The influences of medial-diencephalic lesions on hippocampal and cortical function and plasticity

Medial diencephalon, comprising the mammillary bodies and anterior thalamic nuclei, is important for memory in both humans and animals. However, there is still uncertainty regarding how this region supports memory processes. The mammillary bodies and anterior thalamic nuclei form part of the Papez circuit, a network of brain regions important for episodic memory. Lesions within the medial diencephalon cause distal hypofunctionality in the rest of the Papez circuit, and most consistently in the retrosplenial/posterior cingulate cortex. Patients with diencephalic amnesia often exhibit glucose hypometabolism in the posterior cingulate cortex and animals with medial diencephalic lesions dramatically reduce immediate early gene expression in the retrosplenial cortex. It is still unknown whether these distal effects contribute to the memory impairments. This body of work investigated the distal hypofunctionality following lesions of the mammillothalamic tract in rats, a white matter bundle that connects the mammillary bodies to the anterior thalamic nuclei within the medial diencephalon. Mammillothalamic tract lesions were found to reduce expression levels of the immediate early gene zif268 in the retrosplenial cortex. However, no significant changes were found in the fine dendritic microstructure of the small pyramidal neurones located in the superficial layers of the rostral granular retrosplenial cortex, which receive the anterior thalamic nuclei input. To determine whether the reduced immediate early gene expression contributes to the spatial memory impairments associated with mammillothalamic tract lesions, antisense oligodeoxynucleotides were infused into either the retrosplenial cortex or the dorsal hippocampus. These infusions had no effect on spatial memory performance; however, it was not possible to verify that they were effective in knocking-down zif268 or c-fos at the molecular level. This work expands our understanding of the distal effects of mammillothalamic tract lesions but further studies are needed to determine whether they contribute to the memory impairments observed

How do mammillary body inputs contribute to anterior thalamic function?

It has long been assumed that the main function of the mammillary bodies is to provide a relay for indirect hippocampal inputs to the anterior thalamic nuclei. Such models afford the mammillary bodies no independent role in memory and overlook the importance of their other, non-hippocampal, inputs. This review focuses on recent advances that herald a new understanding of the importance of the mammillary bodies, and their inputs from the limbic midbrain, for anterior thalamic function. It has become apparent that the mammillary bodies’ contribution to memory is not dependent on afferents from the subicular complex. Rather, the ventral tegmental nucleus of Gudden is a vital source of inputs that support memory processes within the medial mammillary bodies. In parallel, the lateral mammillary bodies, via their connections with the dorsal tegmental nucleus of Gudden, are critical for generating head-direction signals. These two parallel, but distinct, information streams converge on the anterior thalamic nuclei and support different aspects of spatial memory

Evidence of increasing recorded diagnosis of autism spectrum disorders in Wales, UK – an e-cohort study

Estimates place the prevalence of autism spectrum disorders (autism) at around 1% in the population. New services for adult diagnosis have been set up in Wales, UK, at a time of ris-ing awareness of the spectrum of autism experiences, however no studies have examined adult autism prevalence in Wales. In this study we use an anonymised e-cohort comprised of healthcare record data to produce all-age estimates of prevalence and incidence of record-ed autism for the years 2001-2016. We found the overall prevalence rate of autism in healthcare records was 0.51%. The number of new-recorded cases of autism increased from 0.188 per 1000 person-years in 2001 to 0.644 per 1000 person-years in 2016. The estimate of 0.51% prevalence in the population is lower than suggested by population survey and co-hort studies study methodologies, but comparable to other administrative record study es-timates. Rates of new incident diagnoses of autism saw a >150% increase in the years 2008-2016, with a trend towards more diagnoses in those over 35 and an eightfold increase in diagnoses in women from 2000-2016. Our study suggests that while the number of people being diagnosed with autism is increasing, many are still unrecognised by healthcare ser-vices

Neurological and psychiatric disorders among autistic adults: a population healthcare record study

Background Co-occurring psychiatric disorders are common in autism, with previous studies suggesting 54–94% of autistic individuals develop a mental health condition in their lifetime. Most studies have looked at clinically-recruited cohorts, or paediatric cohorts followed into adulthood, with less known about the autistic community at a population level. We therefore studied the prevalence of co-occurring psychiatric and neurological conditions in autistic individuals in a national sample. Methods This retrospective case-control study utilised the SAIL Databank to examine anonymised whole population electronic health record data from 2001 to 2016 in Wales, UK (N = 3.6 million). We investigated the prevalence of co-occurring psychiatric and selected neurological diagnoses in autistic adults' records during the study period using International Classification of Diseases-10 and Read v2 clinical codes compared to general population controls matched for age, sex and deprivation Results All psychiatric conditions examined were more common amongst adults with autism after adjusting for age, sex and deprivation. Prevalence of attention-deficit hyperactivity disorder (7.00%), bipolar disorder (2.50%), obsessive-compulsive disorder (3.02%), psychosis (18.30%) and schizophrenia (5.20%) were markedly elevated in those with autism, with corresponding odds ratios 8.24–10.74 times the general population. Depression (25.90%) and anxiety (22.40%) were also more prevalent, with epilepsy 9.21 times more common in autism. Conclusions We found that a range of psychiatric conditions were more frequently recorded in autistic individuals. We add to understanding of under-reporting and diagnostic overshadowing in autism. With increasing awareness of autism, services should be cognisant of the psychiatric conditions that frequently co-occur in this population

Comparable reduction in Zif268 levels and cytochrome oxidase activity in the retrosplenial cortex following mammillothalamic tract lesions

Damage to the mammillothalamic tract (MTT) pro- duces memory impairments in both humans and rats, yet it is still not clear why this diencephalic pathway is vital for memory. One suggestion is that it is an important route for midbrain inputs to reach a wider cortical and subcortical net- work that supports memory. Consistent with this idea, MTT lesions produce widespread hypoactivity in distal brain regions as measured by the immediate-early gene, c-fos. To determine whether these findings were selective to c-fos or reflected more general changes in neuronal function, we assessed the effects of MTT lesions on the expression of the immediate-early gene protein, Zif268 and the metabolic marker, cytochrome oxidase, in the retrosplenial cortex and hippocampus. The lesions decreased levels of both activity markers in the superficial and deep layers of the retrosplenial cortex in both its granular and dysgranular subregions. In contrast, no significant changes were observed in the hip- pocampus, despite the MTT-lesioned animals showing marked impairments on T-maze alternation. These findings are consistent with MTT lesions providing important, indirect inputs for normal retrosplenial cortex functioning. These dis- tal functional changes may contribute to the memory impair- ments observed after MTT lesions

Polygenic risk and hazard scores for Alzheimer's disease prediction.

OBJECTIVE: Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. METHODS: Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association. RESULTS: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10-12) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10-8). The strength of association was weaker with less stringent SNP selection thresholds. INTERPRETATION: Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10-3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10-3, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study)

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair

Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease

A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimer’s Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates. Three novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423 . The ZNF423 gene resides in an Alzheimer’s disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions