Terminal type-specific cannabinoid CB1 receptor alterations in patients with schizophrenia: A pilot study.

BACKGROUND: Individuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types - a factor previously unaccounted for when examining CB1R changes in schizophrenia - may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia. METHODS: Using co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals (nine male pairs and one female pair) diagnosed with schizophrenia and non-psychiatric comparisons. RESULTS: Significantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples. CONCLUSION: Given CB1R's role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia.

Unveiling the Enigma: Exploring Risk Factors and Mechanisms for Psychotic Symptoms in Alzheimer's Disease through Electronic Medical Records with Deep Learning Models.

Around 50% of patients with Alzheimer's disease (AD) may experience psychotic symptoms after onset, resulting in a subtype of AD known as psychosis in AD (AD + P). This subtype is characterized by more rapid cognitive decline compared to AD patients without psychosis. Therefore, there is a great need to identify risk factors for the development of AD + P and explore potential treatment options. In this study, we enhanced our deep learning model, DeepBiomarker, to predict the onset of psychosis in AD utilizing data from electronic medical records (EMRs). The model demonstrated superior predictive capacity with an AUC (area under curve) of 0.907, significantly surpassing conventional risk prediction models. Utilizing a perturbation-based method, we identified key features from multiple medications, comorbidities, and abnormal laboratory tests, which notably influenced the prediction outcomes. Our findings demonstrated substantial agreement with existing studies, underscoring the vital role of metabolic syndrome, inflammation, and liver function pathways in AD + P. Importantly, the DeepBiomarker model not only offers a precise prediction of AD + P onset but also provides mechanistic understanding, potentially informing the development of innovative treatments. With additional validation, this approach could significantly contribute to early detection and prevention strategies for AD + P, thereby improving patient outcomes and quality of life.

Distorted neurocomputation by a small number of extra-large spines in psychiatric disorders.

Human genetics strongly support the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality linking synapse pathology to behavioral changes is lacking. To address this question, we examined the effects of synaptic inputs on dendrites, cells, and behaviors of mice with knockdown of SETD1A and DISC1, which are validated animal models of schizophrenia. Both models exhibited an overrepresentation of extra-large (XL) synapses, which evoked supralinear dendritic and somatic integration, resulting in increased neuronal firing. The probability of XL spines correlated negatively with working memory, and the optical prevention of XL spine generation restored working memory impairment. Furthermore, XL synapses were more abundant in the postmortem brains of patients with schizophrenia than in those of matched controls. Our findings suggest that working memory performance, a pivotal aspect of psychiatric symptoms, is shaped by distorted dendritic and somatic integration via XL spines.

Combination of antidepressants and antipsychotics as a novel treatment option for psychosis in Alzheimer's disease.

Psychotic symptoms are reported as one of the most common complications of Alzheimer's disease (AD), in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second-generation antipsychotics, confer modest efficacy in patients with AD and with psychosis (AD+P) and themselves increase mortality. Recent studies suggested the use and beneficial effects of antidepressants among patients with AD+P. This motivates our rationale for exploring their potential as a novel combination therapy option among these patients. We included electronic medical records of 10,260 patients with AD in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. A protein-protein interaction network representing AD+P was built, and network analysis methods were used to quantify the efficacy of these drugs on AD+P. A combined score was developed to measure the potential synergetic effect against AD+P. Our survival analyses showed that the co-administration of antidepressants with antipsychotics have a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well-separated, and antipsychotics and antidepressants have similar Signed Jaccard Index (SJI) scores to AD+P. Eight drug pairs, including some popular recommendations like aripiprazole/sertraline, showed higher than average scores which suggest their potential in treating AD+P via strong synergetic effects. Our proposed combinations of antipsychotic and antidepressant therapy showed a strong superiority over current antipsychotics treatment for AD+P. The observed beneficial effects can be further strengthened by optimizing drug-pair selection based on our systems pharmacology analysis.

Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer's Disease.

BACKGROUND: Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer's disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known. OBJECTIVE: To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD. METHODS: Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD). RESULTS: In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology. CONCLUSION: Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region's plasticity response in AD.

Terminal type-specific cannabinoid CB1 receptor alterations in patients with schizophrenia: a pilot study.

Background: Individuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types - a factor previously unaccounted for when examining CB1R changes in schizophrenia - may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia. Methods: Using co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals diagnosed with schizophrenia and non-psychiatric comparisons. Results: Significantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples. Conclusion: Given CB1R's role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia.

Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease.

OBJECTIVE: To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. METHODS: Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers. RESULTS: PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53-1.91]) compared with APOE-ε4 carriers (1.53 [1.4-1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65-74 years to 39% at age 85 and older. INTERPRETATION: PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.

Combination of Antidepressants and Antipsychotics as A Novel Treatment Option for Psychosis in Alzheimer's Disease.

Background: Psychotic symptoms are reported as one of the most common complications of Alzheimer's disease (AD), affecting approximately half of AD patients, in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second-generation antipsychotics, confer modest efficacy in AD patients with psychosis (AD+P) and themselves increase mortality. A recent genome-wide meta-analysis and early clinical trials suggest the use and beneficial effects of antidepressants among AD+P patients. This motivates our rationale for exploring their potential as a novel combination therapy option amongst these patients. Methods: We included University of Pittsburgh Medical Center (UPMC) electronic medical records (EMRs) of 10,260 AD patients from January 2004 and October 2019 in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. To provide more valuable insights on the hidden mechanisms of the combinatorial therapy, a protein-protein interaction (PPI) network representing AD+P was built, and network analysis methods were used to quantify the efficacy of these drugs on AD+P. An indicator score combining the measurements on the separation between drugs and the proximity between the drugs and AD+P was used to measure the effect of an antipsychotic-antidepressant drug pair against AD+P. Results: Our survival analyses replicated that antipsychotic usage is strongly associated with increased mortality in AD patients while the co-administration of antidepressants with antipsychotics showed a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well-separated, and antipsychotics and antidepressants have similar proximity scores to AD+P. Eight drug pairs, including some popular recommendations like Aripiprazole/Sertraline and other pairs not reported previously like Iloperidone/Maprotiline showed higher than average indicator scores which suggest their potential in treating AD+P via strong synergetic effects as seen in our study. Conclusion: Our proposed combinations of antipsychotics and antidepressants therapy showed a strong superiority over current antipsychotics treatment for AD+P. The observed beneficial effects can be further strengthened by optimizing drug-pair selection based on our systems pharmacology analysis.

Identification of Rare Damaging Missense and Loss of Function Variants in GWAS Loci Using Genome Sequencing Data from Two Cohorts of Familial Late-Onset Alzheimer's Disease.

PURPOSE: Few rare pathogenic variants have been identified in the 70+ genetic loci from genome wide association studies of late-onset Alzheimer's disease (AD), limiting research on underlying mechanisms, risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in The National Institute on Aging Alzheimer's Disease Family Based Study (AD-FBS), and 214 families in The Estudio Familiar de la Influencia Genética en Alzheimer (EFIGA), we characterized rare coding variants predicted to highly damaging missense or loss of function variants (LoF) within known GWAS loci. RESULTS: Eight coding and one LoF variant segregated in 10 (5.1%) AD-FBS families and 16 coding and two LoF variants segregated in 18 (8.4%) EFIGA families. ABCA7 and AKAP9 contained the most damaging variants. In 51 (25.9%) of the AD-FBS and in 26 (12.1%) of the EFIGA families, APOE-ε4 was the only variant segregating with familial AD (fAD). Neither APOE-ε4 nor missense or LoF variants were found in 44.1% of the AD-FBS and 62.1% of the EFIGA families. CONCLUSIONS: Although rare variants were found in both family groups, many families had no gene variant segregating within the family, indicating that the genetic basis for AD has yet to be fully defined.

More than a marker: potential pathogenic functions of MAP2.

Microtubule-associated protein 2 (MAP2) is the predominant cytoskeletal regulator within neuronal dendrites, abundant and specific enough to serve as a robust somatodendritic marker. It influences microtubule dynamics and microtubule/actin interactions to control neurite outgrowth and synaptic functions, similarly to the closely related MAP Tau. Though pathology of Tau has been well appreciated in the context of neurodegenerative disorders, the consequences of pathologically dysregulated MAP2 have been little explored, despite alterations in its immunoreactivity, expression, splicing and/or stability being observed in a variety of neurodegenerative and neuropsychiatric disorders including Huntington's disease, prion disease, schizophrenia, autism, major depression and bipolar disorder. Here we review the understood structure and functions of MAP2, including in neurite outgrowth, synaptic plasticity, and regulation of protein folding/transport. We also describe known and potential mechanisms by which MAP2 can be regulated via post-translational modification. Then, we assess existing evidence of its dysregulation in various brain disorders, including from immunohistochemical and (phospho) proteomic data. We propose pathways by which MAP2 pathology could contribute to endophenotypes which characterize these disorders, giving rise to the concept of a "MAP2opathy"-a series of disorders characterized by alterations in MAP2 function.

Efficacy difference of antipsychotics in Alzheimer's disease and schizophrenia: explained with network efficiency and pathway analysis methods.

Approximately 50% of Alzheimer's disease (AD) patients will develop psychotic symptoms and these patients will experience severe rapid cognitive decline compared with those without psychosis (AD-P). Currently, no medication has been approved by the Food and Drug Administration for AD with psychosis (AD+P) specifically, although atypical antipsychotics are widely used in clinical practice. These drugs have demonstrated modest efficacy in managing psychosis in individuals with AD, with an increased frequency of adverse events, including excess mortality. We compared the differences between the genetic variations/genes associated with AD+P and schizophrenia from existing Genome-Wide Association Study and differentially expressed genes (DEGs). We also constructed disease-specific protein-protein interaction networks for AD+P and schizophrenia. Network efficiency was then calculated to characterize the topological structures of these two networks. The efficiency of antipsychotics in these two networks was calculated. A weight adjustment based on binding affinity to drug targets was later applied to refine our results, and 2013 and 2123 genes were identified as related to AD+P and schizophrenia, respectively, with only 115 genes shared. Antipsychotics showed a significantly lower efficiency in the AD+P network than in the schizophrenia network (P < 0.001) indicating that antipsychotics may have less impact in AD+P than in schizophrenia. AD+P may be caused by mechanisms distinct from those in schizophrenia which result in a decreased efficacy of antipsychotics in AD+P. In addition, the network analysis methods provided quantitative explanations of the lower efficacy of antipsychotics in AD+P.

Fingolimod mitigates synaptic deficits and psychosis-like behavior in APP/PSEN1 mice.

Introduction: Current treatments for psychosis in Alzheimer's disease (AD), a syndrome characterized by more rapid deterioration and reduced synaptic protein abundance relative to non-psychotic AD, are inadequate. Fingolimod, a currently US Food and Drug Administration (FDA)-approved pharmacotherapy for multiple sclerosis, alters synaptic protein expression and warrants preclinical appraisal as a candidate pharmacotherapy for psychosis in AD. Methods: Presenilin and amyloid precursor protein transgenic mice (APPswe/PSEN1dE9) and wild-type mice were randomized to fingolimod or saline for 7 days. Psychosis-associated behaviors were quantified by open field testing, pre-pulse inhibition of the acoustic startle response testing, and habituation of the acoustic startle response testing. Synaptic proteins were quantified by liquid chromatography/mass spectrometry in homogenate and postsynaptic density fractions. Results: Fingolimod treatment increased the synaptic protein abundance in cortical homogenates and normalized psychosis-associated behaviors in APPswe/PSEN1dE9 mice relative to saline. Mitochondrial-related proteins were preferentially altered by fingolimod treatment and correlated with improvements in psychosis-associated behaviors. Discussion: Preclinical studies employing complementary psychosis-associated behavioral assessments and proteomic evaluations across multiple AD-related models are warranted to replicate the current study and further investigate fingolimod as a candidate treatment for psychosis in AD.

Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk.

DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. Thus, DNAm alterations, acting through effects on gene expression, represent one potential mechanism by which SZ-associated SNPs confer risk. In this study, we investigated genome-wide DNAm in postmortem superior temporal gyrus from 44 subjects with SZ and 44 non-psychiatric comparison subjects using Illumina Infinium MethylationEPIC BeadChip microarrays, and extracted cell-type-specific methylation signals by applying tensor composition analysis. We identified SZ-associated differential methylation at 242 sites, and 44 regions containing two or more sites (FDR cutoff of q = 0.1) and determined a subset of these were cell-type specific. We found mitotic arrest deficient 1-like 1 (MAD1L1), a gene within an established GWAS risk locus, harbored robust SZ-associated differential methylation. We investigated the potential role of MAD1L1 DNAm in conferring SZ risk by assessing for colocalization among quantitative trait loci for methylation and gene transcripts (mQTLs and tQTLs) in brain tissue and GWAS signal at the locus using multiple-trait-colocalization analysis. We found that mQTLs and tQTLs colocalized with the GWAS signal (posterior probability >0.8). Our findings suggest that alterations in MAD1L1 methylation and transcription may mediate risk for SZ at the MAD1L1-containing locus. Future studies to identify how SZ-associated differential methylation affects MAD1L1 biological function are indicated.

Clinical Progression of Baseline Risk States for Mild Cognitive Impairment.

BACKGROUND: This memory-clinic study joins efforts to study earliest clinical signs and symptoms of Alzheimer's disease and related dementias: subjective reports and objective neuropsychological test performance. OBJECTIVE: The memory-clinic denoted two clinical "grey zones": 1) subjective cognitive decline (SCD; n = 107) with normal objective test scores, and 2) isolated low test scores (ILTS; n = 74) without subjective complaints to observe risk for future decline. METHODS: Initial and annual follow-up clinical research evaluations and consensus diagnosis were used to evaluate baseline characteristics and clinical progression over 2.7 years, compared to normal controls (NC; n = 117). RESULTS: The ILTS group was on average older than the NC and SCD groups. They had a higher proportion of people identifying as belonging to a minoritized racial group. The SCD group had significantly more years of education than the ILTS group. Both ILTS and SCD groups had increased risk of progression to mild cognitive impairment. Older age, minoritized racial identity, and baseline cognitive classification were risk factors for progression. CONCLUSION: The two baseline risk groups look different from each other, especially with respect to demographic correlates, but both groups predict faster progression than controls, over and above demographic differences. Varied presentations of early risk are important to recognize and may advance cognitive health equity in aging.

Cell type specific cannabinoid CB1 receptor distribution across the human and non-human primate cortex.

Alterations in cannabinoid CB1 receptor (CB1R) are implicated in various psychiatric disorders. CB1R participates in both depolarization induced suppression of inhibition (DSI) and depolarization induced suppression of excitation (DSE), suggesting its involvement in regulating excitatory and inhibitory (E/I) balance. Prior studies examining neuronal cell type specific CB1R distribution have been conducted near exclusively within rodents. Identification of these distribution patterns within the human and non-human primate cortex is essential to increase our insight into its function. Using co-labeling immunohistochemistry and fluorescent microscopy, we examined CB1R protein levels within excitatory and inhibitory boutons of male human and non-human primate prefrontal cortex and auditory cortices, regions involved in the behavioral effects of exogenous cannabinoid exposures. We found that CB1R was present in both bouton populations within all brain regions examined in both species. Significantly higher CB1R levels were found within inhibitory than within excitatory boutons across all regions in both species, although the cell type by brain region interactions differed between the two species. Our results support the importance of conducting more in-depth CB1R examinations to understand how cell type and brain region dependent differences contribute to regional E/I balance regulation, and how aberrations in CB1R distribution may contribute to pathology.

Psychosis in Alzheimer's Disease Is Associated With Increased Excitatory Neuron Vulnerability and Post-transcriptional Mechanisms Altering Synaptic Protein Levels.

Alzheimer's disease with psychosis (AD+P) is a heritable phenotypic variant of the disease which is associated with more rapid cognitive deterioration compared to Alzheimer's disease without psychosis (AD-P). Cognitive decline in AD correlates with synapse loss, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD-P. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD-P [Mean (SD) AD+P 0.295 (0.061); AD-P 0.324 (0.052), p = 0.026]. mRNA levels contributed only modestly to altered synaptic proteins in AD+P relative to AD-P. Instead, network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. We previously found that neuropathologies account for ~18% of the variance in the occurrence of psychosis in AD. Further inclusion of cell type proportions and differentially expressed modules increased the percent of the variance in psychosis occurrence accounted for in our AD cohort to 67.5%.

The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study: A resource for genetic discovery.

INTRODUCTION: The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD). METHODS: Recruitment focused on families with two living affected siblings and a third first-degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome-wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. RESULTS: APOE genotype modified the age-at-onset in many large families. Novel variants and known variants associated with early- and late-onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. DISCUSSION: The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.

Psychosis in Alzheimer disease - mechanisms, genetics and therapeutic opportunities.

Psychosis is a common and distressing symptom in people with Alzheimer disease, and few safe and effective treatments are available. However, new approaches to symptom assessment and treatment are beginning to drive the field forward. New nosological perspectives have been provided by incorporating the emergence of psychotic symptoms in older adults - even in advance of dementia - into epidemiological and neurobiological frameworks as well as into diagnostic and research criteria such as the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders, the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) research criteria for psychosis in neurodegenerative disease, and the ISTAART criteria for mild behavioural impairment. Here, we highlight the latest findings in genomics, neuroimaging and neurobiology that are informing approaches to drug discovery and repurposing. Current pharmacological and non-pharmacological treatment options are discussed, with a focus on safety and precision medicine. We also explore trial data for pimavanserin, a novel agent that shows promise for the treatment of psychosis in people with dementia, and discuss existing agents that might be useful but need further exploration such as escitalopram, lithium, cholinesterase inhibitors and vitamin D. Although the assessment and management of psychosis in people with dementia remain challenging, new opportunities are providing direction and hope to the field.

A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development.

Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.

Investigating Post-translational Modifications in Neuropsychiatric Disease: The Next Frontier in Human Post-mortem Brain Research.

Gene expression and translation have been extensively studied in human post-mortem brain tissue from subjects with psychiatric disease. Post-translational modifications (PTMs) have received less attention despite their implication by unbiased genetic studies and importance in regulating neuronal and circuit function. Here we review the rationale for studying PTMs in psychiatric disease, recent findings in human post-mortem tissue, the required controls for these types of studies, and highlight the emerging mass spectrometry approaches transforming this research direction.