The BrainLat project, a multimodal neuroimaging dataset of neurodegeneration from underrepresented backgrounds.

The Latin American Brain Health Institute (BrainLat) has released a unique multimodal neuroimaging dataset of 780 participants from Latin American. The dataset includes 530 patients with neurodegenerative diseases such as Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), multiple sclerosis (MS), Parkinson's disease (PD), and 250 healthy controls (HCs). This dataset (62.7 ± 9.5 years, age range 21-89 years) was collected through a multicentric effort across five Latin American countries to address the need for affordable, scalable, and available biomarkers in regions with larger inequities. The BrainLat is the first regional collection of clinical and cognitive assessments, anatomical magnetic resonance imaging (MRI), resting-state functional MRI (fMRI), diffusion-weighted MRI (DWI), and high density resting-state electroencephalography (EEG) in dementia patients. In addition, it includes demographic information about harmonized recruitment and assessment protocols. The dataset is publicly available to encourage further research and development of tools and health applications for neurodegeneration based on multimodal neuroimaging, promoting the assessment of regional variability and inclusion of underrepresented participants in research.

Visual-spatial processing impairment in the occipital-frontal connectivity network at early stages of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is the leading cause of dementia worldwide, but its pathophysiological phenomena are not fully elucidated. Many neurophysiological markers have been suggested to identify early cognitive impairments of AD. However, the diagnosis of this disease remains a challenge for specialists. In the present cross-sectional study, our objective was to evaluate the manifestations and mechanisms underlying visual-spatial deficits at the early stages of AD. Methods: We combined behavioral, electroencephalography (EEG), and eye movement recordings during the performance of a spatial navigation task (a virtual version of the Morris Water Maze adapted to humans). Participants (69-88 years old) with amnesic mild cognitive impairment-Clinical Dementia Rating scale (aMCI-CDR 0.5) were selected as probable early AD (eAD) by a neurologist specialized in dementia. All patients included in this study were evaluated at the CDR 0.5 stage but progressed to probable AD during clinical follow-up. An equal number of matching healthy controls (HCs) were evaluated while performing the navigation task. Data were collected at the Department of Neurology of the Clinical Hospital of the Universidad de Chile and the Department of Neuroscience of the Faculty of Universidad de Chile. Results: Participants with aMCI preceding AD (eAD) showed impaired spatial learning and their visual exploration differed from the control group. eAD group did not clearly prefer regions of interest that could guide solving the task, while controls did. The eAD group showed decreased visual occipital evoked potentials associated with eye fixations, recorded at occipital electrodes. They also showed an alteration of the spatial spread of activity to parietal and frontal regions at the end of the task. The control group presented marked occipital activity in the beta band (15-20 Hz) at early visual processing time. The eAD group showed a reduction in beta band functional connectivity in the prefrontal cortices reflecting poor planning of navigation strategies. Discussion: We found that EEG signals combined with visual-spatial navigation analysis, yielded early and specific features that may underlie the basis for understanding the loss of functional connectivity in AD. Still, our results are clinically promising for early diagnosis required to improve quality of life and decrease healthcare costs.

The Impact of a Yoga-Based Mindfulness Intervention versus Psycho-Educational Session for Older Adults with Mild Cognitive Impairment: The Protocol of a Randomized Controlled Trial.

BACKGROUND: There is a global agreement in the medical community that a significant proportion of dementia cases could be prevented or postponed. One of the factors behind this agreement comes from scientific evidence showing that mind-body interventions such as mindfulness and yoga for the elderly have been related to a range of positive outcomes, including improved cognition performance in seniors with mild cognitive impairment (MCI). OBJECTIVE: This study aims to evaluate the effectiveness of a yoga-based mindfulness intervention (YBM) versus psychoeducational sessions for older adults with MCI attending Hospital Clinic Universidad de Chile in Santiago. METHOD: Two-arm, individually randomized controlled trial (RCT) will be carried out at Clinical Hospital Universidad de Chile in Santiago. Older people over 60 years with any type of MCI using a score < 21 in the Montreal Cognitive Assessment (MoCA) test and a score of 0.05 in the Clinical Dementia Rating (CDR) Scale; and with preserved activities of daily living will be randomly assigned with an allocation ratio of 1:1 in either the yoga-based mindfulness intervention or the active control group based on the psycho-educational program. People who have performed yoga and/or mindfulness in the last 6 months or/and people with a psychiatric clinical diagnosis will be excluded from the study. Montreal Cognitive Assessment, the Lawton Instrumental Activities of Daily Living Scale (IADL), the Barthel Index (BI), the Pemberton happiness index, the Geriatric Anxiety Inventory (GAI) as well as the Geriatric Depression Scale (GDS-5) will be administered by blinded outcomes assessors before random assignment (Pre-test), the week following the last session of the intervention (post-test), and then after 3- and 6-months follow-up. RESULTS: The YBM intervention protocol based on a video recording has been adapted and designed. This is the first RCT to examine the effects of a yoga-based mindfulness intervention in improving cognitive and physical functions and mental health outcomes for Chilean elderly diagnosed with MCI. It is expected to be implemented as an acceptable and effective non-pharmacological option for older people with MCI. CONCLUSION: Providing evidence-based programs such as preventive therapy for Alzheimer's disease has relevant implications for public mental health services in Chile.

Neuronal Rubicon Represses Extracellular APP/Amyloid ß Deposition in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon's role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid ß burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid ß burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid ß secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid ß homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid ß secretion, defining a new way to target AD and other similar diseases therapeutically.

Cancer History Is Associated with Slower Speed of Cognitive Decline in Patients with Amnestic Cognitive Impairment.

BACKGROUND: Several epidemiological studies report a negative association between Cancer and Alzheimer's disease (AD). OBJECTIVE: To characterize the trajectories of memory loss in individuals with early amnestic cognitive impairment with and without history of previous cancer. METHODS: Cognitive deterioration was assessed using the Montreal Cognitive Assessment (MoCA) or MoCA-Memory Index Score (MoCA-MIS) biannually in subjects with early amnestic cognitive impairment followed-up retrospectively from 2007 to 2021. History of Cancer was obtained from clinical records. Simple linear regressions of MoCA-MIS scores were calculated for each subject and analyzed with K-means cluster analysis to identify subgroups with different cognitive decline trajectories. χ2 and t tests were used for descriptive categorical and continuous variables and mixed multiple linear regressions to determine cognitive decline covariates. RESULTS: Analysis of the trajectory of cognitive decline in 141 subjects with early amnestic cognitive impairment identified two subgroups: Fast (n = 60) and Slow (n = 81) progressors. At baseline Fast progressors had better MoCA-MIS (p < 0.001) and functionality (CDR p = 0.02, AD8 p = 0.05), took less anti-dementia medications (p = 0.005), and had higher depression rates (p = 0.02). Interestingly, Fast progressors slowed their speed of memory decline (from 1.6 to 1.1 MoCA-MIS points/year) and global cognitive decline (from 2.0 to 1.4 total MoCA points/year) when Cancer history was present. CONCLUSION: Two trajectories of amnestic cognitive decline were identified, possibly derived from different neurophysiopathologies or clinical stages. This study suggests that a history of previous Cancer slows down amnestic cognitive decline, specifically in a subgroup of subjects with depression at baseline and accelerated deterioration at follow-up.

Impact of social isolation and coping strategies in older adults with mild cognitive impairment during the covid-19 pandemic: A qualitative study.

OBJECTIVES: The objective of this study was to explore the experiences and feelings of older adults with MCI during the COVID-19 outbreak in Chile and to know what strategies they used to overcome social isolation. METHOD: A qualitative design was used. Ten participants with a diagnosis of MCI took part in this study. All interviews were recorded and coded using thematic analysis. RESULTS: The thematic analysis identified three themes related to the quarantine experience of older adults with MCI diagnosis: (1) Effects of social isolation during the COVID-19 pandemic (2) Believes, feelings and behaviors about the SARS-CoV-2 virus (3) Coping with social isolation/response to difficulties during the pandemic. It was found that older adults with MCI have been mainly psychologically and socially affected by social distancing and isolation, particularly individuals who were alone during COVID-19 outbreak. The only physical dimension negatively affected was the level of activity. Social isolation led to a significant number of negative emotions such as anger, fear of contracting the virus or possibility of contagion for their families, worries and sadness as well as emotional loneliness. It is noteworthy that the majority of participants have used several coping strategies during this challenging time. CONCLUSION: Since social isolation and a sedentary life have been associated with poorer cognition and functionality in people with MCI, a rational plan to both prevent the progression of cognitive decline and to increase social contact, is essential. Special attention must be drawn to maintaining people physically active at home and keeping their daily routine (within the possibilities) and also to ensure social connectedness through technology. Implementation of these measures could potentially reduce negative emotions during the pandemic.

DEF8 and Autophagy-Associated Genes Are Altered in Mild Cognitive Impairment, Probable Alzheimer's Disease Patients, and a Transgenic Model of the Disease.

BACKGROUND: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer's disease (AD). However, few studies are available concerning autophagy gene expression in AD patients. OBJECTIVE: To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheralblood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice. METHOD: By real-time PCR and flow cytometry, we evaluated autophagy genes levels in PBMCs from MCI and pAD patients. We evaluated DEF8 levels and its localization in brain samples of the 5xFAD mice by real-time PCR, western blot, and immunofluorescence. RESULTS: Transcriptional levels of DEF8 were significantly reduced in PBMCs of MCI and pAD patients compared with healthy donors, correlating with the MoCA and MoCA-MIS cognitive tests scores. DEF8 protein levels were increased in lymphocytes from MCI but not pAD, compared to controls. In the case of brain samples from 5xFAD mice, we observed a reduced mRNA expression and augmented protein levels in 5xFAD compared to age-matched wild-type mice. DEF8 presented a neuronal localization. CONCLUSION: DEF8, a protein proposed to act at the final step of the autophagy/endolysosomal pathway, is differentially expressed in PBMCs of MCI and pAD and neurons of 5xFAD mice. These results suggest a potential role for DEF8 in the pathophysiology of AD.

Association of Vitamin D Receptor Polymorphisms with Amyloid-ß Transporters Expression and Risk of Mild Cognitive Impairment in a Chilean Cohort.

BACKGROUND: Amyloid-ß peptide (Aß) deposition in Alzheimer's disease (AD) is due to an imbalance in its production/clearance rate. Aß is transported across the blood-brain barrier by LRP1 and P-gp as efflux transporters and RAGE as influx transporter. Vitamin D deficit and polymorphisms of the vitamin D receptor (VDR) gene are associated with high prevalence of mild cognitive impairment (MCI) and AD. Further, vitamin D promotes the expression of LRP1 and P-gp in AD-animal model brains. OBJECTIVE: To associate VDR polymorphisms Apa I (rs7975232), Taq I (rs731236), and Fok I (rs2228570) with the risk of developing MCI in a Chilean population, and to evaluate the relationship of these polymorphisms to the expression of VDR and Aß-transporters in peripheral blood mononuclear cells (PBMCs). METHODS: VDR polymorphisms Apa I, Taq I, and Fok I were determined in 128 healthy controls (HC) and 66 MCI patients. mRNA levels of VDR and Aß-transporters were evaluated in subgroups by qPCR. RESULTS: Alleles A of Apa I and C of Taq I were associated with a lower risk of MCI. HC with the Apa I AA genotype had higher mRNA levels of P-gp and LRP1, while the expression of VDR and RAGE were higher in MCI patients and HC. For Fok I, the TC genotype was associated with lower expression levels of Aß-transporters in both groups. CONCLUSION: We propose that the response to vitamin D treatment will depend on VDR polymorphisms, being more efficient in carriers of protective alleles of Apa I polymorphism.

On the Role of Mining Exposure in Epigenetic Effects in Parkinson's Disease.

To explore the possible influence of heavy metal mining on incidence of Parkinson's disease (PD), global DNA methylation was assessed in blood samples from a population of PD patients (n = 45) and control subjects (n = 52) in Antofagasta neighborhood, a Chilean city built for exclusive use of mining companies. Comparisons were made with PD subjects (n = 52) and control subjects (n = 59) from Santiago Chile, a city having little association with mining. All subjects were assessed by two neurologists and PD diagnosis was based on UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria. From blood samples obtained from each individual, a decrease in global DNA methylation was observed in PD patients either exposed (49% of control, P < 0.001) or not exposed (47% of control, P < 0.001) to mining activity. Although there was no difference in levels of DNA methylation between PD patients from the two cities, there was a lower level of DNA methylation in control subjects from Santiago versus Antofagasta.

Frizzled-1 receptor regulates adult hippocampal neurogenesis.

BACKGROUND: In the adult hippocampus new neurons are continuously generated from neural stem cells (NSCs) present at the subgranular zone of the dentate gyrus. This process is controlled by Wnt signaling, which plays a complex role in regulating multiple steps of neurogenesis including maintenance, proliferation and differentiation of progenitor cells and the development of newborn neurons. Differential effects of Wnt signaling during progression of neurogenesis could be mediated by cell-type specific expression of Wnt receptors. Here we studied the potential role of Frizzled-1 (FZD1) receptor in adult hippocampal neurogenesis. RESULTS: In the adult dentate gyrus, we determined that FZD1 is highly expressed in NSCs, neural progenitors and immature neurons. Accordingly, FZD1 is expressed in cultured adult hippocampal progenitors isolated from mouse brain. To evaluate the role of this receptor in vivo we targeted FZD1 in newborn cells using retroviral-mediated RNA interference. FZD1 knockdown resulted in a marked decrease in the differentiation of newborn cells into neurons and increased the generation of astrocytes, suggesting a regulatory role for the receptor in cell fate commitment. In addition, FZD1 knockdown induced an extended migration of adult-born neurons within the granule cell layer. However, no differences were observed in total dendritic length and dendritic arbor complexity between control and FZD1-deficient newborn neurons. CONCLUSIONS: Our results show that FZD1 regulates specific stages of adult hippocampal neurogenesis, being required for neuronal differentiation and positioning of newborn neurons into the granule cell layer, but not for morphological development of adult-born granule neurons.

[Default mode network and Alzheimer's disease]. / Red neural por defecto y enfermedad de Alzheimer.

Brain functioning is mainly intrinsic, not primarily reflexive. This is supported by the high energy requirements of the resting brain (20% of all the energy consumed) which only marginally increases with changes in brain activity. Modern neuroimaging and neurophysiological techniques have led to the discovery of the so called brain default mode network (DMN), a constellation of brain regions which support brain activity at rest and whose discharges decrease during task-induced activities. Another characteristic of the DMN are the elevated levels of aerobic glycolysis (Warburg effect), that is, metabolism of glucose to lactic acid in the presence of sufficient levéis of oxygen. In Alzheimer's disease there is amyloid deposition and metabolic disruption at the DMN regions. Changes in connectivity among the different nodes of the DMN and its connections with the hippocampus have been reported. The characteristics of the DMN and its relation to Alzheimer's disease are discussed. This issue is of interest in the pathogenesis and possibly for its usefulness as a biomarker of the disease.

Red neural por defecto y enfermedad de Alzheimer / Default mode network and Alzheimer's disease

Brainfunctioning is mainly intrinsic, notprimarily reflexive. This is supported by the high energy requirements ofthe resting brain (20% ofall the energy consumed) which only marginally increases with changes in brain activity. Modern neuroimaging and neurophysiological techniques have led to the discovery of the so called brain default mode network (DMN), a constellation of brain regions which support brain activity at rest and whose discharges decrease during task-induced activities. Another characteristic ofthe DMN are the elevated levéis of aerobic glycolysis (Warburg effect), that is, metabolism ofglucose to lactic acid in thepresence ofsufficient levéis ofoxygen. In Alzheimer's disease there is amyloid deposition and metabolic disruption at the DMN regions. Changes in connectivity among the different nodes ofthe DMN and its connections with the hippocampus have been reported. The characteristics ofthe DMN and its relation to Alzheimer's disease are discussed. This issue is ofinterest in the pathogenesis and possibly for its usefulness as a biomarker ofthe disease.

Olfactory deficits and cognitive dysfunction in Parkinson's disease.

BACKGROUND: Olfactory deficits and executive dysfunction have been reported in Parkinson's disease (PD). However, the association between these deficits has not been thoroughly examined. METHODS: We studied 44 PD subjects and 17 age-matched controls. In PD subjects, symptoms were assessed with the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr scale. Cognition in both groups was assessed by a neuropsychological battery. Olfactory identification and sensitivity was evaluated with the Sniffin' Sticks® test and olfactory detection threshold, respectively. RESULTS: PD subjects showed significant deficits in olfactory function and working memory, executive function, speed of information processing, visuospatial skills and phonological verbal fluency tests when compared with the control group. Moreover, there was a significant correlation between olfactory sensory deficits and executive dysfunction. In PD patients with up to 12 months of motor symptoms, results were equivalent. CONCLUSION: Our preliminary results suggest a significant association between olfactory deficits and impairments of executive functions in PD.

Clinical and genetic analysis of a Chilean family with early-onset autosomal dominant Alzheimer's disease.

Autosomal dominant early-onset Alzheimer's disease (ADEOAD) is associated predominantly with mutations in the genes that codify for presenilin 1 (PSEN1). Only a few ADEOAD families have been reported from Latin America. This is an extended Chilean pedigree affected by ADEOAD along 4 generations. The age of onset of dementia was between 38 and 42 years. Early manifestations were anxiety and depression. Mutation analysis revealed a heterozygous G to C transversion at position 438 of the mRNA in PSEN1 in all affected members. This is the first report of a Chilean family with ADEOAD to include mutation analysis.

Frequency and determinants of poststroke cognitive impairment at three and twelve months in Chile.

BACKGROUND: A higher risk of poststroke cognitive impairment (CI) has been reported in Hispanics in a US cohort but has not been systematically studied in Latin America. OBJECTIVES: Our purpose was to investigate the frequencies and determinants of poststroke CI in the hispano-mestizo population of Santiago, Chile. METHODS: A prospective study of hospitalized patients aged >60 years admitted with an ischemic or hemorrhagic stroke was conducted. The cognitive status was determined at 3 and 12 months after the stroke by informant questionnaires, neuropsychological testing and clinical diagnosis. Cardiovascular risk factors, brain imaging and stroke features were analyzed using regression models to establish determinants for poststroke CI. RESULTS: A total of 164 patients (mean age = 72 +/- 7.5 years) were recruited. Out of 122 patients (74%) evaluated at 3 months, 81 (66%) had CI. Out of 101 patients (62%) evaluated at 12 months, 39 (39%) had CI no dementia, and 22 (22%) were demented. The new-onset dementia frequency at 1 year was 16%. Independent determinants for dementia were higher functional impairment at hospital egress (OR = 4.0), left-hemisphere large-vessel infarction (OR = 6.9) and a larger amount of white matter changes (OR = 1.3). CONCLUSIONS: In this first study on poststroke CI in Latin America, the frequencies and determinants of poststroke CI were similar to those in other cohorts of different ethnic origin.

Ischemia enhances activation by Ca2+ and redox modification of ryanodine receptor channels from rat brain cortex.

Cerebral ischemia stimulates Ca2+ influx and thus increases neuronal intracellular free [Ca2+]. Using a rat model of cerebral ischemia without recirculation, we tested whether ischemia enhances the activation by Ca2+ of ryanodine receptor (RyR) channels, a requisite feature of RyR-mediated Ca2+-induced Ca2+ release (CICR). To this aim, we evaluated how single RyR channels from endoplasmic reticulum vesicles, fused into planar lipid bilayers, responded to cytoplasmic [Ca2+] changes. Endoplasmic reticulum vesicles were isolated from the cortex of rat brains incubated without blood flow for 5 min at 37 degrees C (ischemic) or at 4 degrees C (control). Ischemic brains displayed increased oxidative intracellular conditions, as evidenced by a lower ratio (approximately 130:1) of reduced/oxidized glutathione than controls (approximately 200:1). Single RyR channels from ischemic or control brains displayed the same three responses to Ca2+ reported previously, characterized by low, moderate, or high maximal activity. Relative to controls, RyR channels from ischemic brains displayed with increased frequency the high activity response and with lower frequency the low activity response. Both control and ischemic cortical vesicles contained the RyR2 and RyR3 isoforms in a 3:1 proportion, with undetectable amounts of RyR1. Ischemia reduced [3H]ryanodine binding and total RyR protein content by 35%, and increased at least twofold endogenous RyR2 S-nitrosylation and S-glutathionylation without affecting the corresponding RyR3 endogenous levels. In vitro RyR S-glutathionylation but not S-nitrosylation favored the emergence of high activity channels. We propose that ischemia, by enhancing RyR2 S-glutathionylation, allows RyR2 to sustain CICR; the resulting amplification of Ca2+ entry signals may contribute to cortical neuronal death.