ABSTRACT
OBJECTIVE: Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aß and tau proteins with cognitive and motor phenotype in ALS. METHODS: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aß42, Aß40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype. RESULTS: APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aß42 (-0.8 vs. 0.1, log-transformed values) and Aß42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aß42 levels, possibly reflecting cerebral Aß deposition. While lower Aß42/40 correlated with lower memory score (ß = 0.20), Aß42 positively correlated with both ALS-specific (ß = 0.24) and ALS-nonspecific (ß = 0.24) scores. Although Aß42/40 negatively correlated with T-tau (ß = -0.29) and P-tau181 (ß = -0.33), we found an unexpected positive association of Aß42 and Aß40 with both tau proteins. Regarding motor phenotype, lower levels of Aß species were associated with lower motor neuron (LMN) signs (Aß40: ß = 0.34; Aß42: ß = 0.22). CONCLUSIONS: APOE haplotype and CSF Aß biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.
Subject(s)
Amyloid beta-Peptides , Amyotrophic Lateral Sclerosis , Apolipoproteins E , Biomarkers , Phenotype , tau Proteins , Humans , tau Proteins/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Male , Female , Middle Aged , Amyotrophic Lateral Sclerosis/cerebrospinal fluid , Amyotrophic Lateral Sclerosis/genetics , Aged , Biomarkers/cerebrospinal fluid , Apolipoproteins E/genetics , Apolipoproteins E/cerebrospinal fluid , Genotype , Peptide Fragments/cerebrospinal fluid , Adult , Cognition Disorders/cerebrospinal fluid , Cognition Disorders/genetics , Cognition Disorders/etiologySubject(s)
Biomarkers , Diabetes Mellitus, Type 2 , MicroRNAs , Sirtuin 1 , Humans , Sirtuin 1/genetics , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , MicroRNAs/genetics , Early Diagnosis , Male , Cognitive Dysfunction/genetics , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/etiology , Female , Cognition Disorders/genetics , Cognition Disorders/diagnosis , Cognition Disorders/etiology , Middle Aged , AgedABSTRACT
BACKGROUND AND OBJECTIVES: The APOE ε4 allele confers susceptibility to faster decline in odor identification and subsequently to Alzheimer disease (AD). Odor identification requires recognizing and naming odors and detecting them (odor sensitivity). Whether APOE ε4 is associated with decline of odor sensitivity and whether such decline serves as a harbinger of cognitive decline and AD remains unclear. We determined whether and when APOE ε4 affects decline in odor sensitivity, odor identification, and cognition in the National Social Life Health and Aging Project (NSHAP). METHODS: We used data from NSHAP, a nationally representative survey study of home-dwelling US older adults. Olfaction was measured over time (odor identification in 2005, 2010, and 2015; odor sensitivity in 2010 and 2015; both using validated tests). Cognition was measured with a modified version of the Montreal Cognitive Assessment in 2010 and 2015. Genotyping was performed using DNA samples collected in 2010. Odor sensitivity and identification were compared among APOE ε4 carriers and noncarriers stratified by age. Relationships between APOE ε4, odor sensitivity, odor identification, and cognition were analyzed in cross-section using ordinal logistic regression and longitudinally using mixed-effects models adjusted for confounders. RESULTS: Odor sensitivity was measured in 865 respondents, odor identification in 1,156 respondents, and cognition in 864 respondents; all these respondents had genetic data available. Odor sensitivity deficits in APOE ε4 carriers were apparent at ages 65-69 years, whereas odor identification deficits did not appear until ages 75-79 years. Subsequently, odor sensitivity did not decline more rapidly with aging in APOE ε4 carriers compared with that in noncarriers (carrier status and aging interaction: odds ratio [OR] 1.44, 95% CI 0.94-2.19, p = 0.092), whereas odor identification declined more rapidly in carriers (aging 10 years interaction: OR 0.26, 95% CI 0.13-0.52, p < 0.001). As expected, and in parallel to odor identification, cognition declined more rapidly in APOE ε4 carriers (interaction: OR 0.55, 95% CI 0.34-0.89, p = 0.015). DISCUSSION: APOE ε4 affects decline of odor sensitivity earlier than odor identification or cognition. Thus, testing odor sensitivity may be useful to predict future impaired cognitive function. Identifying the mechanism underlying these relationships will elucidate the key role of olfaction in neurodegeneration during aging.
Subject(s)
Alzheimer Disease , Cognition Disorders , Cognitive Dysfunction , Humans , Adult , Middle Aged , Aged , Apolipoprotein E4/genetics , Odorants , Cognition , Cognitive Dysfunction/genetics , Cognition Disorders/genetics , Cognition Disorders/diagnosis , Alzheimer Disease/genetics , Neuropsychological Tests , Genotype , Apolipoproteins E/geneticsABSTRACT
With the ageing of the population, the health problems of elderly individuals have become particularly important. Through a large number of clinical studies and trials, it has been confirmed that elderly patients can experience postoperative cognitive dysfunction after general anesthesia/surgery. However, the mechanism of postoperative cognitive dysfunction is still unknown. In recent years, the role of epigenetics in postoperative cognitive dysfunction has been widely studied and reported. Epigenetics includes the genetic structure and biochemical changes of chromatin not involving changes in the DNA sequence. This article summarizes the epigenetic mechanism of cognitive impairment after general anesthesia/surgery and analyses the broad prospects of epigenetics as a therapeutic target for postoperative cognitive dysfunction.
Subject(s)
Cognition Disorders , Cognitive Dysfunction , Postoperative Cognitive Complications , Humans , Aged , Cognition Disorders/genetics , Cognition Disorders/psychology , Postoperative Cognitive Complications/genetics , Postoperative Complications/genetics , Postoperative Complications/epidemiology , Cognitive Dysfunction/genetics , Epigenesis, GeneticABSTRACT
With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.
Subject(s)
Cognition Disorders , Down Syndrome , Mice , Animals , Down Syndrome/genetics , Down Syndrome/metabolism , DNA Copy Number Variations/genetics , Disease Models, Animal , Cognition Disorders/genetics , Chromatin/genetics , Mice, TransgenicABSTRACT
Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are important therapeutic options for reducing cardiovascular disease risk; however, questions remain regarding potential differences in the neuropsychiatric impact of long-term PCSK9 inhibition between men and women. Methods and Results Using PCSK9 gene single-nucleotide polymorphisms from European ancestry-based genome-wide association studies of low-density lipoprotein cholesterol (N=1 320 016), circulating PCSK9 protein levels (N=10 186), tissue-specific PCSK9 gene expression, sex-specific genome-wide association studies of anxiety, depression, cognition, insomnia, and dementia (ranging from 54 321 to 194 174), we used drug-target inverse variance-weighted Mendelian randomization (MR) and complementary MR methods (MR Egger, weighted median, and weighted mode) to investigate potential neuropsychiatric consequences of genetically proxied PCSK9 inhibition in men and women. We failed to find evidence surpassing correction for multiple comparisons of relationships between genetically proxied PCSK9 inhibition and the risk for the 12 neuropsychiatric end points in either men or women. Drug-target analyses were generally well-powered to detect effect estimates at several hypothesized thresholds for both combined-sex and sex-specific end points, especially analyses using PCSK9 instruments derived from protein and expression quantitative trait loci. Further, MR estimates across complementary MR methods and additional models using genetic instruments derived from circulating PCSK9 protein levels and tissue-specific PCSK9 expression were in alignment, strengthening causal inference. Conclusions Genetically proxied PCSK9 inhibition showed a neutral neuropsychiatric side effect profile with no major sex-specific differences. Given statistical power considerations, replication with larger samples, as well as data from other ancestral populations, are necessary. These findings may have important clinical implications for lipid-lowering drug-prescribing practices and side effect monitoring of approved and future PCSK9 therapies.
Subject(s)
Cognition Disorders , Dementia , Mood Disorders , Proprotein Convertase 9 , Female , Humans , Male , Cognition , Cognition Disorders/genetics , Dementia/genetics , Genome-Wide Association Study , Mendelian Randomization Analysis , Mood Disorders/genetics , Proprotein Convertase 9/genetics , Proprotein Convertase 9/metabolismABSTRACT
The current study aimed to investigate the effects of LACC1 on cognitive disorder due to stroke, as well as its underlying mechanism. LACC1 promoted inflammation and aggravated cognitive impairment in a mouse model of stroke. In an in vitro model of stroke, inhibition of LACC1 reduced inflammation and ROSinduced oxidative stress by activating AMPactivated protein kinase (AMPK) expression and suppressing NLPR3 expression. Furthermore, our studies revealed that inhibition of AMPK activity reduced the effects of siLACC1 on cognitive disorder in mice after stroke via the AMPK/NLPR3 pathway. AMPK activation also reduced the effects of LACC1 on inflammation and ROSinduced oxidative stress via the NLPR3 pathway in the in vitro model that we evaluated. Our study suggests that LACC1aggravated inflammation causes cognitive impairment after stroke via the AMPK/NLRP3 pathway, which may provide a new therapeutic target for stroke and other neurological diseases and their associated complications. In sum, we identified an important role and regulatory mechanism for LACC1 in maintaining strokeinduced cognitive disorder via the AMPK/NLRP3 pathway.
Subject(s)
AMP-Activated Protein Kinases , Cognition Disorders , Inflammation , Intracellular Signaling Peptides and Proteins , NLR Family, Pyrin Domain-Containing 3 Protein , Stroke , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Animals , Cognition/physiology , Cognition Disorders/etiology , Cognition Disorders/genetics , Cognition Disorders/metabolism , Inflammation/genetics , Inflammation/metabolism , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxidative Stress/genetics , Oxidative Stress/physiology , Reactive Oxygen Species/metabolism , Signal Transduction , Stroke/complications , Stroke/genetics , Stroke/metabolismABSTRACT
Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in ASPM leading to a truncation of the ASPM protein after amino acid position 1830. The phenotype of the patients was associated with microcephaly, epilepsy, and behavioral and cognitive deficits. Despite the obvious genetic similarity, the affected patients show a considerable phenotypic heterogeneity regarding the degree of mental retardation, presence of epilepsy and MRI findings. Interestingly, the degree of mental retardation and the presence of epilepsy correlates well with the severity of abnormalities detected in brain MRI. On the other hand, we detected no evidence for substantial nonsense-mediated ASPM transcript decay in blood samples. This indicates that other factors than ASPM expression levels are relevant for the variability of structural changes in brain morphology seen in patients with primary hereditary microcephaly caused by ASPM mutations.
Subject(s)
Epilepsy , Intellectual Disability , Microcephaly , Biological Variation, Population , Cognition , Cognition Disorders/genetics , Epilepsy/genetics , Humans , Intellectual Disability/diagnostic imaging , Intellectual Disability/genetics , Microcephaly/genetics , Mutation , Nerve Tissue Proteins/geneticsABSTRACT
Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach.
Subject(s)
Autistic Disorder/genetics , Cognition Disorders/genetics , Down Syndrome/genetics , Gene Dosage , Glutamic Acid/metabolism , Intellectual Disability/genetics , Neurons/metabolism , Speech Disorders/genetics , Animals , Brain/pathology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cognition Disorders/complications , Disease Models, Animal , Down Syndrome/complications , Gene Expression Regulation , Humans , Mice , Mice, Transgenic , Proteomics/methods , Synaptic Transmission/genetics , Transcription, GeneticABSTRACT
Schizophrenia is a major mental illness characterized by positive and negative symptoms, and by cognitive deficit. Although cognitive impairment is disabling for patients, it has been largely neglected in the treatment of schizophrenia. There are several reasons for this lack of treatments for cognitive deficit, but the complexity of its etiology-in which neuroanatomic, biochemical and genetic factors concur-has contributed to the lack of effective treatments. In the last few years, there have been several attempts to develop novel drugs for the treatment of cognitive impairment in schizophrenia. Despite these efforts, little progress has been made. The latest findings point to the importance of developing personalized treatments for schizophrenia which enhance neuroplasticity, and of combining pharmacological treatments with non-pharmacological measures.
Subject(s)
Cognition Disorders/etiology , Cognition Disorders/therapy , Schizophrenia/complications , Antioxidants/pharmacology , Antioxidants/therapeutic use , Clinical Trials as Topic , Cognition Disorders/genetics , Cognition Disorders/physiopathology , Humans , Synaptic Transmission/physiologyABSTRACT
Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD-like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5-7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.
Subject(s)
Alzheimer Disease/genetics , Cognition Disorders/genetics , Epigenomics/methods , Neurofibrillary Tangles/metabolism , Tauopathies/physiopathology , Animals , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Neurofibrillary Tangles/pathologyABSTRACT
Much progress has been made toward deciphering RHO GTPase functions, and many studies have convincingly demonstrated that altered signal transduction through RHO GTPases is a recurring theme in the progression of human malignancies. It seems that 20 canonical RHO GTPases are likely regulated by three GDIs, 85 GEFs, and 66 GAPs, and eventually interact with >70 downstream effectors. A recurring theme is the challenge in understanding the molecular determinants of the specificity of these four classes of interacting proteins that, irrespective of their functions, bind to common sites on the surface of RHO GTPases. Identified and structurally verified hotspots as functional determinants specific to RHO GTPase regulation by GDIs, GEFs, and GAPs as well as signaling through effectors are presented, and challenges and future perspectives are discussed.
Subject(s)
GTPase-Activating Proteins/genetics , Rho Guanine Nucleotide Exchange Factors/genetics , cdc42 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/genetics , rho Guanine Nucleotide Dissociation Inhibitor alpha/genetics , rhoA GTP-Binding Protein/genetics , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Cognition Disorders/genetics , Cognition Disorders/metabolism , Cognition Disorders/pathology , Communicable Diseases/genetics , Communicable Diseases/metabolism , Communicable Diseases/pathology , GTPase-Activating Proteins/metabolism , Gene Expression Regulation , Humans , Multigene Family , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Rho Guanine Nucleotide Exchange Factors/metabolism , Signal Transduction , cdc42 GTP-Binding Protein/metabolism , rac1 GTP-Binding Protein/metabolism , rho Guanine Nucleotide Dissociation Inhibitor alpha/metabolism , rhoA GTP-Binding Protein/metabolismABSTRACT
Importance: We previously reported that children with the autosomal dominant Alzheimer disease (ADAD) presenilin 1 (PSEN1) E280A variant had early life plasma biomarker findings consistent with amyloid ß overproduction. However, the cognitive functioning of children with this variant has not been characterized vs those without the variant. Objective: To test whether cognitive functioning of children with and without the PSEN1 E280A variant in the same ADAD cohort differed by genetic status (ie, PSEN1 variant) and sex. Design, Setting, and Participants: This cohort study was conducted among 1354 children (including 265 children with the variant) aged 6 to 16 years recruited from the Alzheimer Prevention Initiative Colombia Registry. Participants from the city of Medellín and surrounding suburban areas traveled to the University of Antioquia to undergo all procedures. Participants were administered a Spanish version of the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) to measure general cognitive functioning. Data were analyzed from July through November 2020. Main Outcomes and Measures: Univariate general linear models were used to characterize differences on WISC-IV cognitive performance by genetic status, sex, and the interaction of genetic status with sex. Urbanity, socioeconomic status, and education were entered as covariates. Results: Among 1354 children with ADAD (695 [51.3%] girls; mean [SD] age, 11.64 [2.64] years), there were 265 children with the variant (19.6%) and 1089 children without the variant (80.4%). Children with and without the variant did not differ by demographic variables or performance on WISC-IV indices. Irrespective of genetic status, boys had statistically significantly decreased mean scores on indices for working memory (90.27 [95% CI, 89.21-91.34] vs 92.99 [95% CI, 91.98-93.99]; mean difference = -2.72; P < .001), perceptual reasoning (91.56 [95% CI, 90.47-92.65] vs. 93.27 [95% CI, 91.23-94.30]; mean difference = -1.71; P = .03), and verbal comprehension (88.69 [95% CI, 87.54-89.84] vs. 90.81 [95% CI, 89.73-91.90]; mean difference = -2.12; P = .009) compared with girls. In the interaction between sex and genetic status, boys with the variant had worse mean working memory index performance (88.78 [95% CI, 86.86-90.70]) than girls with the variant (93.75 [95% CI, 91.95-95.55]; mean difference = -4.97; P = .001), as well as boys (91.77 [95% CI, 90.85-92.70]; mean difference = -2.99; P = .04) and girls (92.22 [95% CI, 91.32-93.13]; mean difference = -3.44; P = .009) without the variant. Conclusions and Relevance: This study found that boys with the PSEN1 variant had decreased working memory abilities compared with girls with the variant and boys and girls without the variant, suggesting a sex-specific genetic risk in early life cognitive performance among individuals with the PSEN1 variant. This increased risk of future cognitive difficulties among boys with the variant may have important downstream implications for learning and academic achievement and could be associated with sex differences seen in adulthood on episodic memory measures.
Subject(s)
Alzheimer Disease/blood , Alzheimer Disease/genetics , Cognition Disorders/genetics , Genetic Predisposition to Disease , Predictive Value of Tests , Presenilins/blood , Presenilins/genetics , Adolescent , Adult , Age of Onset , Biomarkers/blood , Child , Cognition Disorders/blood , Cohort Studies , Colombia , Female , Healthy Volunteers , Humans , Male , Sex FactorsABSTRACT
BACKGROUND: Cognitive dysfunction is increasingly recognized as an important complication of diabetes mellitus (DM). Accumulating evidence indicates that the abnormality of cerebrovascular structure and function plays an essential role in diabetic cognitive impairment (DCI), however, changes in cerebrovascular factors have been blurred during the development of diabetes. OBJECTIVE: To evaluate the changes in the structure and function of cerebrovascular in DCI mice and to investigate the changes of cerebral angiogenesis and stability factors during the development of DM. METHODS: Diabetes was induced by feeding with high-fat diet combined with intraperitoneal injection of streptozotocin (STZ,120 mg/kg). Cognitive function was evaluated at different stages of DM, cerebral neovascularization, blood-brain barrier (BBB) permeability and hippocampal neurons were measured of DCI mice, and the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor ß (PDGFRß) in hippocampus was detected during the development of DM. RESULTS: With the progress of diabetes, the learning and memory ability of mice gradually decreased, and DCI mice showed neuronal degeneration, increased BBB permeability and pathological cerebral neovascularization. Moreover, the expression of VEGF in the hippocampus increased first and then decreased at DM+8week, PDGFRß decreased continuously with the development of diabetes. CONCLUSIONS: Our results demonstrate that DCI may be attributed to the dynamic expression of VEGF/PDGFRß in diabetic hippocampus, and pathological cerebral neovascularization, increased BBB permeability and neuronal degeneration are the key links.
Subject(s)
Brain Chemistry/genetics , Cognition Disorders/genetics , Cognition Disorders/psychology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/psychology , Receptor, Platelet-Derived Growth Factor beta/biosynthesis , Vascular Endothelial Growth Factor A/biosynthesis , Animals , Blood-Brain Barrier , Diet, High-Fat , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Neovascularization, Physiologic/drug effects , Psychomotor PerformanceABSTRACT
Individuals with sex chromosome trisomies ([SCT], XXX, XXY, and XYY)) are at increased risk for neurodevelopmental problems, given that a significant portion of the sex chromosome genes impact brain functioning. An elevated risk for psychopathology has also been described, including attention deficit-hyperactivity disorder (ADHD). The present study aimed at identifying early markers of ADHD, providing the first investigation of ADHD symptomology in very young children with SCT. The variety, type, and severity of ADHD symptomology in 1-6-year-old children with SCT (n = 104) were compared with population-based controls (n = 101) using the strengths and weaknesses of ADHD symptoms and normal-behavior (SWAN) parent-report questionnaire. ADHD symptomology was significantly more prevalent in SCT and already present from toddlerhood on, compared to controls. ADHD inattention symptoms were significantly increased in all karyotypes (XXX, XXY, and XYY), boys with XYY also showed significantly more hyperactivity/impulsivity symptoms than controls. Inattentiveness was more pronounced with increasing age for SCT, in contrast to controls. Within the SCT group, 24% of the children had significantly elevated ADHD symptoms at a clinical level. Already from an early age on, SCT is associated with a risk for ADHD, suggesting that its neurodevelopmental risk lies anchored in early brain maturation. Studying this genetically vulnerable population allows for the prospective study of risk markers to facilitate early and preventive interventions.
Subject(s)
Attention Deficit Disorder with Hyperactivity/diagnosis , Cognition Disorders/diagnosis , Sex Chromosome Aberrations , Trisomy/genetics , Abnormal Karyotype , Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/physiopathology , Child , Child, Preschool , Cognition Disorders/genetics , Cognition Disorders/physiopathology , Female , Humans , Infant , Male , Sex Chromosomes/genetics , XYY Karyotype/geneticsABSTRACT
A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10-11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10-8) and WWOX (HR = 2.12, P = 2.37 × 10-8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
Subject(s)
Cognition , Disease Progression , Genetic Loci , Genome-Wide Association Study , Multifactorial Inheritance/genetics , Parkinson Disease/genetics , Parkinson Disease/pathology , Synapses/genetics , Apolipoprotein E4/genetics , Cognition Disorders/genetics , Genetic Predisposition to Disease , Glucosylceramidase/genetics , Humans , Longitudinal Studies , Mutation/genetics , Parkinson Disease/physiopathology , Proportional Hazards Models , Risk Factors , Survival AnalysisABSTRACT
Body mass index (BMI) is associated with cognitive abilities, but the nature of the relationship remains largely unexplored. We aimed to investigate the bidirectional relationship from midlife through late-life, while considering sex differences and genetic predisposition to higher BMI. We used data from 23,892 individuals of European ancestry from the Health and Retirement Study, with longitudinal data on BMI and three established cognitive indices: mental status, episodic memory, and their sum, called total cognition. To investigate the dynamic relationship between BMI and cognitive abilities, we applied dual change score models of change from age 50 through 89, with a breakpoint at age 65 or 70. Models were further stratified by sex and genetic predisposition to higher BMI using tertiles of a polygenic score for BMI (PGSBMI). We demonstrated bidirectional effects between BMI and all three cognitive indices, with higher BMI contributing to steeper decline in cognitive abilities in both midlife and late-life, and higher cognitive abilities contributing to less decline in BMI in late-life. The effects of BMI on change in cognitive abilities were more evident in men compared to women, and among those in the lowest tertile of the PGSBMI compared to those in the highest tertile, while the effects of cognition on BMI were similar across groups. In conclusion, these findings highlight a reciprocal relationship between BMI and cognitive abilities, indicating that the negative effects of a higher BMI persist from midlife through late-life, and that weight-loss in late-life may be driven by cognitive decline.
Subject(s)
Body Mass Index , Cognition Disorders/etiology , Cognitive Aging , Aged , Aged, 80 and over , Cognition , Cognition Disorders/genetics , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Sex FactorsABSTRACT
Cognitive impairments are prevalent in Parkinson's disease (PD), but the underlying mechanisms of their development are unknown. In this study, we aimed to predict global cognition (GC) in PD with machine learning (ML) using structural neuroimaging, genetics and clinical and demographic characteristics. As a post-hoc analysis, we aimed to explore the connection between novel selected features and GC more precisely and to investigate whether this relationship is specific to GC or is driven by specific cognitive domains. 101 idiopathic PD patients had a cognitive assessment, structural MRI and blood draw. ML was performed on 102 input features including demographics, cortical thickness and subcortical measures, and several genetic variants (APOE, MAPT, SNCA, etc.). Using the combination of RRELIEFF and Support Vector Regression, 11 features were found to be predictive of GC including sex, rs894280, Edinburgh Handedness Inventory, UPDRS-III, education, five cortical thickness measures (R-parahippocampal, L-entorhinal, R-rostral anterior cingulate, L-middle temporal, and R-transverse temporal), and R-caudate volume. The rs894280 of SNCA gene was selected as the most novel finding of ML. Post-hoc analysis revealed a robust association between rs894280 and GC, attention, and visuospatial abilities. This variant indicates a potential role for the SNCA gene in cognitive impairments of idiopathic PD.
Subject(s)
Cognition Disorders/genetics , Cognitive Dysfunction/genetics , Machine Learning , Parkinson Disease/genetics , alpha-Synuclein/genetics , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Male , Middle Aged , NeuroimagingABSTRACT
BACKGROUND: Limited extant research on neurocognitive endophenotypes in obsessive-compulsive disorder (OCD) show inconsistent results. Limitations of this body of literature include small sample sizes, strict exclusion criteria, lack of objective standard normalized test scores, and significant lack of studies utilizing pediatric probands. This study aimed to address these limitations. METHODS: A large carefully screened cohort of pediatric OCD (n = 102), their unaffected siblings (n = 78), and parents (n = 164), completed a neuropsychological battery. To compare participants at different ages and developmental stages, standard scores were computed using test norms. Cluster-robust regression with sample size-adjusted sandwich estimates of variance, and interclass correlations were computed. False Discovery Rate procedures were employed to correct for multiplicity. RESULTS: Probands, siblings and parents demonstrated deficient task performance (Z < -0.5) on the 'number of trials to complete first category' on the Wisconsin Card Sorting Test, and on the Stroop color naming trials. Compared to test norms, the three groups exhibited medium to large effect sizes on these outcome measures. No other meaningful familial trends were found. CONCLUSIONS: OCD probands, their unaffected siblings and parents exhibited deficiencies in specific subdomains of cognitive flexibility and inhibitory control, namely, initial concept formation and proactive control, which may be valid candidate neurocognitive endophenotypes of OCD. No other meaningful familial effect has been found on other functions, including other executive function indices such as perseverations and interference control. These results highlight the need to carefully examine individual outcomes from executive function tests instead of the tendency to focus largely on major outcome measures.