Disorders of Tetrahydrobiopterin Metabolism: Experience from South India.

BACKGROUND: Disorders of tetrahydrobiopterin metabolism represent a rare group of inherited neurotransmitter disorders that manifests mainly in infancy or childhood with developmental delay, neuroregression, epilepsy, movement disorders, and autonomic symptoms. METHODOLOGY: A retrospective review of genetically confirmed cases of disorders of tetrahydrobiopterin metabolism over a period of three years (Jan 2018 to Jan 2021) was performed across two paediatric neurology centres from South India. RESULTS: A total of nine patients(M:F=4:5) fulfilled the eligibility criteria. The genetic variants detected include homozygous mutations in the QDPR(n=6), GCH1(n=2), and PTS(n=1) genes. The median age at onset of symptoms was 6-months(range 3-78 months), while that at diagnosis was 15-months (8-120 months), resulting in a median delay in diagnosis of 9-months. The main clinical manifestations included neuroregression (89%), developmental delay(78%), dystonia(78%) and seizures(55%). Management strategies included a phenylalanine restricted diet, levodopa/carbidopa, 5-Hydroxytryphtophan, and folinic acid. Only, Patient-2 afforded and received BH4 supplementation at a sub-optimal dose later in the disease course. We had a median duration of follow up of 15 months (range 2-48 months). Though the biochemical response has been marked; except for patients with GTPCH deficiency, only mild clinical improvement was noted with regards to developmental milestones, seizures, or dystonia in others. CONCLUSION: Tetrahydrobiopterin deficiencies represent a rare yet potentially treatable cause for non-phenylketonuria hyperphenylalaninemia with better outcomes when treated early in life. Screening for disorders of biopterin metabolism in patients with hyperphenylalaninemia prevents delayed diagnosis. This study expands the genotype-phenotype spectrum of patients with disorders of tetrahydrobiopterin metabolism from South India.

Pediatric neurobrucellosis: a systematic review with case report.

Pediatric neurobrucellosis represents a common anthropozoonosis in endemic areas but only anecdotal reports are available till date. Using appropriate search terms in the database platforms of MEDLINE, SCOPUS and Web of Sciences, we performed a systematic review of all the cases of pediatric neurobrucellosis published in the medical literature till date, in the light of a case report. The protocol was registered under PROSPERO (CRD42022333907). Our search strategy yielded 187 citations of which 51 citations were included. A total of 119 cases were reviewed. Of these cases, eight of them had insufficient data. The most common presentation was meningitis with or without encephalitis (n = 79, 71.2%). A high prevalence of cranial neuropathies (n = 22, 20.7%) was observed in the pediatric population in which abducens palsy was the most common (n = 9, 8.1%). Diagnosis was based on multimodal investigations including standard agglutination test (n = 44, 39.6%), Rose Bengal test (n = 37, 33.3%), blood culture (n = 23, 20.7%), serology (n = 20, 18.0%) and cerebrospinal fluid (CSF) culture (n = 11, 9.9%). Rifampicin-based triple drug regimen was the most commonly employed (83/102, 81.4%). Pediatric neurobrucellosis was associated with greater frequency of sequalae (5.4%), deafness (2.7%) and mortality (2.7%), when compared to that of general population. Neurobrucellosis mimics neuro-tuberculosis in various aspects. The review highlights several unique aspects of this entity in children. A high index of suspicion can ensure prompt diagnosis, timely initiation of management and favorable outcomes.

Pediatric neurobrucellosis represents a common zoonosis in endemic areas but only anecdotal reports are available till date. Using appropriate search terms in the database platforms of MEDLINE, SCOPUS and Web of Sciences, we performed a systematic review of all the cases of pediatric neurobrucellosis published in the medical literature till date, in the light of a case report. Our search strategy yielded 187 citations of which 51 citations were included. A total of 119 cases were reviewed. When compared to the largest series in neurobrucellosis, a higher frequency of meningitis was observed in the pediatric age group (71.2% vs. 37%). A high prevalence of cranial neuropathies (n = 22, 20.7%) was observed in the pediatric population in which abducens palsy was the most common (n = 9, 8.1%). Diagnosis was based on multimodal investigations including standard agglutination test (n = 44, 39.6%), Rose Bengal test (n = 37, 33.3%), blood culture (n = 23, 20.7%), serology (n = 20, 18.0%) and CSF culture (n = 11, 9.9%). Rifampicin-based triple drug regimen was the most commonly employed (83/102, 81.4%). Our systematic review highlighted the wide and heterogeneous spectrum of manifestations of neurobrucellosis in the pediatric population. A high index of suspicion can ensure prompt diagnosis, timely initiation of management and favorable outcomes.

Standardising Dementia Diagnosis Across Linguistic and Educational Diversity: Study Design of the Indian Council of Medical Research-Neurocognitive Tool Box (ICMR-NCTB).

OBJECTIVES: While the burden of dementia is increasing in low- and middle-income countries, there is a low rate of diagnosis and paucity of research in these regions. A major challenge to study dementia is the limited availability of standardised diagnostic tools for use in populations with linguistic and educational diversity. The objectives of the study were to develop a standardised and comprehensive neurocognitive test battery to diagnose dementia and mild cognitive impairment (MCI) due to varied etiologies, across different languages and educational levels in India, to facilitate research efforts in diverse settings. METHODS: A multidisciplinary expert group formed by Indian Council of Medical Research (ICMR) collaborated towards adapting and validating a neurocognitive test battery, that is, the ICMR Neurocognitive Tool Box (ICMR-NCTB) in five Indian languages (Hindi, Bengali, Telugu, Kannada, and Malayalam), for illiterates and literates, to standardise diagnosis of dementia and MCI in India. RESULTS: Following a review of existing international and national efforts at standardising dementia diagnosis, the ICMR-NCTB was developed and adapted to the Indian setting of sociolinguistic diversity. The battery consisted of tests of cognition, behaviour, and functional activities. A uniform protocol for diagnosis of normal cognition, MCI, and dementia due to neurodegenerative diseases and stroke was followed in six centres. A systematic plan for validating the ICMR-NCTB and establishing cut-off values in a diverse multicentric cohort was developed. CONCLUSIONS: A key outcome was the development of a comprehensive diagnostic tool for diagnosis of dementia and MCI due to varied etiologies, in the diverse socio-demographic setting of India.

Apolipoprotein E Polymorphism and Oxidative Stress in Peripheral Blood-Derived Macrophage-Mediated Amyloid-Beta Phagocytosis in Alzheimer's Disease Patients.

Peripheral blood-derived macrophages isolated from Alzheimer's disease (AD) patients have earlier been reported to demonstrate ineffective phagocytosis of amyloid-beta compared to the age-matched control subjects. However, the mechanisms causing unsuccessful phagocytosis remain unclear. Oxidative stress and the presence of ApoEε4 allele has been reported to play a major role in the pathogenesis of AD, but the contribution of oxidative stress and ApoEε4 in macrophage dysfunction leading to ineffective Aß phagocytosis needs to be analyzed. Aß phagocytosis assay has been performed using FITC-labeled Aß and analyzed using flow cytometry and confocal imaging in patient samples and in THP-1 cells. Oxidative stress in patient-derived macrophages was analyzed by assessing the DNA damage using comet assay. ApoE polymorphism was analyzed using sequence-specific PCR and Hixson & Vernier Restriction isotyping protocol. In this study, we have analyzed the patterns of phagocytic inefficiency of macrophages in Indian population with a gradual decline in the phagocytic potential from mild cognitive impairment (MCI) to AD patients. Further, we have shown that the presence of ApoEε4 allele might also have a possible effect on the phagocytosis efficiency of the macrophages. Here, we demonstrate for the first time that oxidative stress could affect the amyloid-beta phagocytic potential of macrophages and hence by alleviating oxidative stress using curcumin, an anti-oxidant could enhance the amyloid-beta phagocytic efficacy of macrophages of patients with AD and MCI, although the responsiveness to curcumin might depends on the presence or absence of APOEε4 allele. Oxidative stress contributes significantly to decreased phagocytosis of Aß by macrophages. Moreover, the phagocytic inefficiency of macrophages was correlated to the presence of ApoEε4 allele. This study also found that the Aß-phagocytic potential of macrophage gets significantly enhanced in curcumin-treated patient-derived macrophages.

A new scoring system and norms for, and the performance of cognitively-unimpaired older adults on the cube copying test.

BACKGROUND: Cube copying test is often used as screening test for dementia. However, there is a paucity of an effectively scoring system, and very little is known about how healthy older adults perform on this test. In this study, we present a modified scoring system for the wire-cube copying, evaluate the performance of cognitively unimpaired elderly individuals, and generate norms on community-dwelling older adults. MATERIALS AND METHODS: The task consisted of copying a three-dimensional printed cube (i.e., wire-cube) of size 2.5 cm3. The scoring system devised by Maeshma et al. was modified and used. The target population consisted of cognitively normal individuals aged ≥65 years living in a predefined geographical area. RESULTS: In this study, there were 511 participants (62% females) aged 69 ± 7.2 years. Of the 295 figures available, 51 were rejected. Among the candidates with acceptable cubes, 182 (74.5%) had ≥9 years of education. Of the 51 rejected cubes, 37 (72.5%) participants had <9 years of education. Education was found to be significantly correlated with composite score (P < 0.001) whereas age and sex had no correlation. The total score as well as subgroup scores of the cubes were correlating well with Mini-mental state examination (MMSE) as well as Addenbrooke's Cognitive Examination (ACE) composite scores (P < 0.0001). CONCLUSION: Good correlation was found between composite scores and subscores with most of the ACE parameters. The test can be used as a rapid screening test for dementia in view of its good correlation with ACE composite scores and subscores; it also has the advantage of being independent of culture and language.

Interaction with the MAPT H1H1 Genotype Increases Dementia Risk in APOE ε4 Carriers in a Population of Southern India.

BACKGROUND: This study delineates the role of the interaction of apolipoprotein E (APOE) and MAPT alleles in contributing to disease risks of dementia in a southern Indian population. METHODS: A sample of 419 patients comprising Alzheimer's disease (AD; n = 156), mild cognitive impairment (MCI; n = 87), frontotemporal dementia (FTD; n = 127), vascular dementia (VD; n = 37), and dementia with Lewy bodies (DLB; n = 12) was analysed in comparison with a control group (n = 138). APOE genotyping and MAPT haplotyping were performed on all study subjects. RESULTS: Multivariate logistic regression analysis showed that variability on the APOE locus influenced the relative risk of dementia in the study population. The APOE ε4 allele increased the disease risk most significantly for AD (OR = 3.468, p < 0.0001) and MCI (OR = 2.901, p < 0.0001). The APOE ε2 allele remained protective for AD (OR = 0.205, p < 0.05). For FTD, VD, and DLB, the APOE ε4 allele was ineffectual in modulating disease risk. The MAPT H1 haplotype was not an overrepresented marker of neurodegenerative diseases. The H1H1 genotype had an additive effect in contributing to either disease risk in combination with the APOE ε4 allele or protection in combination with the APOE ε2 or ε3 allele. CONCLUSIONS: This study is a reappraisal of the strong association of APOE variability with AD in southern India when compared to other dementia groups, while the transcriptional differences between MAPT haplotypes have a limited role in Indian dementia patients.

Collagen XII-Related Myopathy: An Emerging Spectrum of Extracellular Matrix-Related Myopathy.

Collagen XII, a member of a protein family called fibril associated collagen with interrupted triple helices (FACIT), is an important component of extracellular matrix and is essential for bridging the neighbouring fibrils. Mutations in collagen XII have been recently described to cause a rare extracellular matrix-related myopathy in those whose phenotype resembles collagen VI-related dystrophies and were negative for pathogenic variants in COL6A genes. The authors report a 4-year old girl presented with a phenotype mimicking Ullrich congenital muscular dystrophy and genetically confirmed to have pathogenic variants in COL12A1 gene thus, expanding the phenotypic spectrum of COL12A1-related myopathy.

Incidence of Alzheimer's disease in India: a 10 years follow-up study.

OBJECTIVE: To determine overall and age-specific incidence rates of Alzheimer's disease (AD) in a southern Indian province, Kerala. MATERIALS AND METHODS: A 10-year (2001-2011) prospective epidemiologic study of community residing subjects aged ≥55 years at enrollment. The catchment area included four urban and semi-urban regions of Trivandrum city in Kerala, India, was selected to provide a range of demographic and socioeconomic representation. Cognitive and functional ability screening were done at baseline and 24-month follow-up assessments. Consensus diagnostic procedures were done using the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition (DSM-IV), and the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINDS-ADRDA) criteria for the diagnosis of dementia and AD. RESULTS: Among the 1066 eligible participants who were cognitively normal at baseline, 104 developed dementia (98 with AD) over a follow-up period of 8.1 years. The incidence rates per 1000 person-years for AD was 11.67 (95% CI: 10.9-12.4) for those aged ≥55 years and higher for those aged ≥65 years (15.54, 95% CI: 14.6-16.5). In those aged ≥65 years, the world age standardized incidence rate was 21.61 per 100,000, and standardized against the age distribution for the year 2000 U.S. Census, the age-adjusted incidence rate was 9.19 (95% CI: 9.03-9.35) per 1000 person-years. Incidence rate of AD increased significantly and proportionately with increasing age. CONCLUSION: These are the first AD incidence rates to be reported from southern India. The incidence rates appear to be much higher than that reported from rural north India, comparable with that reported from China, and marginally lower than that reported from the western world.

Insights from Magnetic Evoked Field Analysis in Patients with Wilson's Disease.

Aims: To study the latency, amplitude, and source localization of magnetic evoked field (MEF) responses to visual, auditory, and somatosensory stimuli in Wilson's disease (WD) using magnetoencephalography (MEG) and compare it with "healthy" controls, and correlate the observations with disease severity and brain MRI. Methods: MEF of 28 patients with neurological WD (age: 22.82 ± 5.8 years; M:F = 12:16) and 21 matched controls (age: 25.0 ± 4.6 years; M:F = 10:11) were recorded using MEG. Source localization was performed using standard models on the components of M100, M20, and M100 for visual, somatosensory, and auditory evoked fields, respectively and its latency/amplitude was correlated with disease severity. Results: There were significant differences in source location between control and WD during visual evoked field (VEF) and auditory evoked field (AEF) studies. Latencies of M20 (right-p = 0.02; left-p = 0.04) and M32 (right-p = 0.01) components of SSEF were significantly prolonged. The amplitude of M20 was significantly reduced in patients bilaterally (P = 0.001). There was a trend for the prolonged latency of M100 of VEF in patients (P = 0.09). Five patients had reduced right M145 compared to 8 controls. The left somatosensory evoked fields (SSEF) latency correlated with disease severity (P = 0.04). There was no significant correlation between major components of other MEF with disease severity or MRI score. Conclusions: This study, first of its kind to use MEF analysis in a large cohort of patients with WD, detected subclinical but a variable degree of abnormalities, most consistently of SSEF. It provides valuable insights of functioning and localization of various pathways in a disease known to have protean clinical manifestations and widespread MRI changes.

Dementia in Kerala, South India: prevalence and influence of age, education and gender.

BACKGROUND: Data on the prevalence of dementia in India with a large and aging population is scant. We studied prevalence of AD and dementia in Kerala, South India, and effects of age, education and gender on it. METHODS: 2-phase survey on 2466 individuals aged > or = 55 years living in community. Men constituted 41%, < 75 years age in 76.9% and education > or = 4 years in 69.6%. Screening (Phase I) using the instrumental activity of daily living scale for the elderly (IADL-E) and the Addenbrooke's cognition examination (ACE). Diagnostic-assessment (Phase II) was in 532 screen-positives and 247 (10%) screen-negatives. RESULTS: 93 (3.77%) > or = 55 years and 81 (4.86%) > or = 65 years of age had dementia. Age adjusted (against US-population in 2000) dementia (and AD) rates were 4.86% (1.91%) in age > or = 55 years and 6.44% (3.56%) in > or = 65 years. Odds for dementia (and AD) were high with increasing-age 5.89 (15.33) in 75-84, 13.23 (25.92) > or = 85 years, and in women 1.62 (2.95); and low 0.27 (0.16) if education was > or = 9 years. Age and low education increased dementia. Age and female gender increased AD. CONCLUSION: Prevalence of dementia and AD is higher than any reported from the subcontinent suggesting that dementia in Kerala in South India is not uncommon. Increasing age increased dementia and AD. Low-education is associated with dementia and female-gender with AD.

Gray matter volume covariance patterns associated with gait speed in older adults: a multi-cohort MRI study.

Accelerated gait decline in aging is associated with many adverse outcomes, including an increased risk for falls, cognitive decline, and dementia. Yet, the brain structures associated with gait speed, and how they relate to specific cognitive domains, are not well-understood. We examined structural brain correlates of gait speed, and how they relate to processing speed, executive function, and episodic memory in three non-demented and community-dwelling older adult cohorts (Overall N = 352), using voxel-based morphometry and multivariate covariance-based statistics. In all three cohorts, we identified gray matter volume covariance patterns associated with gait speed that included brain stem, precuneus, fusiform, motor, supplementary motor, and prefrontal (particularly ventrolateral prefrontal) cortex regions. Greater expression of these gray matter volume covariance patterns linked to gait speed were associated with better processing speed in all three cohorts, and with better executive function in one cohort. These gray matter covariance patterns linked to gait speed were not associated with episodic memory in any of the cohorts. These findings suggest that gait speed, processing speed (and to some extent executive functions) rely on shared neural systems that are subject to age-related and dementia-related change. The implications of these findings are discussed within the context of the development of interventions to compensate for age-related gait and cognitive decline.

Expert Group Meeting on Aphasia: A Report.

A multidisciplinary team of experts took stock of the current state of affairs about many aspects of aphasia in India, including community burden, diagnostic assessment, therapy, rehabilitation, research, education, and advocacy. The broad spectrum of aphasiology was matched by the types of participants ranging from neurologists, speech-language pathologists, clinical psychologists, linguists, to experts in neuroimaging and computer sciences. Threadbare discussion in 16 sessions over 3 days leads to the identification of pressing problems and possible solutions. Many action plans have been envisaged and recommendations made. A few examples with high priority are community-based and hospital-based study incidence and prevalence of aphasia, development of test batteries for the assessment of many components of speech and communication in Indian languages which are validated on rigorous psychometric, and linguistic criteria, national registry for aphasia, educational modules about aphasia for different target groups, resources for advocacy and its training, a bank of research questions and outlines of research protocols for young professionals to pursue. The expert group will continue to oversee execution of some of the actionable plans in short and long term.