Genetic associations with psychosis and affective disturbance in Alzheimer's disease.

INTRODUCTION: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. METHODS: Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). RESULTS: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. DISCUSSION: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.

Proteome Network Analysis Identifies Potential Biomarkers for Brain Aging.

BACKGROUND: Alzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults. OBJECTIVE: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome. METHODS: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up). RESULTS: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities. CONCLUSIONS: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

Physical performance in older age by sex and educational level: the HUNT Study.

BACKGROUND: Population-based studies on physical performance provide important information on older people's health but rarely include the oldest and least-healthy segment of the population. The aim of this study was to provide representative estimates of physical performance by age, sex, and educational level based on recent data from a population-based health study in Norway that includes older people with a wide range in age and function. METHODS: In the fourth wave of the Trøndelag Health Study (2017-2019), all participants aged 70 + were invited to an additional examination of physical performance assessed by the Short Physical Performance Battery (SPPB), either by attending a testing station or by visits from ambulatory teams. The distribution and variation in SPPB total and subscores, as well as gait speed, are presented by sex, age, and educational level. RESULTS: The SPPB was registered in 11,394 individuals; 54.8% were women; the age range was 70-105.4 years, with 1,891 persons aged 85 + . SPPB scores decreased by 0.27 points (men) and 0.33 points (women) for each year of age, and gait speed by 0.02 m/sec (men) and 0.03 m/sec (women). Using a frailty cut-off for gait speed at < 0.8 m/sec, the proportion of participants categorized as frail increased from 13.9% in the 70-74 years cohort to 73.9% in participants aged 85 + . Level of education [Formula: see text] 10 years corresponded to 6 years (men) and 4 years (women) earlier onset of frailty (SPPB [Formula: see text] 9) compared to education [Formula: see text] 14 years. CONCLUSION: We found that the SPPB captured a gradual decline and wide distribution in physical performance in old age. The results provide information about physical performance, health status, and risk profiles at a population level and can serve as reference data for clinicians, researchers, and healthcare planners.

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Temporal changes in cardiorespiratory fitness and risk of dementia incidence and mortality: a population-based prospective cohort study.

BACKGROUND: Cardiorespiratory fitness is associated with risk of dementia, but whether temporal changes in cardiorespiratory fitness influence the risk of dementia incidence and mortality is still unknown. We aimed to study whether change in estimated cardiorespiratory fitness over time is associated with change in risk of incident dementia, dementia-related mortality, time of onset dementia, and longevity after diagnosis in healthy men and women at baseline. METHODS: We linked data from the prospective Nord-Trøndelag Health Study (HUNT) done in Nord-Trøndelag, Norway with dementia data from the Health and Memory Study and cause of death registries (n=30 375). Included participants were apparently healthy individuals for whom data were available on estimated cardiorespiratory fitness and important confounding factors. Datasets were matched to each participant through their 11-digit personal identification number. Cardiorespiratory fitness was estimated on two occasions 10 years apart, during HUNT1 (1984-86) and HUNT2 (1995-97). HUNT2 was used as the baseline for follow-up. Participants were classified into two sex-specific estimated cardiorespiratory fitness groups according to their age (10-year categories): unfit (least fit 20% of participants) and fit (most fit 80% of participants). To assess the association between change in estimated cardiorespiratory fitness and dementia, we used four categories of change: unfit at both HUNT1 and HUNT2, unfit at HUNT1 and fit at HUNT2, fit at HUNT1 and unfit at HUNT2, fit at both HUNT1 and HUNT2. Using Cox proportional hazard analyses, we estimated adjusted hazard ratios (AHR) for dementia incidence and mortality related to temporal changes in estimated cardiorespiratory fitness. FINDINGS: During a median follow-up of 19·6 years for mortality, and 7·6 years for incidence, there were 814 dementia-related deaths, and 320 incident dementia cases. Compared with participants who were unfit at both assessments, participants who sustained high estimated cardiorespiratory fitness had a reduced risk of incident dementia (AHR 0·60, 95% CI 0·36-0·99) and a reduced risk of dementia mortality (0·56, 0·43-0·75). Participants who had an increased estimated cardiorespiratory fitness over time had a reduced risk of incident dementia (AHR 0·52, 95% CI 0·30-0·90) and dementia mortality (0·72, 0·52-0·99) when compared with those who remained unfit at both assessments. Each metabolic equivalent of task increase in estimated cardiorespiratory fitness was associated with a risk reduction of incident dementia (adjusted HR 0·84, 95% CI 0·75-0·93) and dementia mortality (0·90, 0·84-0·97). Participants who increased their estimated cardiorespiratory fitness over time gained 2·2 (95% CI 1·0-3·5) dementia-free years, and 2·7 (0·4-5·8) years of life when compared with those who remained unfit at both assessments. INTERPRETATION: Change in estimated cardiorespiratory fitness is an independent risk factor for incidence dementia and dementia mortality. Maintaining or improving cardiorespiratory fitness over time may be a target to reduce risk of dementia incidence and mortality, delay onset, and increase longevity after diagnosis. Our data highlight the importance of assessing cardiorespiratory fitness in health risk assessment for people at risk of dementia. FUNDING: The KG Jebsen Foundation, the Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority, and the Norwegian University of Science and Technology.

Time-lapse phenotyping of invasive glioma cells ex vivo reveals subtype-specific movement patterns guided by tumor core signaling.

The biology of glioblastoma invasion and its mechanisms are poorly understood. We demonstrate using time-lapse microscopy that grafting of glioblastoma (GBM) tumorspheres into rodent brain slices results in experimental ex vivo tumors with invasive properties that recapitulate the invasion observed after orthotopic transplantation into the rodent brain. The migratory movements and mitotic patterns were clearly modified by signals extrinsic to the invading cells. The cells migrated away from the tumorspheres, and removal of the spheres reduced the directed invasive movement. The cell cultures contained different populations of invasive cells that had distinct morphology and invasive behavior patterns. Grafts of the most invasive GBM culture contained 91±8% cells with an invasive phenotype, characterized by small soma with a distinct leading process. Conversely, the majority of cells in less invasive GBM grafts were phenotypically heterogeneous: only 6.3±4.1% of the cells had the invasive phenotype. Grafts of highly and moderately invasive cultures had different proportions of cells that advanced into the brain slice parenchyma during the observation period: 89.2±2.2% and 23.1±6.8%, respectively. In grafts with moderately invasive properties, most of the cells (76.8±6.8%) invading the surrounding brain tissue returned to the tumor bulk or stopped centrifugal migration. Our data suggest that the invasion of individual GBM tumors can be conditioned by the prevalence of a cell fraction with particular invasive morphology and by signaling between the tumor core and invasive cells. These findings can be important for the development of new therapeutic strategies that target the invasive GBM cells.

Short-Term Differentiation of Glioblastoma Stem Cells Induces Hypoxia Tolerance.

Glioblastoma is the most common and malignant brain cancer. In spite of surgical removal, radiation and chemotherapy, this cancer recurs within short time and median survival after diagnosis is less than a year. Glioblastoma stem cells (GSCs) left in the brain after surgery is thought to explain the inevitable recurrence of the tumor. Although hypoxia is a prime factor contributing to treatment resistance in many cancers, its effect on GSC has been little studied. Especially how differentiation influences the tolerance to acute hypoxia in GSCs is not well explored. We cultured GSCs from three patient biopsies and exposed these and their differentiated (1- and 4-weeks) progeny to acute hypoxia while monitoring intracellular calcium and mitochondrial membrane potential (ΔΨm). Undifferentiated GSCs were not hypoxia tolerant, showing both calcium overload and mitochondrial depolarization. One week differentiated cells were the most tolerant to hypoxia, preserving intracellular calcium stability and ΔΨm during 15 min of acute hypoxia. After 4 weeks of differentiation, mitochondrial mass was significantly reduced. In these cells calcium homeostasis was maintained during hypoxia, although the mitochondria were depolarized, suggesting a reduced mitochondrial dependency. Basal metabolic rate increased by differentiation, however, low oxygen consumption and high ΔΨm in undifferentiated GSCs did not provide hypoxia tolerance. The results suggest that undifferentiated GSCs are oxygen dependent, and that limited differentiation induces relative hypoxia tolerance. Hypoxia tolerance may be a factor involved in high-grade malignancy. This warrants a careful approach to differentiation as a glioblastoma treatment strategy.

Expansion of multipotent stem cells from the adult human brain.

The discovery of stem cells in the adult human brain has revealed new possible scenarios for treatment of the sick or injured brain. Both clinical use of and preclinical research on human adult neural stem cells have, however, been seriously hampered by the fact that it has been impossible to passage these cells more than a very few times and with little expansion of cell numbers. Having explored a number of alternative culturing conditions we here present an efficient method for the establishment and propagation of human brain stem cells from whatever brain tissue samples we have tried. We describe virtually unlimited expansion of an authentic stem cell phenotype. Pluripotency proteins Sox2 and Oct4 are expressed without artificial induction. For the first time multipotency of adult human brain-derived stem cells is demonstrated beyond tissue boundaries. We characterize these cells in detail in vitro including microarray and proteomic approaches. Whilst clarification of these cells' behavior is ongoing, results so far portend well for the future repair of tissues by transplantation of an adult patient's own-derived stem cells.

Mitochondria are more resistant to hypoxic depolarization in the newborn than in the adult brain.

Hypoxic-ischemic brain injury subsequent to asphyxia represents a major cause of morbidity and death in the newborn. The newborn brain has been considered more resistant to hypoxia than the adult brain because of lower energy demand. The mechanisms underlying hypoxic brain injury, in particular the age-related vulnerability, are still only partially understood. The mitochondrial function is pivotal for the function and survival of neurons. Acutely isolated CA1 neurons from neonatal (3-6 days) and adult rats (5-6 weeks) were loaded with Rh 123, and the effect of hypoxia on the inner mitochondrial membrane potential (Delta psi(m)) was compared. During prolonged hypoxia (15 min), Delta psi(m) was lost in a majority of the neonatal neurons (83%) and in all the adult neurons. During hypoxia (5 min) followed by reoxygenation the mitochondria in 23% of the neonatal neurons were completely depolarized, whereas 85% of the adult neurons demonstrated a complete loss of Delta psi(m). In conclusion hippocampal CA1 mitochondria in the newborn rat are more resistant to hypoxic depolarization than in the adult rat.

Depolarization of mitochondria in isolated CA1 neurons during hypoxia, glucose deprivation and glutamate excitotoxicity.

During cerebral ischemia neuronal injury is induced by a combination of hypoxia, hypoglycemia and glutamate excitotoxicity. To evaluate the relative importance of these factors on the mitochondrial function, acutely isolated rat hippocampal CA1 neurons were loaded with Rhodamine 123 to monitor the mitochondrial membrane potential (Deltapsim). During 15 min of hypoxia, a rapid and complete mitochondrial depolarization was observed in all neurons also when complex V of the respiratory chain was blocked by oligomycin. Glucose deprivation caused 77% of the neurons to loose the Deltapsim completely, whereas most oligomycin-treated neurons retained their Deltapsim. During oxygen and glucose deprivation, a similar mitochondrial response was seen as in hypoxia. Although 15 min of high glutamate concentration (1 mM) provoked a rapid and irreversible increase in [Ca2+]i, only 25% of the neurons lost the Deltapsim. All oligomycin-treated neurons, however, lost the Deltapsim during glutamate exposure. In conclusion, the mitochondrial function of acutely isolated CA1 neurons is more sensitive to hypoxia than to glucose deprivation and glutamate excitotoxicity.

Endoplasmic reticulum dysfunction and Ca2+ deregulation in isolated CA1 neurons during oxygen and glucose deprivation.

Intracellular calcium ([Ca2+]i) plays a pivotal role in neuronal ischemia. The aim of the present study was to investigate the routes of Ca2+ entry during non-excitotoxic oxygen and glucose deprivation (OGD) in acutely dissociated rat CA1 neurons. During OGD the fluo-3/fura red ratio reflecting [Ca2+]i increased rapidly and irreversibly. [Ca2+]i increased to the same degree in Ca2 + depleted medium, and also when both the ryanodine receptors (RyR) and the inositol 1,4,5-trisphosphate (IP3) receptors were blocked. When the endoplasmic reticulum (ER) Ca2+ stores were emptied with thapsigargin no increase in [Ca2+]i was observed independent of extracellular Ca2+. The OGD induced Ca2+ deregulation in isolated CA1 neurons is not prevented by removing Ca2+, or by blocking the IP3- or RyR receptors. However, when SERCA was blocked, no increase in [Ca2+]i was observed suggesting that SERCA dysfunction represents an important mechanism for ischemic Ca2+ overload.