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Background: Vascular Dementia (VaD) is the second most prevalent cause of dementia, arising from the blockage of blood vessels in the brain. One event responsible for the blockage or narrowing of small blood vessels is transient ischemic attack (TIA), and these changes resolve within 24 hours in humans. The molecular mechanism underlying these changes in recovery in small vessels still needs to be investigated. To address this gap, we have developed a mouse model by administering endothelin‐1 (ET‐1) into the lateral ventricles. This disrupts small vessel integrity, which leads to learning and memory deficits after 3 days of a single ET‐1 injection. Intriguingly, there is a subsequent recovery in these deficits after 30 days, mimicking the clinical scenario of TIAs. Bulk RNA sequencing from microvessels was performed to elucidate further the factors involved in recovery mechanisms. Method: ET‐1 injection was given to 4 groups of C57BL6/J mice, and mice were sacrificed at different time points of 3, 15, and 30 days along with saline counterparts. Microvessels were extracted from the pooled cortex and hippocampus, followed by RNA isolation. RNA samples were subjected to the cDNA library preparation, and RNA sequencing was conducted using the Illumina NovaSeq 6000® instrument. Transcriptomic analysis was carried out in the Linux environment. Differential gene expression was performed using R. Result: We observed biological processes such as vasculature development, angiogenesis, and wound healing start upregulating after 3 days of a single ET‐1 injection, whereas several processes involved in ion transport chains were downregulated. Further, biological processes for muscle development, mitochondrial electron transport chain, and neuronal development were upregulated after 15 days of a single ET‐1 injection. No biological processes were affected after 30 days of a single ET‐1 injection, suggesting a possible complete recovery from ET‐1‐mediated vascular insult by the 30th day. Conclusion: Our results highlight the temporal dynamics of biological processes in response to a single ET‐1 injection. It offers valuable insight for understanding the mechanism behind the recovery and factors involved in this process after vascular insult, paving the way for therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Subjective Cognitive Decline (SCD), defined as a self‐experienced persistent cognitive decline with a normal performance in objective neuropsychological assessments is one of the first clinical manifestations of dementia. SCD has a strong association with depression, and more research is needed to understand the relationship between the two. When they co‐occur the risk of developing dementia increases. Despite the increased focus on the preclinical stages of dementia such as SCD there is limited research on its prevalence specifically in India. The present study aims to bridge this research gap by estimating the prevalence of SCD in India and assessing urban‐rural differences in its prevalence as well as sociodemographic factors. Method: The study used data from two ongoing community‐based prospective cohort studies, namely the Tata Longitudinal Study of Ageing (TLSA) and Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) in urban Bangalore and Srinivaspura respectively (Sundarakumar et al., 2020). Baseline data collected from 4429 participants aged 45 years and older were included in the analysis. The study used Clinical Dementia Rating Scale (CDR) scores and participants' responses to the questions pertaining to subjective cognitive impairment in Cognitive Function Instrument (CFI) and Geriatric Depression Scale (GDS) to estimate the prevalence of SCD. Result: Of 4429 participants recruited between 2015 and 2022, a total of 1010 (22.8%) participants [median (IQR) age, 60 (15)] were classified as having SCD. As shown in Tabe1, the prevalence was higher in the rural cohort than in the urban cohort (25.1% vs 14.0%, p<0.001). The rural cohort was also found to be comparatively younger (57 (15) vs 63 (14)), and have fewer years of education (4 (9) vs 15(2)). Depression was found to have significant association with SCD in both the cohorts, with more depressive symptoms observed in the rural cohort. As shown in Table 2, the prevalence of SCD was higher in women than men in the urban cohort. Conclusion: The study's findings indicate that despite being comparatively younger, the rural cohort had a higher prevalence of SCD, potentially due to the protective effect of higher years of education in the urban cohort. [ABSTRACT FROM AUTHOR]

Background: Eye are the extension of brain, any vascular abnormalities in the brain might reflect in ocular structures. The retinal microcirculation of an individual is similar to the small blood vessels found in the brain. The changes to the retina that result from neurodegenerative diseases can be observed through the eye. Studies have shown reduced retinal thickness in MCI when compared to healthy controls (HC). Therefore, OCT plays an important role in neurodegenerative diseases, and also in the MCI (Dudekova et al., 2016) (Sefton et al., 2022). Method: This is a case‐control study. Total of 19 eyes from 11 MCI subjects, and 20 eyes from 15 HC were taken for analysis from Tata Longitudinal Study on Aging (TLSA) cohort (Sundarakumar et al., 2020). Clinical dementia rating (CDR) score was used to group the participants as having normal cognition and MCI. A score of 0 and 0.5 was considered as subjects having normal cognition and MCI respectively. Macular and radial peripapillary angiography were done using SD OCT‐A to compare foveal avascular zone (FAZ), Superficial capillary plexus (SCP) vessel density VD and SCP perfusion density (PD), and radial peripapillary capillary perfusion (CPD) and radial peripapillary capillary flux index (CFI) between both the MCI and HC groups. Result: Table 1 shows demographic details, and Table 2 shows comparison of SD OCT‐A data between MCI and HC. MCI subjects showed significant decrease in mean CPD compared to HC (44.19% ± 1.59% vs 45.05% ± 2.03%; p < 0.05). Also, MCI group showed significant decrease in mean CFI (0.42 ± 0.03 vs 0.43 ± 0.02; p <0.05) compared to HC. Conclusion: We demonstrated that there is decreased radial peripapillary perfusion and flux index in MCI subjects. By using SD OCT‐A, microvascular changes in early stage of dementia offers as a new way of detecting ocular biomarkers. [ABSTRACT FROM AUTHOR]

Background: Vascular pathology is often seen in cases of mixed dementia affecting elderly population including Alzheimer's disease (AD). AD is generally characterized by the presence of amyloid‐β (Aβ) plaques and tau deposits. However, many factors influence the onset and progression of AD pathology. In the present study, we are looking for brain vascular pathology like blood brain barrier (BBB) breach by vascular insult and associated microglial activation in small vessels increase risk of developing pathology over age. It is often hypothesized that in presence of increased Aβ, vascular insults could synergistically trigger neuroinflammation leading to cognitive impairment accelerating neurodegeneration. Method: Learning and memory deficits were performed in slow progressing APPswe mice injected with 2µg/2μl of ET‐1(endothelin‐1) bilaterally into lateral ventricles after 30 days of ET‐1 injection. BBB structural changes were assessed by immunohistochemistry for markers of endothelial cells and pericytes. Aβ plaque load and vascular deposition of Aβ were tested to understand the effect of vascular insult on AD pathology in double transgenic J20 mice. Further, microglial activation was estimated using specific markers. Result: BBB breaching was increased after vasoconstriction following ET‐1 injection after 30 days with increasing age causing memory deficits in AD mice. The extent of structural changes in BBB increased with age indicating the susceptibility with mutation. Aβ plaque load and glial activation was increased in J20 mice after ET‐1 injection. Conclusion: APP mutation increases susceptibility to ET‐1 induced single vascular insult bringing about BBB leakage, memory deficits, increased Aβ aggregation and glial activation with increasing age given enough time of 30 days to rescue. However, there was rescue in case of wild type mice. [ABSTRACT FROM AUTHOR]

Background: Recruitment and retention of participants is a crucial step in any longitudinal study. The TATA Longitudinal Study for Aging (TLSA) is an urban cohort study to gather long term data to identify risk and protective factors for dementia in India. Method: We have recruited more than 1000 individuals with age ≥ 45 years for the study. Our recruitment strategies centered around existing urban community centers in Bangalore, India, where we have conducted more than 50 awareness programs to inform the participants about the healthy aging and our study. We maintain the periodic contact with participants through telephone, in person visits and mental health awareness programs. Though we do not offer any treatment the clinical team provides brief feedback on participants blood test reports, ECG and MRI and makes appropriate referrals to the health system if necessary. To emphasize participant convenience and reduce burden, our study team has a mobile unit that conducts clinical and cognitive sessions at the participant's location. Transportation is also offered for each participant to attend the sessions at the study center. During the COVID 19 pandemic period, all participants were given special attention in terms of enquiring about their well‐being and using standard methods to assess their anxiety and depression. To keep the participants engaged during COVID 19 pandemic, we had shared the links for virtual museums, materials to read and offered psychosocial support. Result: We have approached 2225 individuals out of which 52% consented and able to complete the baseline assessment for them. It is been observed that good support and willingness to contribute to the study with the notion of potentially helping their future generations. Currently up to 50% of the participants completed first follow‐up sessions. Conclusion: The recruitment and retention of participants in the longitudinal clinical studies is a challenging task. However, TLSA study provides the unique insights on recruitment approaches that can be tailored and adopted for increasing the study enrolment and retaining in the urban cohorts of developing countries like India. [ABSTRACT FROM AUTHOR]

Background: Anthropometric characteristics of individuals and populations are simple and strong predictors of nutrition, future ill health, functional impairment and mortality (WHO‐TRS 854). Our objective was to observe differences in various anthropometric measurements between urban and rural aging participants in India. The Tata Longitudinal Study of Aging (TLSA) and Srinivaspura Aging Neurosenescence and COGnition (SANSCOG) study are ongoing, large‐scale, prospective, population‐based cohort studies in urban and rural India respectively (Sundarakumar J et.al 2020). Method: A cross‐sectional comparative study that included 1089 urban and 4913 rural participants of both the genders aged 45 years and above were selected from ongoing TLSA and SANSCOG studies. Anthropometric measurements such as Height, Weight, Waist circumference, Hip circumference, Waist‐Hip ratio, Waist‐Height ratio, Body fat and Visceral fat of both the groups were obtained through a structured clinical protocol by trained physicians and nurses and Tanita body composition analyzer. Chi‐square and Mann Whitney U tests were used to analyze the results as the data was not normally distributed. Result: Urban participants were older and had more years of education. The proportion of males and females did not differ between both cohorts as shown in Table 1. Mann‐Whitney U test was conducted to determine whether there was a difference in various anthropometric measures between Urban and Rural cohorts. The results indicate significant difference between the groups as shown in Table 2. Conclusion: Urban participants were observed to have comparatively high range of anthropometric measurements compared to rural participants. This difference may be because mean age of rural cohort was less where they mostly engage in more physically demanding occupation such as farming while their urban counterparts were elder and may engage in sedentary occupation. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a transitional phase between normal cognitive ageing and dementia. The prevalence of MCI in rural populations is an understudied area. Risk factors such as hypertension, diabetes, and depression are more prevalent in rural areas, which can contribute to the development of MCI (Longfei et al, 2020). The purpose of this study is to find out the prevalence of MCI amongst a rural cohort and to study the relationship between MCI and hypertension, diabetes and depression. Method: Cross sectional analysis on the subset of data taken from ongoing longitudinal study on dementia named Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) (Sundarakumar et al, 2020), which has a target of 10000 participants. MCI was diagnosed in the subject whose Clinical Dementia Rating (CDR) score was 0.5, as per the NIA‐AA (National Institute on Aging‐Alzheimer's Association) criteria, 2011. Presence of hypertension and diabetes were collected through a structured clinical questionnaire. Depression was assessed using the Geriatric Depression Scale 30 (GDS‐30) and a score above 9 was considered as depression. Chi‐square analysis(χ2) was used to study the association between MCI and hypertension, diabetes and depression. Result: A total of 3789 participants were examined amongst which 293 had a CDR score of 0.5, indicating presence of MCI in 7.7% of the study group. Prevalence of depression in non‐MCI and MCI subjects was 14.91% and 30.73% respectively and depression was found to be significantly associated with MCI(χ2 =24.522, p< 0.001). Hypertension was seen in 13.83% of non‐MCI subjects and in 17.76% of subjects with MCI. Diabetes was seen in 16.93% of non‐MCI subjects and in 18.25% of subjects with MCI. Both hypertension (χ2 =2.086, p = 0.149) and diabetes (χ2=0.195, p = 0.659) were not significantly associated with MCI. Conclusion: Depression was significantly associated with MCI. It is known that late onset depression, which is diagnosed above the age of 50, may be a predisposing factor for dementia in later life. Our results may indicate this relationship between depression and cognitive impairment. However, further longitudinal studies are necessary to evaluate causal relationship. [ABSTRACT FROM AUTHOR]

Background: Older adults living in urban areas differ from their rural counterparts in many ways, including the cognitive performance. Executive functioning is one of the few cognitive domains that is implicated to be affected in early stages of dementia. However, there are very few studies that have explored differences in cognitive functioning across rural and urban contexts in India. Our objective was to evaluate differences in executive functioning across urban and rural participants. Method: Our study sample includes ageing individuals (≥ 45 years): 1089 from the urban Tata Longitudinal Study on Ageing (TLSA) cohort and 4913 from the rural Srinivaspura Ageing, Neuro Senescence and COGnition (SANSCOG) study cohort. The TLSA and SANSCOG are parallel, harmonised, community‐based cohort studies in urban and rural India exploring the risk and protective factors associated with cognitive changes due to normal ageing, dementia and other related disorders. The difference in executive functioning measured by Categorical fluency, Letter fluency, Visuospatial span and Stroop tests were compared across both cohorts. Result: Urban participants were older, had more years of education had less Geriatric Depression Score (GDS) as shown in Table 1. They did not differ in gender and proportion of cognitive impairment. Multiple Linear Regression analysis was performed to examine the effects of each executive functioning tests between both the cohorts (urban participants were coded as reference category) while age, years of education and GDS were adjusted. Urban participants performed better than Rural participants on Categorical fluency (β = ‐2.379, p < 0.001), Letter fluency (β = ‐4.343, < 0.001), Visuospatial span (β = ‐0.279, < 0.001) and Stroop (β = 0.934, < 0.001). Similar results were obtained after gender stratification as shown in Table 2. Conclusion: Urban participants performed better than their rural counterparts in all tests examining executive functioning. Poorer cognitive functioning in the rural ageing cohort could be due to a number of reasons including limited or less cognitively demanding occupations. There is a need for more such longitudinal studies in India that explore community environment on cognitive function across different cohorts. [ABSTRACT FROM AUTHOR]

Background: Mild Cognitive Impairment (MCI) is a transition state of cognitive decline from healthy brain to dementia. It is a prodrome of Alzheimer's disease. Verbal‐Language/Orientation‐Memory (VLOM) ratio, a simply calculated index compares its language and memory scores helps to differentiate between Alzheimer's disease and frontotemporal dementia (Mathuranath, et al.,2000). VLOM ratio is helpful in prognosticating and planning future management of the disease. The previous studies have shown the association of scores in cognitive domains with years of education (Nieto A, et al.,2016). Therefore, the objective of the study is to explore the association of years of education with VLOM ratio in MCI participants and normal participants. Method: Cross sectional analysis was done using the baseline data from the cohort study Tata Longitudinal Study of Ageing (TLSA) from urban Bengaluru, India. Clinical dementia rating scale (CDR) was used to classify participants into normal and MCI category. CDR score of 0 was considered as normal, score of 0.5 as MCI. ACE III‐R (Addenbrooke's Cognitive Examination III‐R) a neuropsychological test was administered and verbal fluency plus language to orientation plus memory (VLOM) ratio was calculated. Further, years of education was classified into three levels and comparison of VLOM ratio was made within these levels of education groups in both MCI and normal participants. Mann Whitney U test was used to compare the VLOM ratio between MCI and normal participants. VLOM ratio and years of education among the MCI and normal participants was compared using Kruskal‐Wallis test. Results: Among 953 participants, 69 had MCI and 884 participants had normal cognition. Comparison of VLOM ratio between MCI and normal participants showed a significant difference, with higher VLOM ratio in MCI participants (Median (IQR)) = 0.97 (0.11) vs 0.95 (0.09); p = 0.01). There was no significant difference in VLOM ratio between years of education in both normal and MCI participants. Conclusion: The VLOM ratio found to be higher in MCI group indicating that the scores in orientation and memory domain might be lower in MCI compared to Normal participants. There was no association of VLOM ratio with years of education in normal and MCI participants. [ABSTRACT FROM AUTHOR]

Background: Homocysteine (Hcy) is a sulfur containing amino acid generated in the metabolism of methionine involving co‐factors such as B vitamins and folic acid. Deficiency of these co‐factors have been associated with increased Hcy levels (Hutto, 1997). Relationship between differing levels of plasma Hcy, vitamin B12, folic acid and cognitive impairment is inconclusive. Method: Cross sectional analysis was done using the baseline data from two ongoing longitudinal studies such as Tata Longitudinal Study of Ageing (TLSA, N = 984) and Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG, N = 4404), an urban and rural cohorts (Sundarakumar et al, 2020) respectively. Hcy, vitamin B12, folic acid levels were compared between the subjects of both cohorts. Comparison of these levels between healthy and MCI (Mild Cognitive Impairment) subjects within and across the cohorts were done. CDR (Clinical Dementia Rating) scale was used to classify subjects having normal cognition and MCI, considering score of 0.5 as MCI. Mann‐Whitney U test was used to compare these levels between the groups. Result: Hcy, vitamin B12, folic acid levels between the two cohorts showed significant difference, with higher levels of Hcy (median (IQR)) = (17.08 (11) vs 14.63 (10); p <0.001), vitamin B12 (247 (252) vs 220 (143); p <0.001) and folic acid (8.55 (9) vs 5.55(4); p <0.05) in TLSA than SANSCOG. Significant difference seen in Hcy (17.73(11) vs 14.73 (10); p <0.001), vitamin B12 (246 (249) vs 220 (136); p <0.001) and folic acid (8.42 (9) vs 5.53 (4): p <0.001) levels for healthy subjects between cohorts, higher levels were seen in TLSA subjects. Hcy (16.08 (8) vs 14.43 (12); p <0.001) vitamin B12 (305 (341) vs 216 (174); p = 0.03) and folic acid (8.52 (9) vs 5.34 (4): p <0.001) levels were significantly high in TLSA than SANSCOG for MCI subjects. However, these levels were not significantly different between healthy and MCI subjects within cohorts. Conclusion: Consistently elevated levels of Hcy was observed in urban cohort. Though elevated level of Hcy was observed with normal vitamin B12 and folic acid, it was not associated with MCI. [ABSTRACT FROM AUTHOR]

Background: The burden of Cardiovascular risk factors is increasing in India and the rural population is more susceptible due to rapidly changing lifestyle. There cardiovascular risk factors are known to occur in clusters and are implicated in poor cognitive performance. The Framingham risk score (FRS) is a simplified and common tool for the assessment of risk of developing Cardiovascular events over 10 years using six risk factors, such as, age, gender, total cholesterol (TC), high density lipoprotein cholesterol (HDL), smoking habits, and systolic blood pressure. Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) is a longitudinal, prospective cohort study in healthy aging individuals in a town located near Bangalore, India, where participants are recruited from the community. Method: Our objective was to examine to effect of FRS on cognitive performance measured by COGNITO among SANSCOG cohort participants. We performed separate multiple linear regression analysis to examine to effect of FRS on various COGNITO domains after adjusting for years of education and Geriatric Depression Scale (GDS) scores. Result: In a sample of 3929 individuals, 2022 (51.5%) were women. The median (IQR) age of the sample was 58 (50,65), the median (IQR) years of education was 4 (0,9) and the median (IQR) GDS was 2 (1,6). Multiple linear regression analysis was used to see the association of FRS with various cognitive tests after adjusting for years of education and GDS revealed that individuals with higher FRS performed poorly in all cognitive domains as shown in Table 1. When we examined this in men and women separately the results remained the same. Conclusion: We have demonstrated that higher FRS affects cognitive performance among rural elderly Indian individuals of both genders. It is imperative to design and implement strategies for risk‐reduction such as early identification and management of risk factors, a healthy lifestyle, balanced diet and regular physical exercise. [ABSTRACT FROM AUTHOR]

Background: Depression and Anxiety are the most widespread forms of psychiatric disorders. Studies on families and twins indicate that genetic variations can be a risk factor. Apolipoprotein ε4 gene is one such gene (APOE ε4). Studies on both humans and animals indicate that APOE ε4 may be a susceptibility gene in depression and anxiety disorders mean while the contradictory observations also reported. The purpose of the study was to investigate the effects of APOE isoforms on depression and anxiety among two aging Indian cohorts. Method: The study participants are from ongoing Srinivaspura Aging Neuro Senescence and COGnition (SANSCOG) (n = 4913) and TATA Longitudinal Study for Aging (TLSA) (n = 1089) study which are longitudinal, observational studies on aging from rural and urban India respectively. Depression and Anxiety were assessed using the Geriatric Depression Scale (GDS‐30) and Generalized Anxiety Disorder Assessment (GAD‐7). APOE gene polymorphism was determined by polymerase chain reaction (PCR). We performed the Chi‐square test to examine the relationship between prevalence of depression and anxiety in APOE ε4 homozygous, heterozygous and, non‐carriers. Result: The basic socio demographic characteristics of both cohorts are escribed in Table 1. There was no significant association between APOE ε4 isoforms and prevalence of depression and anxiety in both cohorts as described in Table 2. Conclusion: APOE ε4 did not show any association with depression or anxiety in both cohorts. There may be other factors are predominant in modulating the depression and anxiety. Moreover, ethnicity plays a significant role in the prevalence of APOE ε4 gene and its modulation effects. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is characterized by a severe loss of the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Perturbation of protein thiol redox homeostasis has been shown to play a role in the dysregulation of cell death and cell survival signaling pathways in these neurons. Glutaredoxin 1 (Grx1) is a thiol/disulfide oxidoreductase that catalyzes the deglutathionylation of proteins and is important for regulation of cellular protein thiol redox homeostasis. Objectives: We evaluated if the downregulation of Grx1 could lead to dopaminergic degeneration and PD‐relevant motor deficits in mice. Methods: Grx1 was downregulated unilaterally through viral vector‐mediated transduction of short hairpin RNA against Grx1 into the SNpc. Behavioral assessment was performed through rotarod and elevated body swing test. Stereological analysis of tyrosine hydroxylase–positive and Nissl‐positive neurons was carried out to evaluate neurodegeneration. Results: Downregulation of Grx1 resulted in contralateral bias of elevated body swing and reduced latency to fall off, accelerating rotarod. This was accompanied by a loss of tyrosine hydroxylase–positive neurons in the SNpc and their DA projections in the striatum. Furthermore, there was a loss Nissl‐positive neurons in the SNpc, indicating cell death. This was selective to the SNpc neurons because DA neurons in the ventral tegmental area were unaffected akin to that seen in human PD. Furthermore, Grx1 mRNA expression was substantially decreased in the SNpc from PD patients. Conclusions: Our study indicates that Grx1 is critical for the survival of SNpc DA neurons and that it is downregulated in human PD. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Small vessel infarcts, ischemic attacks, microbleeds are considered a common cause of vascular dementia appears as white matter hyperintensities (WMH) in MRI of many patients. However, we don't know how these WMH contribute to cognitive decline, and little is known about the underlying pathogenesis of Blood Brain Barrier (BBB) dysfunction. Thus, in the current study we have developed a mouse model with recurrent small vessel strokes leading to memory dysfunction and BBB loss. Further, we infused pleiotrophin (PTN) a trophic factor important for maintaining pericyte, the component of BBB for regulation of cerebral blood flow to rescue from multiple vascular insults. Method: 3‐4 months old C57/BL6J male mice was implanted with cannula into intracerebroventricular cavity. ET‐1 (Endothelin‐ 1), a 21 amino acid vasoconstricting peptide was injected through guide cannula into the ventricle for a period of 9 weeks at an interval of 21 days. Another set of mice were given 3 doses of ET‐1 along with PTN two days earlier and 3 days after along with ET‐1 injection. Mice were assessed for memory deficits with different behavioral task after 9 weeks. Animals were perfused and brain was processed for immunohistochemistry to assess vascular pathology. Result: Mice injected over a period of three weeks with ET‐1 showed discrepancies in the blood vessel integrity and loss of pericytes potentiating multiple vascular insults cause BBB dysfunction leading to memory impairment. However, maintaining PTN level during ET‐1 injections in mice significantly improved memory function in novel object task and contextual fear conditioning test as well as protected BBB. These data suggest that rescue of BBB integrity by PTN infusion during chronic vascular insults prevents memory decline in mice. Conclusion: Repeated vasoconstriction by ET‐1 in small vessels lead to BBB breach resulting in irreversible learning and memory deficits. This could be rescued by PTN treatment restoring BBB structure and memory function intriguing to further study novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Vascular insults, such as microinfarcts play a major role in mixed dementia including Alzheimer's disease (AD). Neuroimaging from longitudinal studies have shown involvement of white matter hyperintensities due to blood brain barrier (BBB) breakdown. In patients with AD the combined neurotoxic effects of amyloid‐β (Aβ) converge on brain vasculature synergistically leading to neuronal and synaptic dysfunction, which in turn leads to cognitive impairment. In the present study we examined the effect of vascular insult induced by enothelin‐1 (ET‐1, a vasoconstrictor peptide) on Aβ pathology in mouse models of AD. We further studied behavioral deficits during reduced cerebral blood flow changes and structural changes in BBB components. Method: We injected 2µg/2μl of ET‐1 bilaterally into lateral ventricles APPswe mice carrying point mutation for APP. Behavioral assays were performed to compare associative learning and spatial memory deficits, if any after 30 days of ET‐1 injection. Immunohistochemistry for markers of endothelial cells and pericytes were done to look at the structural changes in BBB. Aβ ELISA and plaque load were tested to understand the effect of vascular insult on AD pathology. Result: Vasoconstriction following ET‐1 injection after 30 days leads to memory deficits in AD mice while wildtype mice recovered. There were structural changes in BBB showing decreased expression of endothelial and pericyte marker, however these changes were not observed in wildtype mice. Aβ levels were increased in brain lysates of APPswe mice injected with ET‐1. Conclusion: Single vascular insult was adequate to bring about impairment in learning and memory in APPswe mice and structural changes in BBB, which were not seen in WT type mice indicating that ET‐1 induced cerebral hypoperfusion accelerated AD pathogenesis. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), a neurodegenerative disorder, causes severe motor impairment due to loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MPTP, a neurotoxin that causes dopaminergic cell loss in mice, was used in an animal model to study the pathogenic mechanisms leading to neurodegeneration. We observed the activation of apoptosis signal regulating kinase (ASK1, MAPKKK) and phosphorylation of its downstream targets MKK4 and JNK, 12 h after administration of a single dose of MPTP. Further, Daxx, the death-associated protein, translocated to the cytosol selectively in SNpc neurons seemingly due to MPTP mediated down-regulation of DJ-1, the redox-sensitive protein that binds Daxx in the nucleus. Coadministration of α-lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation of downstream kinases, MKK4, and JNK and prevented the down-regulation of DJ-1 and translocation of Daxx to the cytosol seen after MPTP. ALA also attenuated dopaminergic cell loss in SNpc seen after subchronic MPTP treatment. Our studies demonstrate for the first time that MPTP triggers death signaling pathway by activating ASK1 and translocating Daxx, in vivo, in dopaminergic neurons in SNpc of mice and thiol antioxidants, such as ALA terminate this cascade and afford neuroprotection. [ABSTRACT FROM AUTHOR]

Background: Vascular dysfunction is being increasingly recognized as a major contributor to dementia burden. Repeated occurrence of vascular insults in small vessels results in Blood Brain Barrier (BBB) dysfunction potentially contributing to cognitive impairments. The small vessel infracts is seen as white matter hyperintensities in MRI of many patients. Postmortem studies have shown BBB damage in dementia including AD and accumulation blood‐derived proteins as well as loss of BBB associated cells like pericytes. In view of such a scenario we wanted to establish an animal model to study multiple small vessel insults impacting BBB leading to learning and memory deficits. Method: C57/BL6J mice aged 4‐5 months was implanted with cannula on left side of the hemisphere. ET‐1 (Endothelin‐ 1), a 21 amino acid vasoconstricting peptide was infused through guide cannula into the intracerebroventricular space of lateral ventricle. Mice were injected for 3 doses of ET‐1 at intervals of 3 weeks over a period of 9 weeks. The animals were assessed for associative learning and spatial memory deficits with different behavioral task. Animals were perfused and brain was processed for immunohistochemistry to assess vascular pathology. Result: To simulate the clinical conditions the animals were injected over a period of three weeks to make sure that animal completely recovers from first vascular insult and then subsequent insults were given. There was BBB leakage, discrepancies in the blood vessel integrity and loss of pericytes after multiple ET‐1 injection. Further there was significant memory deficits in novel object task, contextual fear conditioning test and Morris water maze. Our results demonstrated that chronic vascular insults cause BBB dysfunction and cognitive deficits seen as memory impairment. Conclusion: We were able to establish that repeated vasoconstriction by ET‐1 in small vessels leads to BBB breach resulting in irreversible learning and memory deficits. This animal model could help us to study molecular underpinnings of white matter hyperintensities. [ABSTRACT FROM AUTHOR]

Background: Women have higher burden of Alzheimer's disease (AD) compared to men. Although neuroprotective effect of estrogen is well established, the underlying pathogenic mechanisms explaining the higher burden of AD in women remains unknown. Therefore, we attempted to investigate the sex‐specific differences through the progression of AD in familial AD mouse model. Synaptic dysfunction is considered to occur prior to the appearance of the pathophysiological and behavioural symptoms of AD. Akt1‐mTOR signaling has a critical role at the synapse in AD. Here, we investigated behavioural and synaptic deficits in female AD mice of different age and compared it male mice of similar age in order to study the progression of AD in mouse models. Methods: Recall memory test was assessed by contextual fear conditioning (cFC). We isolated synaptosomes prepared from brain cortices of WT and APP/PS1 mice at different ages. Synaptosomes were resolved on SDS‐PAGE and immunoblotted against respective antibodies. WT and APP/PS1 female mice underwent an ovariectomy and sham surgery. After ovariectomy and behavioural assessment we prepared synaptoneurosomes from hippocampus and performed 35[S] methionine incorporation assay. Results: APP/PS1 female mice protected from cFC recall deficits and activity dependent synaptic protein translation until 8 months of age. However, these mice started showing cFC recall deficits and activity dependent synaptic protein translation after 8 months of age unlike APP/PS1 male mice wherein these deficits were observed very early (2‐4 months). Ovariectomized APP/PS1 female mice induced cFC recall deficits and activity dependent protein translation at 4 months of age which is similar to young APP/PS1 male mice. Synaptosomal pAkt1, pGSK3β, pmTOR, p70S6K, p4E‐BP1 levels were significantly increased at 4 months but when they entered into menopause (at 8 months of age) these protein levels were significantly decreased in APP/PS1 female mice. Conclusions: We conclude that the appearance of recall deficits and loss of synaptosomal Akt1‐mTOR signaling occurred in females only as they aged and attained menopause. Our findings indicate that the neuroprotective effects of estrogen may play an important role in protecting from b‐amyloid induced toxicity at the synapse. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (SVD) has gained prominence worldwide as a major factor for cognitive impairment seen in dementia. Micro infracts causing elusive changes in cognitive function clinically will not get diagnosed are found to be the main risk factor for SVD. We were interested in creating micro infarcts rather than a severe insult to replicate small vessel damage, so we opted for Intra cerebroventricular (ICV) bilateral stereotaxic injection of endothelin‐1 (ET‐1) into lateral ventricles. Sub cortical injections of ET‐1 in brain has been used in many studies to accomplish long lasting vasoconstriction and gradual reperfusion causing lesion. Therefore, we tried to overcome this by injecting into lateral ventricles allowing it to spread through cerebrospinal fluid. Method: ET‐1 (Endothelin‐ 1) a 21 amino acid vasoconstricting peptide was injected bilaterally into lateral ventricles of C57 mice. Some animals were injected unilaterally to see whether there are any motor deficits. Expression of CD31, a marker of endothelial cells was done by immunohistochemistry to assess vasoconstriction. Contextual fear conditioning, object recognition and Morris water maze task was performed to examine associative learning and spatial memory deficits. Gait and rotarod was performed to examine if there are any motor deficits. Synaptic plasticity was evaluated as activity dependent protein translation was measured in synaptoneurosomes prepared from hippocampus. Result: The obstruction in cerebral blood flow due to vasoconstriction caused by ET‐1 injection leads to deficits in associative learning and spatial memory after 7 days. There was no change in gait or rotarod performance indicating no effect on motor function. However, the behavioral dysfunction was temporary and reversed after 30 days of ET‐1 treatment once the blood flow was restored. These changes were demonstrated as drop in the activity dependent protein translation after 7 days of ET‐1 injection and raise after 30 days of treatment as it is an indicator for synaptic plasticity. Conclusion: Bilateral injection of ET‐1 leads to prominent associative and spatial memory deficit and decline in activity dependent protein translation in hippocampus. Still these defects are reversible once the blood flow is restored. Unilateral injection of ET‐1 did not show any motor dysfunction. [ABSTRACT FROM AUTHOR]

Background: Vascular dementia may begin as mild cognitive changes due to blockade of blood vessels that worsen gradually as a result of multiple minor strokes. Such vascular insults occurring in the aging human brain can induce various types of cerebral tissue lesions like hemorrhage, infarction, hippocampal sclerosis and white matter lesions leading to cognitive decline. Studies have shown that multi‐infarct dementia is accounted for most cases of vascular dementia. We wanted to develop an animal model to study the vascular pathology affecting synaptic function during such multiple vascular insult to pave way for better understanding of vascular dementia. Method: Vasoconstriction was induced by ET‐1, a 21 amino acid peptide. C57/BL6J mice aged 4‐5 months was implanted with cannula on left side of the hemisphere. ET‐1 2ug/2ul was injected through guide cannula into the intracerebroventricular space of lateral ventricle. The animals were injected with 3 doses of ET‐1 at interval of three weeks for each dose for a period of 9 weeks, at the end of dosing mice were subjected behavioral task. Animals were sacrificed, different brain regions like cortex and hippocampus were dissected out to process for biochemical analysis. Result: Animals were injected for a period of three weeks to make sure that animal completely recovers from first vascular insult. There was significant difference in novel object task, contextual fear conditioning test and Morris water maze in ET‐1 injected mice indicating memory deficits. Gait analysis demonstrated discrepancies in stride and stance length in chronic ET‐1 injected mice compared to vehicle control. Actin treadmilling plays important role in maintaining F/G‐actin equilibrium for optimal synaptic function. Hence, we wanted to know whether chronic vascular insult affects F/G‐actin equilibrium and our results demonstrated that synaptic dysfunction seen as F‐actin disassembly might be contributing to behavioral dysfunction. Conclusion: Repeated vascular insult resulted in irreversible learning and memory deficits in ET‐1 injected mice compared to controls leading to vascular dementia. Gait analysis indicated changes in stride and stance length after three injections of ET‐1. We observed loss of F‐actin in synaptosomes prepared from cortex of mice with chronic dose of ET‐1. [ABSTRACT FROM AUTHOR]

Background: Female sex is one of the major risk factor for developing late‐onset Alzheimer's disease (AD). Human studies have demonstrated that the prevalence of AD is higher in women compared with men. Although neuroprotective effect of estrogen is well recognized, the underlying pathogenic mechanisms explaining the higher burden of AD in women are unclear, taking into account the longer lifespan in women. Thus, we attempted to investigate the gender‐specific differences during the progression of the disease in an AD mouse model. We examined behavioural and activity dependent protein translation in female AD mice after ovariectomy and compared it with sham‐operated female mice of similar age in order to study the effect of female sex hormones in female AD mouse. Methods: Wild type and APP/PS1 female mice underwent an ovariectomy and sham surgery. The cognitive task we used in AD mouse model is the recall following contextual fear‐conditioning (cFC). After ovariectomy and behavioural assessment we prepared synaptoneurosomes from hippocampus and performed 35S methionine incorporation assay without or with KCl stimulation. Results: Female APP/PS1 mice did not show deficient recall upon cFC at 2, 4 and 6 months of age. However, female APP/PS1 mice showed deficient recall following cFC only after 8 months of age and this was sustained as mice aged further. Activity dependent synaptic protein translation was affected only at 8 months of age and no deficits were observed in 4 months old APP/PS1 female mice. In contrast, ovariectomized APP/PS1 mice displayed deficient recall upon cFC at 4 months of age and this recall deficits were sustained until 8 months of age as examined. Further, activity dependent protein translation was also impaired in 4 months old ovariectomized APP/PS1 mice compared with sham female APP/PS1 mice and this impairment was persistent until 8 months of age in these ovariectomized APP/PS1 mice. Conclusions: Our results indicate that deficits in recall following cFC and loss of activity dependent protein translation occurred in female APP/PS1 mice only as they aged or if they were ovariectomized at younger age. Thus, estrogen plays a protective role even in the presence of relatively higher levels of β‐amyloid. [ABSTRACT FROM AUTHOR]

Examines the molecular mechanisms underlying neuroprotection in female mice using the dopaminergic neurotoxin methylphenyltetrahydropyridine (MPTP). Resistance of female mice to MPTP neurotoxicity; Expression of growth stimulating hormone and glutaredoxin in female mouse brain; Influence of estrogen receptor blockade on the vulnerability of female mice to MPTP neurotoxicity.