Parkinson's disease genome-wide association study-linked PARK16 variant is associated with a lower risk of cognitive impairment: A 4-year observational study.

BACKGROUND AND PURPOSE: A genome-wide association study-linked variant (PARK16 rs6679073) modulates the risk of Parkinson's disease (PD). We postulate that there may be differences in clinical characteristics between PARK16 rs6679073 carriers and noncarriers. In a prospective study, we investigate the clinical characteristics between PARK16 rs6679073 A allele carriers and noncarriers over 4 years. METHODS: A total of 204 PD patients, comprising 158 PARK16 rs6679073 A allele carriers and 46 noncarriers, were recruited. All patients underwent motor and nonmotor symptom and cognitive assessments yearly over 4 years. RESULTS: PARK16 rs6679073 carriers were less likely to have mild cognitive impairment (MCI) compared to noncarriers at both baseline (48.1% vs. 67.4%, p = 0.027) and 4-year follow-up (29.3% vs. 58.6%, p = 0.007). CONCLUSIONS: PD PARK16 rs6679073 carriers had significantly lower frequency of MCI in a 4-year follow-up study, suggesting that the variant may have a neuroprotective effect on cognitive functions.

Identifying clinical features and blood biomarkers associated with mild cognitive impairment in Parkinson disease using machine learning.

BACKGROUND AND PURPOSE: A broad list of variables associated with mild cognitive impairment (MCI) in Parkinson disease (PD) have been investigated separately. However, there is as yet no study including all of them to assess variable importance. Shapley variable importance cloud (ShapleyVIC) can robustly assess variable importance while accounting for correlation between variables. Objectives of this study were (i) to prioritize the important variables associated with PD-MCI and (ii) to explore new blood biomarkers related to PD-MCI. METHODS: ShapleyVIC-assisted variable selection was used to identify a subset of variables from 41 variables potentially associated with PD-MCI in a cross-sectional study. Backward selection was used to further identify the variables associated with PD-MCI. Relative risk was used to quantify the association of final associated variables and PD-MCI in the final multivariable log-binomial regression model. RESULTS: Among 41 variables analysed, 22 variables were identified as significantly important variables associated with PD-MCI and eight variables were subsequently selected in the final model, indicating fewer years of education, shorter history of hypertension, higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor score, higher levels of triglyceride (TG) and apolipoprotein A1 (ApoA1), and SNCA rs6826785 noncarrier status were associated with increased risk of PD-MCI (p < 0.05). CONCLUSIONS: Our study highlighted the strong association between TG, ApoA1, SNCA rs6826785, and PD-MCI by machine learning approach. Screening and management of high TG and ApoA1 levels might help prevent cognitive impairment in early PD patients. SNCA rs6826785 could be a novel therapeutic target for PD-MCI. ShapleyVIC-assisted variable selection is a novel and robust alternative to traditional approaches for future clinical study to prioritize the variables of interest.

Increased expression of pathological markers in Parkinson's disease dementia post-mortem brains compared to dementia with Lewy bodies.

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-APPT668 (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 Aß42 and DD2R, IBA1, and p-LRRK2S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-TauS199/202 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.

NOTCH2NLC GGC Repeat Expansions Are Associated with Sporadic Essential Tremor: Variable Disease Expressivity on Long-Term Follow-up.

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well-characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion-weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 "intermediate" repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614-618.

The splenial angle: a novel radiological index for idiopathic normal pressure hydrocephalus.

OBJECTIVES: To evaluate the utility of the splenial angle (SA), an axial angular index of lateral ventriculomegaly measured on diffusion tensor MRI color fractional anisotropy maps, in differentiating NPH from Alzheimer's disease (AD), Parkinson's disease (PD), and healthy controls (HC), and post-shunt changes in NPH, compared to Evans' index and callosal angle. METHODS: Evans' index, callosal angle, and SA were measured on brain MRI of 76 subjects comprising equal numbers of age- and sex-matched subjects from each cohort of NPH, AD, PD, and HC by two raters. Receiver operating characteristics (ROC) and multivariable analysis were used to assess the screening performance of each measure in differentiating and predicting NPH from non-NPH groups respectively. Temporal changes in the measures on 1-year follow-up MRI in 11 NPH patients (with or without ventriculoperitoneal shunting) were also assessed. RESULTS: Inter-rater and intra-rater reliability were excellent for all measurements (intraclass correlation coefficients > 0.9). Pairwise comparison showed that SA was statistically different between NPH and AD/PD/HC subjects (p < 0.0001). SA performed the best in predicting NPH, with an area under the ROC curve of > 0.98, and was the only measure left in the final model of the multivariable analysis. Significant (p < 0.01) change in SA was seen at follow-up MRI of NPH patients who were shunted compared to those who were not. CONCLUSIONS: The SA is readily measured on axial DTI color FA maps compared to the callosal angle and shows superior performance differentiating NPH from neurodegenerative disorders and sensitivity to ventricular changes in NPH after surgical intervention. KEY POINTS: • The splenial angle is a novel simple angular radiological index proposed for idiopathic normal pressure hydrocephalus, measured in the ubiquitous axial plane on DTI color fractional anisotropy maps. • The splenial angle quantitates the compression and stretching of the posterior callosal commissural fibers alongside the distended lateral ventricles in idiopathic normal pressure hydrocephalus (NPH) using tools readily accessible in clinical practice and shows excellent test-retest reliability. • Splenial angle outperforms Evans' index and callosal angle in predicting NPH from healthy, Parkinson's disease, and Alzheimer's disease subjects on ROC analysis with an area under the curve of > 0.98 and is sensitive to morphological ventricular changes in NPH patients after ventricular shunting.

Encephalitis as a neurological complication of COVID-19: A systematic review and meta-analysis of incidence, outcomes, and predictors.

BACKGROUND AND PURPOSE: Although COVID-19 predominantly affects the respiratory system, recent studies have reported the occurrence of neurological disorders such as stroke in relation to COVID-19 infection. Encephalitis is an inflammatory condition of the brain that has been described as a severe neurological complication of COVID-19. Despite a growing number of reported cases, encephalitis related to COVID-19 infection has not been adequately characterised. To address this gap, this systematic review and meta-analysis aims to describe the incidence, clinical course, and outcomes of patients who suffer from encephalitis as a complication of COVID-19. METHODS: All studies published between 1 November 2019 and 24 October 2020 that reported on patients who developed encephalitis as a complication of COVID-19 were included. Only cases with radiological and/or biochemical evidence of encephalitis were included. RESULTS: In this study, 610 studies were screened and 23 studies reporting findings from 129,008 patients, including 138 with encephalitis, were included. The average time from diagnosis of COVID-19 to onset of encephalitis was 14.5 days (range = 10.8-18.2 days). The average incidence of encephalitis as a complication of COVID-19 was 0.215% (95% confidence interval [CI] = 0.056%-0.441%). The average mortality rate of encephalitis in COVID-19 patients was 13.4% (95% CI = 3.8%-25.9%). These patients also had deranged clinical parameters, including raised serum inflammatory markers and cerebrospinal fluid pleocytosis. CONCLUSIONS: Although encephalitis is an uncommon complication of COVID-19, when present, it results in significant morbidity and mortality. Severely ill COVID-19 patients are at higher risk of suffering from encephalitis as a complication of the infection.

Stroke as a Neurological Complication of COVID-19: A Systematic Review and Meta-Analysis of Incidence, Outcomes and Predictors.

INTRODUCTION: COVID-19 is a multi-system infection which predominantly affects the respiratory system, but also causes systemic inflammation, endothelialitis and thrombosis. The consequences of this include renal dysfunction, hepatitis and stroke. In this systematic review, we aimed to evaluate the epidemiology, clinical course, and outcomes of patients who suffer from stroke as a complication of COVID-19. METHODS: We conducted a systematic review of all studies published between November 1, 2019 and July 8, 2020 which reported on patients who suffered from stroke as a complication of COVID-19. RESULTS: 326 studies were screened, and 30 studies reporting findings from 55,176 patients including 899 with stroke were included. The average age of patients who suffered from stroke as a complication of COVID-19 was 65.5 (Range: 40.4-76.4 years). The average incidence of stroke as a complication of COVID-19 was 1.74% (95% CI: 1.09% to 2.51%). The average mortality of stroke in COVID-19 patients was 31.76% (95% CI: 17.77% to 47.31%). These patients also had deranged clinical parameters including deranged coagulation profiles, liver function tests, and full blood counts. CONCLUSION: Although stroke is an uncommon complication of COVID-19, when present, it often results in significant morbidity and mortality. In COVID-19 patients, stroke was associated with older age, comorbidities, and severe illness.

Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort.

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.

Patient attitudes towards brain donation across both neurodegenerative and non-neurodegenerative neurological disorders.

Brain donations are imperative for research; understanding possible barriers to entry is required to improve brain donation rates. While a few surveys have studied attitudes towards brain banking in patients with neurodegenerative disorders, none have surveyed patients with chronic neurological disorders but without neurodegeneration. This cross-sectional study was conducted on 187 participants, with both neurodegenerative (n = 122) and non-neurodegenerative disorders (n = 65), to compare their attitudes and preferences towards brain donation. Encouragingly, patients with non-neurodegenerative disorders were just as likely to consider brain donation as those with neurodegenerative diseases. Approximately half of each group were willing to consider brain donation, and majority of participants across both groups would not be offended if asked to participate in brain donation (71%). Across both groups, altruistic reasons such as desire to advance medical knowledge and benefit to other patients were the main motivating factors for brain donation, while perceived stress for family members, fears of body disfigurement and religious reasons were the main reasons against brain donation. Of note, nearly two-thirds of all participants were agreeable to allow their family to decide on their behalf. Overall, participants with non-neurodegenerative disorders appeared equally likely to consider brain donation as participants with neurodegenerative disorders. This is an important finding as they represent a significant population seen in specialist neurology clinics who may be overlooked in brain donor recruitment and awareness efforts. Healthcare professionals involved in brain banking should consider actively approaching these potential donors and involving their family members in these discussions.

SNCA Rep1 promoter variability influences cognition in Parkinson's disease.

BACKGROUND: While the association between alpha-synuclein gene promoter (Rep1) variability and risk of PD is well established, its association with cognition is unclear. OBJECTIVES: To investigate the association between Rep1 and motor and cognitive outcomes in PD. METHODS: Rep1 allele lengths were determined in 172 PD patients who were grouped into "long" and "short" carriers according to previous methods. Multivariable regression analysis was performed to investigate the effect of Rep1 length on cognitive and motor scores. RESULTS: Long Rep1 allele carriers had significantly lower MMSE (P = 0.010) and higher UPDRS Part III (P = 0.026) and H & Y (P = 0.008) scores compared to short allele carriers (controlled for age, sex, and disease duration). Interaction analyses of Rep1 with apolipoprotein 4 revealed no significant effect on clinical outcomes. CONCLUSIONS: PD patients carrying long Rep1 alleles are more impaired on cognitive and motor function independent of apolipoprotein 4 genotype. © 2019 International Parkinson and Movement Disorder Society.

Identifying patients with neuronal intranuclear inclusion disease in Singapore using characteristic diffusion-weighted MR images.

PURPOSE: Adult-onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder described mainly in the Japanese population, with characteristic DWI abnormalities at the junction between gray and white matter. We identify possible cases of NIID in the picture archive and communication system (PACS) of a tertiary neurological referral hospital in Singapore and describe their radiological features. METHODS: The neuroradiology imaging database was reviewed using keyword search of radiological reports to identify patients who had "subcortical U fibre" abnormalities on DWI. MRI were retrospectively reviewed, and those fulfilling inclusion criteria were invited for skin biopsy to detect nuclear inclusions by light and electron microscopy. RESULTS: Twelve Chinese patients (nine female; median age 70.5 years) were enrolled. Seven patients were being assessed for dementia and five for other neurological indications. In all patients, DWI showed distinctive subcortical high signal with increased average apparent diffusion coefficient (ADC), involving frontal, parietal, and temporal more than occipital lobes; the corpus callosum and external capsule were affected in some patients. On T2-weighted images, cerebral and cerebellar atrophy and white matter hyperintensity of Fazekas grade 2 and above were seen in all patients. Three patients underwent skin biopsy; all were positive for intranuclear hyaline inclusion bodies on either p62 staining or electron microscopy, which are pathognomonic for NIID. CONCLUSION: Previously undiagnosed patients with NIID can be identified by searching for abnormalities at the junction between gray and white matter on DWI in PACS and subsequently confirmed by skin biopsy. Radiologists should recognize the distinctive neuroimaging pattern of this dementing disease.

Attitudes of Asian Parkinson patients towards brain donation.

Histopathological examination of brain tissue is required for better understanding of neurodegenerative conditions such as Parkinson's disease and related disorders. However, patient willingness remains the greatest hurdle hampering participation in brain donation for research. While there is extensive research being conducted on the subject in West, to the best of our knowledge, there are no studies done in this regard in Asia. This cross-sectional survey was conducted on 105 Parkinson's disease patients to assess their knowledge, beliefs and attitude towards brain donation in an Asian population. The majority of the participants (78%) acknowledged the importance of donation of brain for research, and 70% believed that their donated brain samples would be handled professionally. Fifty percent participants were willing to consider donating their brain for research. Motivating factors for brain donation included altruism (87%) and contribution to advance medical knowledge (80%). Common reasons for unwillingness towards brain donation were stress for family (30%), disfigurement of body (25%), and having a conservative mindset (23%). About one-third of the participants preferred to be approached for brain donation after their first clinic visit. Most patients preferred either their treating neurologists (66%) or research staff (18%) to discuss brain donation with. Participation for brain donation may be increased further with greater patient and public education to overcome misconceptions and change mindsets.

Dyslexic Characteristics of Chinese-Speaking Semantic Variant of Primary Progressive Aphasia.

Reading disorder is a recognized feature in primary progressive aphasia (PPA). Surface dyslexia, characterized by regularization errors, is typically seen in the English-speaking semantic variant of PPA (svPPA). However, dyslexic characteristics of other languages, particularly logographical languages such as Chinese, remain sparse in the literature. This study aims to characterize and describe the dyslexic pattern in this group of patients by comparing an English-speaking svPPA group with a Chinese-speaking svPPA group. The authors hypothesized that Chinese-speaking individuals with svPPA would likely commit fewer surface dyslexic errors. By accessing the database of Singapore's National Neuroscience Institute and the National Alzheimer's Coordinating Center of the United States, the authors identified three Chinese-speaking and 18 English-speaking patients with svPPA, respectively, for comparison. The results suggest that, instead of surface dyslexia, svPPA in Chinese-speaking individuals is characterized by a profound deep dyslexic error. Based on current evidence suggesting the role of the temporal pole as a semantic convergence center, the authors conclude that this region also mediates and converges lexical-semantic significance in logographical languages.

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

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.

Early detection of dementia in multilingual populations: Visual Cognitive Assessment Test (VCAT).

BACKGROUND: Early diagnosis of cognitive impairment allows timely intervention with pharmacological and non-pharmacological measures. However, current cognitive evaluation tools do not cater for multilingual populations. OBJECTIVE: To develop and validate a visual-based cognitive evaluation tool, the Visual Cognitive Assessment Test (VCAT), which can be administered to multilingual populations without the need for translation or adaptation. METHOD: We designed a battery of tests to evaluate the domains of memory, executive function, visuospatial function, language and attention. Pilot testing of individual test items, followed by test refinement and development of a field version was performed. We subsequently validated VCAT for the diagnosis of mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Diagnostic performance was assessed by the area under the curve (AUC), sensitivity (Se) and specificity (Sp). RESULTS: VCAT was validated in a sample of 206 participants. The sample comprised 53.9% males; mean age (SD) was 67.8 (8.86) years; mean years of education was 10.5(6.0). AUC of VCAT for detection of cognitive impairment was found to be 93.3 (95% CI 90.1 to 96.4). Also, the Se and Sp of VCAT for the diagnosis of cognitive impairment (MCI and mild AD) were 85.6% and 81.1%, respectively. VCAT's diagnostic Se and Sp comparable to those of the Montreal Cognitive Assessment in the same cohort. Mean time-to-complete VCAT was 15.7 ± 7.3 min. CONCLUSIONS: The VCAT has good Se and Sp for the diagnosis of MCI and mild AD. The visual-based test paradigm allows easy application to multilingual populations without the need for translation or adaptation.

Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria.

Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation.