Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

Presenilin Gene Mutation-associated Psychosis: Phenotypic Characteristics and Clinical Implications.

Although psychotic symptoms have been described in association with rare presenilin ( PSEN ) gene mutations underlying early-onset Alzheimer disease (AD), no contemporary reviews on this topic exist. The purpose of this review is to characterize the psychiatric phenotype (specifically with respect to psychosis) of PSEN1 and PSEN2 variant-associated AD. A PubMed search was completed in July 2023. Only articles that described individuals harboring a PSEN1 or PSEN2 mutation who experienced symptoms of psychosis were included in the review. Thirty-three articles describing 52 individuals were included in the review, as well as one other study that provided limited information pertaining to an additional 21 cases. While visual hallucinations were the most common psychotic symptom, followed by persecutory delusions, auditory hallucinations occurred in ~17% of individuals. In ~33% of the reviewed cases psychotic symptoms were present at or near disease onset, and 9 of these individuals experienced auditory hallucinations and/or delusions in the absence of visual hallucinations (~17% of all cases). In many cases, symptoms developed at a relatively young age. As presenilin gene variant-associated psychosis may resemble a primary psychotic disorder, clinicians should be vigilant with respect to screening for signs/symptoms suggestive of neurodegeneration in first-episode psychosis.

Alzheimer's Disease-Related Psychosis: An Overview of Clinical Manifestations, Pathogenesis, and Current Treatment.

Behavioral and psychotic manifestations, including aggression, delusions, and hallucinations, are frequent comorbidities in patients with debilitating nervous illnesses such as Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Parkinson's disease. ADrelated psychosis may be linked to a poor disease prognosis, highlighting that early detection and management are mandatory. The manifestations are variable and may be very heterogeneous, imposing a real diagnostic issue. Some assessment tools such as BEHAVE-AD, CERAD-BRSD, and the Psycho-Sensory Hallucinations Scale have been designed to facilitate the diagnosis. The mechanisms behind neurodegeneration-related psychosis are complex and are not fully understood, imposing a burden on researchers to find appropriate management modalities. Familial history and some genetic disturbances may have a determinant role in these delusions and hallucinations in cases with AD. The loss of neuronal cells, atrophy in some regions of the central nervous, and synaptic dysfunction may also contribute to these comorbidities. Furthermore, inflammatory disturbances triggered by pro-inflammatory agents such as interleukins and tumor necrosis factors are stratified among the potential risk factors for the onset of numerous psychotic symptoms in Alzheimer's patients. Little is known about the possible management tools; therefore, it is urgent to conduct well-designed trials to investigate pharmacological and non-pharmacological interventions that can improve the care process of these patients. This review summarizes the current findings regarding the AD-related psychosis symptoms, pathological features, assessment, and management.

Cannabis, schizophrenia genetic risk, and psychotic experiences: a cross-sectional study of 109,308 participants from the UK Biobank.

Cannabis is known to produce acute, transient psychotic-like experiences. However, it is unclear whether cannabis disproportionately increases the risk of specific types of psychotic experiences and whether genetic predisposition influences the relationship between cannabis use and psychotic experiences. In this cross-sectional study of 109,308 UK Biobank participants, we examined how schizophrenia polygenic risk modulates the association between self-reported cannabis use and four types of self-reported psychotic experiences (auditory hallucinations, visual hallucinations, persecutory delusions, and delusions of reference). Cohort-wide, we found a strong, dose-dependent relationship between cannabis use and all four types of psychotic experiences, especially persecutory delusions. Cannabis users' psychotic experiences tended to be earlier-onset and cause greater distress than non-users', but were not more likely to lead to help-seeking. Participants with high schizophrenia polygenic risk scores showed stronger associations between cannabis use and auditory hallucinations, visual hallucinations, and delusions of reference, as well as psychotic experiences overall. For instance, cannabis ever-use was associated with 67% greater adjusted odds of delusions of reference among individuals in the top fifth of polygenic risk, but only 7% greater adjusted odds among the bottom fifth. Our results suggest that cannabis use is a predictive risk factor for psychotic experiences, including early-onset and distressing experiences. Individuals genetically predisposed to schizophrenia may be especially vulnerable to psychotic experiences as a result of using cannabis, supporting a long-postulated hypothesis. This study exemplifies the utility of population-scale biobanks for elucidating gene-by-environment interactions relating substance use to neuropsychiatric outcomes and points to the translational potential of using polygenic risk scores to inform personalized harm reduction interventions.

New-Onset Delusions Heralding an Underlying Neurodegenerative Condition: A Case Report and Review of the Literature.

OBJECTIVE: To present a striking case of new-onset psychosis in a middle-aged woman subsequently diagnosed with behavioral variant frontotemporal dementia (bvFTD). To review the data regarding key red-flag features that may suggest a diagnosis of a neurodegenerative process, and specifically bvFTD, rather than a primary psychotic disorder. To examine the role of genetics, especially mutations of the microtubule-associated protein tau (MAPT) gene, in familial cases of frontotemporal dementia (FTD). DATA SOURCES: The pertinent literature was searched online (PubMed, Google Scholar) using the following search terms: frontotemporal dementia (FTD), Pick's disease, behavioral variant FTD (bvFTD), psychosis, delusions, MAPT, and genetics. No date or language limit was applied. STUDY SELECTION: The case report was generated through detailed assessment of clinical notes, imaging studies, and laboratory results. The brain autopsy was carried out and summarized by our neuropathology team. Previously published literature was selected for inclusion in the review section based on relevance to the topic. RESULTS: A neurodegenerative etiology for psychosis (and specifically bvFTD) should be suspected in patients with progressive deficits in executive function, language, or memory. Other key warning features include the presence of a strong family history of a late-life psychotic disorder (or institutional placement or suicide), loss of empathy, impaired recognition of facial expression, or the development of emotional blunting and apathy, abnormal movements, or seizures. CONCLUSIONS: Neurodegenerative disease should be on the differential diagnosis for any patient presenting with new-onset psychosis and behavioral changes in mid to late adulthood. Should red-flag features be present, early referral to a clinic specializing in dementia is recommended for further evaluation. This case highlights that MAPT mutations can be associated with psychosis in FTD and should be considered in the genetic workup. Ongoing research into the cellular and neural circuit mechanisms of psychosis in neurodegenerative disease may shed light on pathologic processes underlying psychosis in primary psychiatric disorders.

The influence of religious activity and polygenic schizophrenia risk on religious delusions in schizophrenia.

BACKGROUND: Religious delusions are a common symptom in patients experiencing psychosis, with varying prevalence rates of religious delusions across cultures and societies. To enhance our knowledge of this distinct psychotic feature, we investigated the mutually-adjusted association of genetic and environmental factors with occurrence of religious delusions. METHODS: We studied 262 adult German patients with schizophrenia or schizoaffective disorder. Association with lifetime occurrence of religious delusions was tested by multiple logistic regression for the following putative predictors: self-reported degree of religious activity, DSM-IV diagnosis, sex, age, education level, marital status, presence of acute delusion at the time of interview and an individual polygenic schizophrenia-risk score (SZ-PRS, available in 239 subjects). RESULTS: Of the 262 patients, 101 (39%) had experienced religious delusions. The risk of experiencing religious delusions was significantly increased in patients with strong religious activity compared to patients without religious affiliation (OR = 3.6, p = 0.010). Low or moderate religious activity had no significant effect. The same analysis including the SZ-PRS confirmed the effect of high religious activity on occurrence of religious delusions (OR = 4.1, p = 0.008). Additionally, the risk of experiencing religious delusions increased with higher SZ-PRS (OR 1.4, p = 0.020, using pT = 0.05 for SZ-PRS calculation). None of the other variables were significantly associated with lifetime occurrence of religious delusions. CONCLUSIONS: Our results suggest that strong religious activity and high SZ-PRS are independent risk factors for the occurrence of religious delusions in schizophrenia and schizoaffective disorder.

Apolipoprotein E-ε4 allele predicts escalation of psychotic symptoms in late adulthood.

BACKGROUND: Research on a putative link between apolipoprotein-ε4 allele (APOE-ε4) and schizophrenia has been inconclusive. However, prior studies have not investigated the association between APOE-ε4 and symptom trajectories, nor has the existing literature taken into account the potentially moderating effect of age in genetic association studies. METHODS: The association between APOE-ε4 and four symptom dimensions was investigated in a longitudinal study of 116 individuals with schizophrenia initially assessed during their first admission for psychosis and evaluated five times over the following 20years. A meta-analysis identified 29 case-control studies of APOE-ε4 allele frequency in schizophrenia, which were analyzed using random-effects meta-regression to test the potentially moderating effect of age. RESULTS: Longitudinal models identified a specific association between APOE-ε4 and symptom trajectories, showing that APOE-ε4 portends worsening severity of hallucinations and delusions in late adulthood among people with schizophrenia, at a rate of a 0.46 standard deviation increase per decade. Meta-analysis showed a significant effect of age: the association between APOE-ε4 and schizophrenia was not detectable in younger people but became pronounced with age, such that APOE-ε4 increased the odds of diagnosis by 10% per decade. CONCLUSIONS: Taken together, the meta-analysis and longitudinal analysis implicate APOE-ε4 as an age-related risk factor for worsening hallucinations and delusions, and suggest APOE-ε4 may play an age-mediated pathophysiological role in schizophrenia. The presence of an APOE-ε4 allele may also identify a subgroup of patients who require intensive monitoring and additional targeted interventions, especially in mid-to late-life.

A Genetic Study of Psychosis in Huntington's Disease: Evidence for the Involvement of Glutamate Signaling Pathways.

BACKGROUND: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. OBJECTIVE: To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. METHODS: DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. RESULTS: Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling. CONCLUSIONS: This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis.

C4A mRNA expression in PBMCs predicts the presence and severity of delusions in schizophrenia and bipolar disorder with psychosis.

Altered immune function is an established finding in psychotic disorders such as schizophrenia and bipolar disorder with psychosis, though its role in their development and progression remains to be understood. Evidence suggests altered JAK-STAT1 pathway activity in peripheral blood cells from participants with schizophrenia compared to controls. Activation of this pathway leads to increased expression of complement component 4A (C4A), which has recently been implicated in schizophrenia. Here, we examine mRNA expression of C4A in peripheral blood cells from participants with schizophrenia, bipolar disorder and controls. STAT1 and IRF-1 mRNA expression are included as measures of JAK-STAT1 pathway activation in the same participants. Further, we examine the association of each genes mRNA expression with clinical symptom measures using the Positive and Negative Syndrome Scale (PANSS) and the Psychotic Symptom Rating Scale (PSYRATS). We demonstrate that C4A, STAT1 and IRF-1 mRNA expression levels are correlated across the entire sample, indicating shared transcriptional regulatory mechanisms. Further, we show that C4A mRNA expression alone is positively associated with psychotic symptomatology, specifically the presence and severity of delusions. These findings are noteworthy given recent findings that demonstrate a critical role for complement proteins in synaptic pruning, alterations of which are proposed to contribute to psychopathology in psychosis.

Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease.

BACKGROUND: Psychosis is a common phenomenon in Alzheimer's disease (AD). The APOE ε4 allele is the strongest genetic risk factor for the development of AD, but its association with psychosis remains unclear. OBJECTIVE: We investigated the associations between psychosis, subdivided into delusions and hallucinations, as well as APOE ε4 allele on cognitive and functional outcomes. Secondarily, we investigated the associations between APOE ε4, Lewy bodies, and psychosis. METHODS: Data from the National Alzheimer's Coordinating Center (NACC) were used. Nine hundred patients with a confirmed diagnosis of AD based on the NIA-AA Reagan were included in the analysis. Global cognition was assessed using the Mini-Mental State Exam (MMSE) and functional status was assessed using the Functional Activities Questionnaire (FAQ). Psychosis status was determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Factorial design was used to assess the effects of psychosis and APOE ε4, as well as their interaction. RESULTS: Psychosis and the presence of APOE ε4 were both associated with lower MMSE scores, while only psychosis was associated with higher FAQ scores. Furthermore, patients with hallucinations had lower MMSE and higher FAQ scores than patients with only delusions. There was a significant interaction effect between psychosis and APOE ε4 on MMSE scores, with APOE ε4 negatively affecting patients with hallucinations-only psychosis. APOE ε4 was positively associated with the presence of Lewy body pathology, and both were found to be more prevalent in psychotic patients, with a stronger association with hallucinations. CONCLUSION: Psychosis in AD was associated with greater cognitive and functional impairments. Patients with hallucinations-with or without delusions-conferred even greater deficits compared to patients with only delusions. The APOE ε4 allele was associated with worse cognition, especially for patients with hallucination-only psychosis. APOE ε4 may mediate cognitive impairment in the hallucinations phenotype through the development of Lewy bodies. Our findings support that subtypes of psychosis should be evaluated separately.

Brief psychotic episode in a patient with chromosome 2q37 microdeletion syndrome.

A 21-year-old woman with moderate learning disability secondary to chromosome 2 microdeletion at q37 was admitted to a general adult psychiatric ward following a period of agitation with incessant pressure of speech, nihilistic delusions and worsening of sleep and eating patterns. Her presentation was preceded for a number of weeks by social stressors of an ill family member and another family member moving away. She had also been diagnosed and treated for a respiratory infection several weeks prior to presentation. Her presentation improved with low-dose antipsychotic medication and parallel input from the general adult mental health team and the psychiatry of intellectual disability team.

Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves.

The CCC2000 Birth Cohort Study of Register-Based Family History of Mental Disorders and Psychotic Experiences in Offspring.

Psychotic experiences (PE) in individuals of the general population are hypothesized to mark the early expression of the pathology underlying psychosis. This notion of PE as an intermediate phenotype is based on the premise that PE share genetic liability with psychosis. We examined whether PE in childhood was predicted by a family history of mental disorder with psychosis rather than a family history of nonpsychotic mental disorder and whether this association differed by severity of PE. The study examined data on 1632 children from a general population birth cohort assessed at age 11-12 years by use of a semistructured interview covering 22 psychotic symptoms. The Danish national registers were linked to describe the complete family history of hospital-based psychiatric diagnoses. Uni- and multivariable logistic regressions were used to test whether a family history of any mental disorder with psychosis, or of nonpsychotic mental disorder, vs no diagnoses was associated with increased risk of PE in offspring (hierarchical exposure variable). The occurrence of PE in offspring was significantly associated with a history of psychosis among the first-degree relatives (adjusted relative risk [RR] = 3.29, 95% CI: 1.82-5.93). The risk increased for combined hallucinations and delusions (adjusted RR = 5.90, 95% CI: 2.64-13.16). A history of nonpsychotic mental disorders in first-degree relatives did not contribute to the risk of PE in offspring nor did any mental disorder among second-degree relatives. Our findings support the notion of PE as a vulnerability marker of transdiagnostic psychosis. The effect of psychosis in first-degree relatives may operate through shared genetic and environmental factors.

Evidence that environmental and genetic risks for psychotic disorder may operate by impacting on connections between core symptoms of perceptual alteration and delusional ideation.

BACKGROUND: Relational models of psychopathology propose that symptoms are dynamically connected and hypothesize that genetic and environmental influences moderate the strength of these symptom connections. Previous findings suggest that the interplay between hallucinations and delusions may play a crucial role in the development of psychotic disorder. The current study examined whether the connection between hallucinations and delusions is impacted by proxy genetic and environmental risk factors. METHODS: Hallucinations and delusions at baseline and at 3-year follow-up were assessed in a sample of 1054 healthy siblings and 918 parents of 1109 patients with psychosis, and in 589 healthy controls (no familial psychosis risk). Environmental factors assessed were cannabis use, childhood trauma, and urbanicity during childhood. Logistic regression analyses tested whether familial psychosis risk predicted increased risk of delusions, given presence of hallucinations. Moderating effects of environmental factors on the hallucination-delusion association were tested in a similar fashion, restricted to the control and sibling groups. RESULTS: The risk of delusions, given hallucinations, was associated with proxy genetic risk: 53% in parents, 47% in siblings, and 36% in controls. The hallucination-delusion association was stronger in those reporting cannabis use (risk difference: 32%) and childhood trauma (risk difference: 15%) although not all associations were statistically conclusive (respectively: p = .037; p = .054). A directionally similar but nonsignificant effect was found for urb anicity during childhood (risk difference: 14%, p =.357). CONCLUSION: The strength of the connection between delusions and hallucinations is associated with familial and environmental risks for psychotic disorder, suggesting that specific symptom connections in the early psychosis psychopathology network are informative of underlying mechanisms.

Clinicopathological Study of Patients With C9ORF72-Associated Frontotemporal Dementia Presenting With Delusions.

BACKGROUND: Several clinical studies point to a high prevalence of psychotic symptoms in frontotemporal dementia associated with C9ORF72 mutations, but clinicopathological studies addressing the association between C9ORF72 mutations and delusions are lacking. METHOD: Seventeen patients with pathologically proven frontotemporal lobar degeneration (FTLD) associated with C9ORF72 mutations were identified from Neurodegenerative Disease Brain Bank. Of the 17 cases with C9ORF72 mutation, 4 exhibited well-defined delusions. The clinical history, neurological examination, neuropsychological testing, neuroimaging analysis, and postmortem assessment of the patients with delusions were evaluated and compared with the other cases. RESULT: The content of the delusions was mixed including persecution, infidelity, and grandiosity. All cases showed parkinsonism; voxel-based morphometry analysis showed greater precuneus atrophy in patients with delusions than those without delusions. All 4 had unclassifiable FTLD with TAR DNA-binding protein inclusions, with characteristics of both type A and type B. Three cases had additional τ pathology and another had α-synuclein pathology. CONCLUSION: C9ORF72 carriers with well-defined delusions likely associated with additional pathologies and parietal atrophy in neuroimaging. Patients presenting with middle-aged onset of delusions should be screened for C9ORF72 mutations, especially if family history and parkinsonism are present.

Role of the extended MAPT haplotype in the worsening of psychotic symptoms and treatment response in Alzheimer disease.

INTRODUCTION: There is evidence that neurofibrillary tangle (NFT) burden is associated with psychotic symptoms in Alzheimer disease (AD). However, it is not clear whether this association is direct or mediated through the increased cognitive impairment associated with NFTs. METHODS: We sought to determine whether the extended MAPT haplotype was associated with the worsening of delusions and hallucinations in a combined cohort of 95 patients who participated in 2 clinical trials of treatment with memantine. RESULTS: After controlling for baseline dementia severity, exposure to memantine, and antipsychotics, analysis shows that carriers of at least one H2 allele had a 5.4-fold (P = .03) increased risk of worsening hallucinations. There was some evidence of association with worsening delusions but only in analysis by allele. CONCLUSION: These results are the first to indicate that the H2 allele of the extended MAPT haplotype negatively affects the course of psychotic symptoms in AD independently of disease severity. It will be important for future research to examine MAPT transcription in people with AD with and without psychotic symptoms to understand the exact mechanisms underlying these findings.

Determining the association of the 5HTTLPR polymorphism with delusions and hallucinations in Lewy body dementias.

OBJECTIVES: To determine whether the 5HTTLPR serotonin transporter polymorphism is associated with delusions and hallucinations in people with dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). DESIGN: Prospective cohort study. PARTICIPANTS: A total of 187 individuals, recruited from centres in Norway, Sweden, and the United Kingdom were included in this study; 97 with clinically or neuropathologically diagnosed DLB/PDD and 90 cognitively normal individuals as a comparison group. MEASUREMENTS: All participants with dementia underwent serial evaluation of neuropsychiatric symptoms to assess the presence of persistent delusions and hallucinations using the Columbia University Scale for Psychopathology in Alzheimer disease, the Neuropsychiatric Inventory, or the Present Behavioural Examination. Severity of cognitive impairment was measured using the Mini Mental State Examination (MMSE). Individuals were genotyped for the 5HTTLPR polymorphism. RESULTS: Logistic regression demonstrated that homozygosity for the L/L genotype and lower MMSE were associated with an increased risk for delusions (odds ratio: 11.5 and 1.16, respectively). Neither was significantly associated with hallucinations. CONCLUSIONS: This study is the first to demonstrate the 5HTTLPR polymorphism is associated with delusions in Lewy body dementias, with important implications regarding the mechanisms underlying this symptom across the AD/DLB/PDD spectrum. Further studies are warranted to investigate this relationship further and examine treatment opportunities.

Delusion of pregnancy: a case revisited.

A patient with delusion of pregnancy as an early feature of frontotemporal dementia with motor neurone disease (FTD/MND) who was reported some years ago was posthumously found to harbor the C9ORF72 hexanucleotide repeat expansion, now known to be the most common genetic cause of FTD/MND. Some series have found psychosis to be common in FTD associated with this mutation, so this test should be considered in individuals with clinical features of FTD and MND and/or with a family history of either disorder who present with bizarre delusions.

Cognitive impairment in studies of 5HTTLPR and psychosis in Alzheimer's disease: a systematic review.

BACKGROUND/AIMS: Cognitive impairment is a well-established correlate of psychotic symptoms in Alzheimer's disease (AD-P). We review whether this relationship has confounded previous genetic association studies of 5HTTLPR and AD-P. METHODS: We reviewed all studies on 5HTTLPR and conducted a semi-quantitative analysis. RESULTS: Three out of 4 studies with low MMSE reported a significant association, while 1 out of 4 with high MMSE reported a significant association. CONCLUSIONS: Variation in cognitive impairment in past studies has contributed to the inconsistency in findings. The findings presented here bring a greater clarity to our understanding of the role of 5HTTLPR in AD-P.