SHARPIN: Role in Finding NEMO and in Amyloid-Beta Clearance and Degradation (ABCD) Pathway in Alzheimer's Disease?

SHANK- associated RH domain-interacting protein (SHARPIN) is a multifunctional protein associated with numerous physiological functions and many diseases. The primary role of the protein as a LUBAC-dependent component in regulating the activation of the transcription factor NF-κB accounts to its role in inflammation and antiapoptosis. Hence, an alteration of SHARPIN expression or genetic mutations or polymorphisms leads to the alteration of the above-mentioned primary physiological functions contributing to inflammation-associated diseases and cancer, respectively. However, there are complications of targeting SHARPIN as a therapeutic approach, which arises from the wide-range of LUBAC-independent functions and yet unknown roles of SHARPIN including neuronal functions. The identification of SHARPIN as a postsynaptic protein and the emerging studies indicating its role in several neurodegenerative diseases including Alzheimer's disease suggests a strong role of SHARPIN in neuronal functioning. This review summarizes the functional roles of SHARPIN in normal physiology and disease pathogenesis and strongly suggests a need for concentrating more studies on identifying the unknown neuronal functions of SHARPIN and hence its role in neurodegenerative diseases.

Women with drug-resistant epilepsy: Surgery or pregnancy first?

OBJECTIVE: We compared women with drug-resistant focal epilepsy who had undergone surgery (WWE-S) with those who were managed medically (WWE-M) for maternal and fetal outcomes of their pregnancies. METHODS: We classified all WWE-S who were enrolled in a prospective registry of epilepsy and pregnancy (1998-2015) as those who underwent the surgery before pregnancy (WWE-SF) or after pregnancy (WWE-PF). The comparator group (WWE-M) was twice that number of age-matched women with focal epilepsy in this registry. Their clinical profile, anti-epileptic drug (AED) use, and pregnancy outcomes were extracted from the records of the registry. RESULTS: The number of completed pregnancies with known outcome was 74 for WWE-S (67 WWE-SF and 7 WWE-PF) and 134 for WWE-M. Seizures increased during pregnancy for fewer WWE-SF than for WWE-M (14.9% vs 39.6%, P = .001). Compared to WWE-M, fewer WWE-SF had dose escalation during pregnancy (28.4% vs 14.9%, P = .025). Preterm deliveries were more frequent in WWE-SF than WWE-M (24.6% vs 12.2%, P = .029). The differences between the WWE-SF and WWE-M regarding the rates of fetal loss (10.4% vs 6.7%, P = .255), major congenital malformations (8.5% vs. 11.1%, P = .395), and development quotient at 1 year of age <85 (42.5% vs 42.3%, P = .569) were not statistically significant. Compared to WWE-PF, fewer WWE-SF had AED dose escalation (14.9% vs 85.7%, P = .001) or increase in seizures (14.9% vs 100%, P = .001) during pregnancy. WWE-SF had fewer infants with development quotient <85 (41.0% vs 100%, P = .005). SIGNIFICANCE: WWE-SF can expect better control of seizures and decreased AED burden during pregnancy than WWE with focal epilepsies managed with medicines only. WWE who undergo surgery for epilepsy before their pregnancies can expect fewer seizures and lower AED burden during pregnancy.

A novel role for SHARPIN in amyloid-ß phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer's disease.

Defective immune cell-mediated clearance of amyloid-beta (Aß) and Aß-associated inflammatory activation of immune cells are key contributors in pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms remain elusive. Shank-associated RH domain-interacting protein (SHARPIN) is a critical regulator of inflammatory response. Using in vitro cultures of THP-1-derived macrophages exposed to Aß and AD patient-derived macrophages, we demonstrate the role of SHARPIN as an obligate regulator of Aß phagocytosis and inflammation in macrophages. Specifically, Aß-stimulated SHARPIN in THP-1 macrophages promoted Aß phagocytosis and expression of proinflammatory markers. In addition, Aß-stimulated SHARPIN in macrophages promoted neuronal cell-death in differentiated SHSY5Y neurons. Furthermore, we report a novel regulatory link between SHARPIN and the NLRP3 inflammasome in response to Aß in THP-1 macrophages. In line with our in vitro observations, a strong positive association was demonstrated between levels of Aß42 in blood plasma of mild cognitive impairment and AD patients with SHARPIN expression in macrophages obtained from respective patient-derived peripheral blood mononuclear cells. Together, our findings show SHARPIN as a critical determinant in mediating macrophage response to Aß and pathogenesis of AD.

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.

Feasibility of antiepileptic drug withdrawal following extratemporal resective epilepsy surgery.

OBJECTIVE: To identify the rate of successful antiepileptic drug (AED) withdrawal after resective surgery and the predictors of postwithdrawal seizure recurrence in patients with extratemporal epilepsy. METHODS: We retrospectively analyzed the postoperative AED profile of 106 consecutive patients who had completed 2 or more years after resections involving frontal, parietal, and occipital lobes for AED-resistant epilepsy. To identify the potential predictors of seizure recurrence, we compared the attributes of recurred and nonrecurred groups by univariate and multivariate analyses. RESULTS: We attempted AED withdrawal in 94 (88.7%) patients. Forty-four (41.5%) patients had seizure recurrence while reducing AED, of which 14 (31.8%) did not become seizure-free subsequently. On multivariate analysis, an abnormal postoperative EEG and longer preoperative duration of epilepsy predicted seizure recurrence, while early postoperative seizures and presence of gliosis or dysplasia were additional predictors on univariate analysis. At mean follow-up duration of 4.6 years, 63 (59.4%) patients were seizure-free. The cumulative probability of achieving complete AED-free status was 20% at fourth year, 34% at sixth year, 40% at eighth year, and 52% at 10th year after surgery. CONCLUSIONS: Following resective extratemporal epilepsy surgery, AED can be successfully discontinued in only in a minority of patients. One-third of patients who recur fail to regain seizure control upon AED reintroduction. Longer duration of epilepsy prior to surgery, abnormal postoperative EEG, early postoperative seizures, and focal gliosis or dysplasia as substrate predispose to seizure recurrence. This information will be helpful in making rational decisions on AED withdrawal following extratemporal resective epilepsy surgery.

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.