean age was 73.4 ± 7.2 years (1 male, 4 females) and mean MMSE score was 26.8. In the exemplar cohort of classic NPH patients, mean age was 74.7 ± 5.9 years (10 males, 6 females) and mean MMSE score was 24.1. There were 9 age-matched healthy controls, mean age was 69.4 ± 9.7 years (4 males, 5 females) and mean MMSE score was 28.6. We found that, despite the challenges of acquiring DTI metrics from differing scanners across collaborator sites and NPH patients presenting as differing cohorts along the spectrum of disease, DTI profiles for responsiveness to interventions were comparable. Distinct DTI characteristics were demonstrated for complex NPH responders vs. non-responders. The morphology of DTI profiles for complex NPH responders mimicked DTI patterns found in predominantly shunt-responsive patients undergoing intervention for classic NPH. However, DTI profiles for complex NPH non-responders was suggestive of atrophy. Our findings suggest that it is possible to use DTI profiles to provide a methodology for rapid description of differing cohorts of disease at the clinical-research interface. By describing DTI measures morphologically, it was possible to consistently compare white matter injury patterns across international collaborator datasets.

Co-existence of Parkinson's disease (PD) and essential tremor (ET) may reflect overlapping pathophysiology underlying both conditions. Furthermore, PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present with ET-like features, suggesting the possibility of common genetic underpinnings. Two common LRRK2 variants, R1398H and N551K, have been shown to be protective in multiple PD cohorts. We hypothesized that R1398H and N551K may show a similar effect in ET. In a case-control study involving 3198 subjects (2680 controls and 518 ET cases), R1398H was detected in 16.6% of ET cases compared to 18.0% in controls (OR = 0.91, 95% CI = 0.71-1.17, p = 0.46); while N551K was detected in 16.5% of ET cases compared to 18.0% of controls (OR = 0.89, 95% CI = 0.69-1.15, p = 0.37). While these results suggest that LRRK2 R1398H or N551K do not appear to modulate the risk of ET, it remains possible that a protective trend for both variants may be present in ET and a much larger sample size is required to identify this.

C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson's disease (PD), atypical parkinsonism, Alzheimer's disease (AD) and other aetiologies. We found that, overall, normal or intermediate C9orf72 repeat lengths are not associated with higher disease risk across these disorders, but intermediate allele sizes appear to associate more frequently with neuropsychiatric phenotypes. Intermediate sizes were detected in subjects with personal or family history of FTD and/or psychiatric illness, parkinsonism complicated by psychosis and rarely in psychiatric cohorts. Length of the hexanucleotide repeat may be influenced by ethnicity (with Asian controls displaying shorter normal repeat lengths compared with Caucasians) and underlying haplotype, with more patients and controls carrying the 'risk' haplotype rs3849942 displaying intermediate alleles. There is some evidence that intermediate alleles display increased methylation levels and affect normal transcriptional activity of the C9orf72 promoter, but the 'critical' repeat size required for initiation of neurodegeneration remains unknown and requires further study. In common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms. This has important clinical relevance as intermediate carriers pose a challenge for genetic counselling., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Recent trials of anti-amyloid-β (Aβ) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits and their use comes with a significant risk of serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD and several AD risk genes related to immune response, including but not restricted to CD33 and TREM2. Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers and their role in characterizing the pathophysiology of AD. Main body: Neuroinflammation is recognized to be a crucial and contributing component of AD pathogenesis. The fact that neuroinflammation is most likely present from earliest pre-stages of AD and co-occurs with the deposition of Aβ reinforces the need to precisely define the sequence and nature of neuroinflammatory events. Numerous clinical trials involving anti-inflammatory drugs previously yielded unfavorable outcomes in early and mild-to-moderate AD. Although the reasons behind these failures remain unclear, these may include the time and the target selected for intervention. Indeed, in our review, we observed a stage-dependent neuroinflammatory process in the AD brain. While the initial activation of glial cells counteracts early brain Aβ deposition, the downregulation in the functional state of microglia occurs at more advanced disease stages. To address this issue, personalized neuroinflammatory modulation therapy is required. The emergence of reliable blood-based neuroinflammatory biomarkers, particularly glial fibrillary acidic protein, a marker of reactive astrocytes, may facilitate the classification of AD patients based on the ATI(N) biomarker framework. This expands upon the traditional classification of Aβ ("A"), tau ("T"), and neurodegeneration ("N"), by incorporating a novel inflammatory component ("I"). Conclusions: The present review outlines the current knowledge on potential neuroinflammatory biomarkers and, importantly, emphasizes the role of longitudinal analyses, which are needed to accurately monitor the dynamics of cerebral inflammation. Such a precise information on time and place will be required before anti-inflammatory therapeutic interventions can be considered for clinical evaluation. We propose that an effective anti-neuroinflammatory therapy should specifically target microglia and astrocytes, while considering the individual ATI(N) status of patients. [ABSTRACT FROM AUTHOR]

Background: Infant, junior, and adult patients with neuronal intranuclear inclusion disease (NIID) present with various types of seizures. We aimed to conduct a systematic literature review on the clinical characteristics of NIID with seizures to provide novel insight for early diagnosis and treatment and to improve prognosis of these patients. Methods: We used KEYWORDS: to screen articles related to NIID and seizures, and data concerning the clinical characteristics of patients, including demographic features, disease characteristics of the seizures, treatment responses, imaging examinations, and other auxiliary examination results were extracted. Results: The included studies comprised 21 patients with NIID with seizures. The most common clinical phenotypes were cognitive impairment (76.20%) and impaired consciousness (57.14%), and generalized onset motor seizures (46.15%) represented the most common type. Compared with infantile and juvenile cases, the use of antiepileptic drugs in adults led to significant seizure control and symptom improvement, in addition to providing a better prognosis. The number of GGC sequence repeats in the NOTCH2NLC gene in six NIID patients with seizures who underwent genetic testing ranged 72-134. Conclusion: The most common clinical phenotypes in patients with NIID with seizures were cognitive impairment and consciousness disorders. Patients with NIID presented with various types of seizures, with the most common being generalized onset motor seizures. Adult patients had a better prognosis and were relatively stable. The early diagnosis of NIID with seizures is of great significance for treatment and to improve prognosis. [ABSTRACT FROM AUTHOR]

Background: The use of structural and perfusion brain imaging in combination with behavioural information in the prediction of cognitive syndromes using a data-driven approach remains to be explored. Here, we thus examined the contribution of brain structural and perfusion imaging and behavioural features to the existing classification of cognitive syndromes using a data-driven approach. Methods: Study participants belonged to the community-based Biomarker and Cognition Cohort Study in Singapore who underwent neuropsychological assessments, structural-functional MRI and blood biomarkers. Participants had a diagnosis of cognitively normal (CN), subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and dementia. Cross-sectional structural and cerebral perfusion imaging, behavioural scale data including mild behaviour impairment checklist, Pittsburgh Sleep Quality Index and Depression, Anxiety and Stress scale data were obtained. Results: Three hundred seventy-three participants (mean age 60.7 years; 56% female sex) with complete data were included. Principal component analyses demonstrated that no single modality was informative for the classification of cognitive syndromes. However, multivariate glmnet analyses revealed a specific combination of frontal perfusion and temporo-frontal grey matter volume were key protective factors while the severity of mild behaviour impairment interest sub-domain and poor sleep quality were key at-risk factors contributing to the classification of CN, SCI, MCI and dementia (p < 0.0001). Moreover, the glmnet model showed best classification accuracy in differentiating between CN and MCI cognitive syndromes (AUC = 0.704; sensitivity = 0.698; specificity = 0.637). Conclusions: Brain structure, perfusion and behavioural features are important in the classification of cognitive syndromes and should be incorporated by clinicians and researchers. These findings illustrate the value of using multimodal data when examining syndrome severity and provide new insights into how cerebral perfusion and behavioural impairment influence classification of cognitive syndromes. [ABSTRACT FROM AUTHOR]

Introduction: Diagnosing acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) after the first seizure (early seizure/seizures, ES/ESs) is challenging because a reduced apparent diffusion coefficient (ADC) in the cortical or subcortical white matter, often described as having a “bright-tree appearance (BTA),” is usually not observed until secondary seizures (late seizures, LSs) occur. Previous studies have reported hypoperfusion on arterial spin labeling (ASL) within 24  h after ES/ESs in patients with AESD and hyperperfusion within 24  h after LS onset. This study aimed to investigate cerebral blood flow in the hyperacute phase (between ES/ESs and LSs) using ASL in patients with AESD. Methods: Eight ASL images were acquired in six patients with AESD admitted to our hospital from October 2021 to October 2022. ASL findings in the hyperacute phase were investigated and video-electroencephalogram findings obtained around ASL image acquisition in the hyperacute phase were evaluated. Results: Four ASL images were obtained for three patients before LS onset, with three images showing hyperperfusion areas and one image showing hypoperfusion areas. These hyperperfuion regions coincided with BTA on subsequent images of these patients. In one patient, the first ASL image was obtained in the late hyperacute phase and revealed hyperperfusion areas with a slightly abnormal change on diffusionweighted image (DWI), which were not accompanied by ADC abnormalities. The second ASL image obtained 51  h after the first ASL, and before LS onset revealed more prominent hyperperfusion areas than the first ASL image, which were accompanied by BTA. In another patient, the ASL image obtained 82  h after ES revealed hyperperfusion areas without abnormal change on DWI or ADC. Conclusion: This study revealed that two patients exhibited hyperperfusion regions and another patient exhibited hypoperfusion regions among three patients who underwent ASL imaging during the period from 24  h after ES/ESs to LSs in patients with LSs or cooling initiation in patients without LSs due to early anaesthesia induction (late hyperacute phase). Further prospective studies on cerebral blood flow are required to explore the relationship among the timing of image acquisition, the presence of electrographic seizures, and ASL findings in patients with AESD. [ABSTRACT FROM AUTHOR]

Background: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. Methods: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. Results: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. Conclusion: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges. [ABSTRACT FROM AUTHOR]

Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by widespread intranuclear inclusions in the nervous system as well as multiple visceral organs. In 2019, expanded GGC repeats within the 5′ untranslated region of the NOTCH2NLC gene was identified as the causative factor. NIID is a heterogeneous disorder with variable clinical manifestations including cognitive impairment, cerebellar ataxia, parkinsonism, paroxysmal symptoms, autonomic dysfunction, and muscle weakness. Although NIID primarily affects the central and peripheral nervous systems, growing evidence suggests potential cardiac abnormalities in NIID. However, the link between expanded GGC repeats within NOTCH2NLC and cardiac dysfunction remains uncertain. Results: In this study, we utilized two transgenic mouse models, expressing NOTCH2NLC-(GGC)98 ubiquitously or specifically in cardiomyocytes, and identified p62 (also known as sequestosome 1, SQSTM1)-positive intranuclear NOTCH2NLC-polyG inclusions in cardiomyocytes in two mouse models. We observed that both models exhibited cardiac-related pathological and echocardiographic changes, albeit exhibiting varying degrees of severity. Transcriptomic analysis revealed shared downregulation of genes related to ion channels and mitochondria in both models, with the cardiomyocyte-specific mice showing a more pronounced downregulation of mitochondria and energy metabolism-related pathways. Further investigations revealed decreased expression of mitochondria-related genes and electron transport chain activity. At last, we conducted a retrospective review of cardiac-related examination results from NIID patients at our hospital and also identified some cardiac abnormalities in NIID patients. Conclusions: Our study provided the first in vivo evidence linking GGC repeat expansions within NOTCH2NLC to cardiac abnormalities and highlighted the contribution of mitochondrial dysfunction in the development of cardiac abnormalities. [ABSTRACT FROM AUTHOR]

We have recently published the notion of the “vitals” of Parkinson’s, a conglomeration of signs and symptoms, largely nonmotor, that must not be missed and yet often not considered in neurological consultations, with considerable societal and personal detrimental consequences. This “dashboard,” termed the Chaudhuri’s vitals of Parkinson’s, are summarized as 5 key vital symptoms or signs and comprise of (a) motor, (b) nonmotor, (c) visual, gut, and oral health, (d) bone health and falls, and finally (e) comorbidities, comedication, and dopamine agonist side effects, such as impulse control disorders. Additionally, not addressing the vitals also may reflect inadequate management strategies, leading to worsening quality of life and diminished wellness, a new concept for people with Parkinson’s. In this paper, we discuss possible, simple to use, and clinically relevant tests that can be used to monitor the status of these vitals, so that these can be incorporated into clinical practice. We also use the term Parkinson’s syndrome to describe Parkinson’s disease, as the term “disease” is now abandoned in many countries, such as the U.K., reflecting the heterogeneity of Parkinson’s, which is now considered by many as a syndrome. [ABSTRACT FROM AUTHOR]

Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC "eraser" by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder characterized by intranuclear inclusions. Kidney injury involvement and successful treatment for NIID have rarely been reported. A NIID patient developed crescentic IgA nephropathy. Steroid therapy resolved digestive symptoms and recovered renal function. Steroids are considered for concomitant symptoms of NIID. [ABSTRACT FROM AUTHOR]

GGC repeat expansion in the 5′ untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes. [ABSTRACT FROM AUTHOR]

The increasing availability of molecular genetic testing has changed the landscape of both genetic research and clinical practice. Not only is the pace of discovery of novel disease‐causing genes accelerating but also the phenotypic spectra associated with previously known genes are expanding. These advancements lead to the awareness that some genetic movement disorders may cluster in certain ethnic populations and genetic pleiotropy may result in unique clinical presentations in specific ethnic groups. Thus, the characteristics, genetics and risk factors of movement disorders may differ between populations. Recognition of a particular clinical phenotype, combined with information about the ethnic origin of patients could lead to early and correct diagnosis and assist the development of future personalized medicine for patients with these disorders. Here, the Movement Disorders in Asia Task Force sought to review genetic movement disorders that are commonly seen in Asia, including Wilson's disease, spinocerebellar ataxias (SCA) types 12, 31, and 36, Gerstmann‐Sträussler‐Scheinker disease, PLA2G6‐related parkinsonism, adult‐onset neuronal intranuclear inclusion disease (NIID), and paroxysmal kinesigenic dyskinesia. We also review common disorders seen worldwide with specific mutations or presentations that occur frequently in Asians. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a heterogeneous movement disorder with patients manifesting with either tremor-dominant (TD) or postural instability and gait disturbance (PIGD) motor subtypes. Small nerve fiber damage occurs in patients with PD and may predict motor progression, but it is not known whether it differs between patients with different motor subtypes. Objective: The aim of this study was to explore whether there was an association between the extent of corneal nerve loss and different motor subtypes. Methods: Patients with PD classified as TD, PIGD, or mixed subtype underwent detailed clinical and neurological evaluation and corneal confocal microscopy (CCM). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were compared between groups, and the association between corneal nerve fiber loss and motor subtypes was investigated. Results: Of the 73 patients studied, 29 (40%) had TD, 34 (46%) had PIGD, and 10 (14%) had a mixed subtype. CNFD (no./mm2, 24.09 ± 4.58 versus 28.66 ± 4.27; p < 0.001), CNBD (no./mm2, 28.22 ± 11.11 versus 37.37 ± 12.76; p = 0.015), and CNFL (mm/mm2, 13.11 ± 2.79 versus 16.17 ± 2.37; p < 0.001) were significantly lower in the PIGD group compared with the TD group. Multivariate logistic regression showed that higher CNFD (OR = 1.265, p = 0.019) and CNFL (OR = 1.7060, p = 0.003) were significantly associated with the TD motor subtype. The receiver operating characteristic (ROC) analysis demonstrated that combined corneal nerve metrics showed excellent discrimination between TD and PIGD, with an area under the curve (AUC) of 0.832. Conclusion: Greater corneal nerve loss occurs in patients with PIGD compared with TD, and patients with a higher CNFD or CNFL were more likely to have the TD subtype. CCM may have clinical utility in differentiating different motor subtypes in PD. [ABSTRACT FROM AUTHOR]

Objective biomarkers for Parkinson's Disease (PD) could aid early and specific diagnosis, effective monitoring of disease progression, and improved design and interpretation of clinical trials. Although alpha-synuclein remains a biomarker candidate of interest, the multifactorial and heterogenous nature of PD highlights the need for a PD biomarker panel. Ideal biomarker candidates include markers that are detectable in easily accessible samples, (ideally blood) and that reflect the underlying pathological process of PD. In the present study, we explored the diagnostic and prognostic PD biomarker potential of the SIMOA neurology 4-plex-A biomarker panel, which included neurofilament light (NFL), glial fibrillary acid protein (GFAP), tau and ubiquitin C-terminal hydrolase L1 (UCHL-1). We initially performed a serum vs plasma comparative study to determine the most suitable blood-based matrix for the measurement of these proteins in a multiplexed assay. The levels of NFL and GFAP in plasma and serum were highly correlated (Spearman rho-0.923, p < 0.0001 and rho = 0.825, p < 0.001 respectively). In contrast, the levels of tau were significantly higher in plasma compared to serum samples (p < 0.0001) with no correlation between sample type (Spearman p > 0.05). The neurology 4-plex-A panel, along with plasma alpha-synuclein was then assessed in a cross-sectional cohort of 29 PD patients and 30 controls. Plasma NFL levels positively correlated with both GFAP and alpha-synuclein levels (rho = 0.721, p < 0.0001 and rho = 0.390, p < 0.05 respectively). As diagnostic biomarkers, the control and PD groups did not differ in their mean NFL, GFAP, tau or UCHL-1 plasma levels (t test p > 0.05). As disease state biomarkers, motor severity (MDS-UPDRS III) correlated with increased NFL (rho = 0.646, p < 0.0001), GFAP (rho = 0.450, p < 0.05) and alpha-synuclein levels (rho = 0.406, p < 0.05), while motor stage (Hoehn and Yahr) correlated with increased NFL (rho = 0.455, p < 0.05) and GFAP (rho = 0.549, p < 0.01) but not alpha-synuclein levels (p > 0.05). In conclusion, plasma was determined to be most suitable blood-based matrix for multiplexing the neurology 4-plex-A panel. Given their correlation with motor features of PD, NFL and GFAP appear to be promising disease state biomarker candidates and further longitudinal validation of these two proteins as blood-based biomarkers for PD progression is warranted. [ABSTRACT FROM AUTHOR]

Repeat expansions in genes other than C9orf72 and ATXN2 have been recently associated with Amyotrophic Lateral Sclerosis (ALS). Indeed, an abnormal number of GGC repeats in NOTCH2NLC has been recently reported in 0.7% of sporadic ALS patients from mainland China. This finding was not confirmed in an ALS cohort of subjects from Taiwan. As the involvement of expanded NOTCH2NLC alleles in ALS is debated, we addressed this point by evaluating NOTCH2NLC repeat expansions in an Italian cohort of ALS patients. A screening analysis of NOTCH2NLC GGC repeats was performed by repeat-primed polymerase chain reaction (RP-PCR) in a cohort of 385 probable/definite ALS Italian patients. Mean age at onset was 60.5 years (SD 13.7), and 60.9% were males. Sporadic cases were 357 (92.7%), and most patients had a spinal onset (71.8%). None of our patients showed the typical sawtooth tail pattern on RP-PCR, thus excluding abnormal repeat expansion in NOTCH2NLC. Overall, we suggest that NOTCH2NLC expanded alleles might be absent or at least extremely rare in ALS Italian patients. Further investigations in larger cohorts with different ethnic backgrounds are required to support the involvement of NOTCH2NLC in ALS. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a heterogeneous movement disorder with patients manifesting with either tremor-dominant (TD) or postural instability and gait disturbance (PIGD) motor subtypes. Small nerve fiber damage occurs in patients with PD and may predict motor progression, but it is not known whether it differs between patients with different motor subtypes. Objective: The aim of this study was to explore whether there was an association between the extent of corneal nerve loss and different motor subtypes. Methods: Patients with PD classified as TD, PIGD, or mixed subtype underwent detailed clinical and neurological evaluation and corneal confocal microscopy (CCM). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were compared between groups, and the association between corneal nerve fiber loss and motor subtypes was investigated. Results: Of the 73 patients studied, 29 (40%) had TD, 34 (46%) had PIGD, and 10 (14%) had a mixed subtype. CNFD (no./mm2, 24.09 ± 4.58 versus 28.66 ± 4.27; p < 0.001), CNBD (no./mm², 28.22 ± 11.11 versus 37.37 ± 12.76; p = 0.015), and CNFL (mm/mm², 13.11 ± 2.79 versus 16.17 ± 2.37; p < 0.001) were significantly lower in the PIGD group compared with the TD group. Multivariate logistic regression showed that higher CNFD (OR = 1.265, p = 0.019) and CNFL (OR = 1.7060, p = 0.003) were significantly associated with the TD motor subtype. The receiver operating characteristic (ROC) analysis demonstrated that combined corneal nerve metrics showed excellent discrimination between TD and PIGD, with an area under the curve (AUC) of 0.832. Conclusion: Greater corneal nerve loss occurs in patients with PIGD compared with TD, and patients with a higher CNFD or CNFL were more likely to have the TD subtype. CCM may have clinical utility in differentiating different motor subtypes in PD. [ABSTRACT FROM AUTHOR]