Psychosis In Alzheimer Research Articles

Revisiting Criteria for Psychosis in Alzheimer's Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research.

Psychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. To establish research criteria for the diagnosis of psychosis in AD. The International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Evidence-Based Pharmacological Management and Treatment of Behavioral and Psychological Symptoms of Dementia

Evidence-Based Pharmacological Management and Treatment of Behavioral and Psychological Symptoms of Dementia

Year in Review: Applying Top Research to the Practice of PALTC Medicine

Year in Review: Applying Top Research to the Practice of PALTC Medicine

GBA and APOE \u03b54 associate with sporadic dementia with Lewy bodies in European genome wide association study

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

Synaptic Proteome Compensation and Resilience to Psychosis in Alzheimer's Disease.

The presence of psychosis in Alzheimer's disease denotes a phenotype with more rapid cognitive deterioration than in Alzheimer's disease without psychosis. Discovery of novel pharmacotherapies that engage therapeutic targets for prevention or treatment of Alzheimer's disease with psychosis would benefit from identifying the neurobiology of resilience to psychosis in Alzheimer's disease. The primary objective of this study was to determine whether alterations in the synaptic proteome were associated with resilience to psychotic symptoms in Alzheimer's disease and, if present, were independent of neuropathologic burden. Quantitative immunohistochemistry was used to measure multiple neuropathologies in dorsolateral prefrontal cortex from subjects with early and middle-stage Alzheimer's disease who differed in psychosis status. Synaptic proteins were quantified by liquid chromatography-mass spectrometry in gray matter homogenates from these subjects and from neuropathologically unaffected subjects. The synaptic proteome was similarly evaluated in cortical gray matter homogenate and in postsynaptic density fractions from an APPswe/PSEN1dE9 mouse model of amyloidosis with germline reduction in Kalrn, which has been shown to confer resilience to progression of psychosis-associated behaviors relative to APPswe/PSEN1dE9 alone. Subjects resilient to psychotic symptoms in Alzheimer's disease had higher levels of synaptic proteins compared with those with psychosis and unaffected control subjects. Neuropathologic burden predicted less than 20% of the variance in psychosis status and did not account for the synaptic protein level differences between groups. Reduction of Kalrn in APPswe/PSEN1dE9 mice resulted in higher levels of synaptic proteins in cortical homogenate and normalized protein levels in the postsynaptic density. Accumulation of synaptic proteins, particularly those that are enriched in the postsynaptic density, is associated with resilience to psychosis in Alzheimer's disease. One candidate mechanism for this synaptic proteome compensation is alteration in levels of proteins that facilitate the transport of synaptic proteins to and from the postsynaptic density.

Gender and Pathology-Specific Effect of Apolipoprotein E Genotype on Psychosis in Alzheimer's Disease.

Symptoms of psychosis is one of the common clinical manifestations of Alzheimer's disease (AD). However, the pathophysiology behind psychosis is unknown. The aim of the present study was to explore the relationship between Apolipoprotein E (APOE) genotype, Lewy body pathology, and psychosis in AD. The data was obtained from the National Alzheimer's disease Coordinating Centre (NACC), using the Uniform Data Set and the Neuropathology Data Set. Subjects with frequent neuritic plaque on CERAD, and Braak Stage of V or VI, corresponding to high probability of AD based on the NIA-AA Regan criteria were included in the analysis. Subjects with two copies of ε4 alleles were significantly more likely to develop psychosis, both delusions and/or hallucinations, during the course of their illness. This association was gender-specific, only reaching significance in females. Our findings further showed that presence of two copies of ε4 allele was positively associated with the formation of Lewy bodies. Only in females with Lewy bodies was the effect of two copies of ε4 allele significant, reaching an odd ratio of 4.5. The APOE ε4 allele has a female-specific effect in inducing psychosis in AD through the formation of Lewy bodies.

Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice

Psychosis in Alzheimer's disease (AD+P) represents a distinct clinical and neurobiological AD phenotype and is associated with more rapid cognitive decline, higher rates of abnormal behaviors, and increased caregiver burden compared with AD without psychosis. On a molecular level, AD+P is associated with greater reductions in the protein kalirin, a guanine exchange factor which has also been linked to the psychotic disease, schizophrenia. In this study, we sought to determine the molecular and behavioral consequences of kalirin reduction in APPswe/PSEN1dE9 mice. We evaluated mice with and without kalirin reduction during tasks measuring psychosis-associated behaviors and spatial memory. We found that kalirin reduction in APPswe/PSEN1dE9 mice significantly attenuated psychosis-associated behavior at 12 months of age without changing spatial memory performance. The 12-month-old APPswe/PSEN1dE9 mice with reduced kalirin levels also had increased levels of the active, phosphorylated forms of p21 protein (Cdc42/Rac)–activated kinases (PAKs), which function in signaling pathways for maintenance of dendritic spine density, morphology, and function.

The regulation of GSK‐3β in nervous system

Glycogen synthase kinase‐3β (GSK‐3β) is a multifunctional serine‐threonine kinase, which is expressesed in all eukaryotic cells. Many diseases, such as metabolic diseases, cancer, digestive diseases and lung diseases, have been confirmed to be associated with the changes of expression level of GSK‐3β. At present, studies have found that it is also involved in the development of nervous system diseases such as traumatic brain injury, Alzheimer's psychosis, etc. This article summarizes the regulatory mechanism of GSK‐3β in the development of nerve diseases and intends to clarify the mechanisms of nervous system disease to guide its application in future clinic trial.

Incident Psychosis in Subjects With Mild Cognitive Impairment or Alzheimer's Disease.

To estimate the incidence of psychotic symptoms in Alzheimer's disease. The study consists of 776 elderly subjects presenting to the Alzheimer Disease Research Center at the University of Pittsburgh (Pittsburgh, Pennsylvania) between May 9, 2000, and August 19, 2014. All participants were diagnosed with mild cognitive impairment (National Institute on Aging-Alzheimer's Association workgroup criteria) or possible or probable Alzheimer's disease (National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) and were without psychosis at entry. Psychotic symptoms were evaluated using the Consortium to Establish a Registry for Alzheimer's Disease Behavioral Rating Scale every 6 months. One-, 3- and 5-year cumulative incidences of psychosis were calculated. The 1-year psychosis incidence was 10% (95% CI, 8%-12%), and this annual rate remained remarkably consistent at 3 and 5 years. Psychosis incidence was related to cognitive status at all time points. However, the incidence rate reached a plateau during the disease course. Cumulative psychosis incidence at 5 years was 61% (95% CI, 52%-69%) in individuals with moderate to severe Alzheimer's disease, not statistically significantly different from the cumulative incidence at 3 years in this group, which was 48% (95% CI, 40%-55%) or from the 5-year incidence in individuals who entered the study with mild Alzheimer's disease, which was 48% (95% CI, 41%-56%). Psychosis in Alzheimer's disease has been associated with a number of adverse clinical outcomes. We provide estimates of the risk of psychosis onset within clinically defined subgroups of individuals, a tool clinicians can use in treatment planning. Anticipating which subjects are at high risk for psychosis and the poor outcomes associated with it can help with family education and support decisions to implement nonpharmacologic strategies that may reduce or prevent symptoms.

Psychosis in Alzheimer’s Disease: a Review of Recent Research Findings

The purpose of this review paper is to examine the latest research findings in psychosis in Alzheimer’s disease (AD) and to reconcile conflicting perspectives regarding whether psychotic symptoms should be considered individually (as delusions/hallucinations) or as a whole. AD patients with psychosis demonstrate accelerated onset of cognitive decline prior to the onset of psychosis and are at increased risk of conversion to AD, emphasizing the importance of early detection. Data from neurobiological studies, including imaging and neuropathological studies, suggest there may be merit in breaking down symptoms into delusions and hallucinations while epidemiologic and genetic studies suggest the opposite conclusion. It is conceivable based on the research to date that genetic factors interact with neurodegeneration to create a vulnerability to the development of psychosis in AD. Future studies are required to clarify the specific mechanisms that lead to individual symptoms (delusions/hallucinations).

Polymorphisms of dopamine receptor genes and risk of visual hallucinations in Parkinson's patients.

Visual hallucinations (VHs) are frequent non-motor complication of Parkinson's disease (PD), associated to a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (DR) variants and psychosis in Alzheimer's disease, addictions, schizophrenia, and bipolar disorder. However, there are only a few studies on DR variants and VHs in PD, which did not provide conclusive results. The present study aimed to determine whether genetic differences of DR are associated with visual hallucinations (VHs) in a cohort of Parkinson's disease (PD) patients. A case-control study of 84 PD subjects, 42 with and 42 without VHs,that were matched for age, gender, disease duration, and dopaminergic medication was conducted. Polymerase chain reaction for SNPs in both D1-like (DRD1A-48G [rs4532] and C62T [rs686], DRD5T798C [rs6283]) and D2-like DR (DRD2G2137A [rs1800497] and C957T [rs6277], DRD3G25A [rs6280] and G712C [rs1800828], DRD4C616G [rs747302] and nR VNTR 48bp) analyzed genomic DNA. Patients carrying allele T at DRD1C62T had an increased risk of VHs, expressed as OR (95% CI, p value), of 10.7 (2.9-40, p=0.0001). Moreover, patients with DRD1-48 GG and 62TT genotype displayed shorter time to VHs, whereas a longer time to VHs was found in subjects carrying the DRD4 CG alleles. PD patients with VHs display higher frequency of DR SNPs associated with increased D1-like activity and decreased D2-like activity. Our data are in line with associations reported in other neurodegenerative and psychiatric conditions. Results likely provide valuable information for personalizing pharmacological therapy in PD patients.

Poster Number: NR 10 - Vascular Risk Factors and Subcortical Arteriosclerotic Leukoencephalopathy, but Not Alzheimer Lesion Load, are Associated with Development of Psychosis in Alzheimer's Disease

Poster Number: NR 10 - Vascular Risk Factors and Subcortical Arteriosclerotic Leukoencephalopathy, but Not Alzheimer Lesion Load, are Associated with Development of Psychosis in Alzheimer's Disease

Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease.

Psychosis is common in Alzheimer’s disease (AD). However, studies on neuropathology in vascular etiology contributing to psychosis in AD is lacking to date. The aim of this study was to investigate neuropathological vascular related changes in Alzheimer’s disease with psychosis. Data of patients with AD from the National Alzheimer’s Coordinating Center between 2005 to September 2013 was accessed and reviewed. Presence of psychosis was determined based on Neuropsychiatric Inventory Questionnaire taken from the last visit within one year prior to death, and patients were divided into psychosis positive and negative group. Comparison of clinical details and neuropathological vascular changes between the groups was performed using Wilcoxon rank sum test and Chi-square/ Fisher’s exact test. Significant variables were further included in a multivariate logistic model. Overall, 145 patients was included. Of these, 50 patients were psychosis positive. Presence of one or more cortical microinfarcts and moderate to severe arteriosclerosis was found to be positively associated with psychosis. Our results suggest vascular changes correlate with psychosis in Alzheimer’s disease.

Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer's Disease.

The neuropathological correlates of psychosis in Alzheimer's disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association. To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD. We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to the NPI-Q, were analyzed separately. 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis. Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.

Genome-wide copy-number variation study of psychosis in Alzheimer's disease.

About 40–60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is ~61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD−P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD−P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD−P controls (P=0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E−10). We also observed suggestive associations of duplications with AD+P in the SET (P=1.95E−06), JAG2 (P=5.01E−07) and ZFPM1 (P=2.13E−07) genes and marginal association of a deletion in CNTLN (P=8.87E−04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large-scale independent studies.

Genome-wide copy-number variation study of psychosis in Alzheimer’s disease

Genome-wide copy-number variation study of psychosis in Alzheimer’s disease

Pimavanserin.

Pimavanserin (ACP-103) is a selective inverse agonist of the 5-hydroxytryptamine 2A (5-HT2A) receptor intended to treat patients with Parkinson's disease psychosis (PDP). Currently there are no FDA-approved medications in the United States for the treatment of PDP, although on September 2, 2014, the United States Food and Drug Administration granted breakthrough therapy status to pimavanserin, highlighting the unmet need for therapeutics in this class. Most antipsychotic medications worsen motor dysfunction due to dopamine antagonism, and all carry a black box warning for an increased risk of mortality in elderly patients with dementia-related psychosis. Data from phase II and phase III clinical trials suggest that pimavanserin is a safe and effective treatment option for PDP. Trial results indicate a significant reduction in hallucinations and delusions in patients with PDP without worsening motor symptoms. Additional studies are ongoing for the treatment of Alzheimer's psychosis, schizophrenia and insomnia. Such promising outcomes warrant a review of the available literature regarding pimavanserin and its use in the treatment of PDP symptoms.

A rare duplication on chromosome 16p11.2 is identified in patients with psychosis in Alzheimer's disease.

Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer's disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. A chromosome 16p11.2 duplication CNV (chr16: 29,554,843-30,105,652) was identified in 2 of 440 AD+P subjects, but not in 136 AD subjects without psychosis, or in 593 AD subjects with intermediate psychosis status, or in 855 non-AD individuals. The frequency of this duplication CNV in AD+P (0.46%) was similar to that reported previously in schizophrenia (0.46%). This duplication CNV was further validated using the NanoString nCounter CNV Custom CodeSets. The 16p11.2 duplication has been associated with developmental delay, intellectual disability, behavioral problems, autism, schizophrenia (SCZ), and bipolar disorder. These two AD+P patients had no personal of, nor any identified family history of, SCZ, bipolar disorder and autism. To the best of our knowledge, our case report is the first suggestion that 16p11.2 duplication is also linked to AD+P. Although rare, this CNV may have an important role in the development of psychosis.

Optimal treatment of Alzheimer's disease psychosis: challenges and solutions.

Psychotic symptoms emerging in the context of neurodegeneration as a consequence of Alzheimer’s disease was recognized and documented by Alois Alzheimer himself in his description of the first reported case of the disease. Over a quarter of a century ago, in the context of attempting to develop prognostic markers of disease progression, psychosis was identified as an independent predictor of a more-rapid cognitive decline. This finding has been subsequently well replicated, rendering psychotic symptoms an important area of exploration in clinical history taking – above and beyond treatment necessity – as their presence has prognostic significance. Further, there is now a rapidly accreting body of research that suggests that psychosis in Alzheimer’s disease (AD+P) is a heritable disease subtype that enjoys neuropathological specificity and localization. There is now hope that the elucidation of the neurobiology of the syndrome will pave the way to translational research eventuating in new treatments. To date, however, the primary treatments employed in alleviating the suffering caused by AD+P are the atypical antipsychotics. These agents are approved by the US Food and Drug Administration for the treatment of schizophrenia, but they have only marginal efficacy in treating AD+P and are associated with troubling levels of morbidity and mortality. For clinical approaches to AD+P to be optimized, this syndrome must be disentangled from other primary psychotic disorders, and recent scientific advances must be translated into disease-specific therapeutic interventions. Here we provide a review of atypical antipsychotic efficacy in AD+P, followed by an overview of critical neurobiological observations that point towards a frontal, tau-mediated model of disease, and we suggest a new preclinical animal model for future translational research.

Towards a therapeutic window of D2/3 occupancy for treatment of psychosis in Alzheimer's disease, with [18F]fallypride positron emission tomography

Dopamine D2/3 receptor positron emission tomography tracers have guided antipsychotic prescribing in young people with schizophrenia by establishing a 'therapeutic window' of striatal D2/3 receptor occupancy. Older people, particularly those with dementia, are highly susceptible to motor side effects and may benefit from the appropriate application of imaging techniques. The study aimed to adapt [18F]fallypride imaging for use in occupancy studies in Alzheimer's disease (AD) and to investigate whether data acquisition could be made more tolerable by piloting the protocol in a small sample. Six participants with AD (three men; 85.0 ± 5.6 years old; MMSE = 16.0 ± 2.4) were recruited prior to commencing amisulpride for the treatment of psychosis and associated agitation. [18F]fallypride binding potential (BPND ) was determined using an interrupted scanning protocol at baseline (n = 6) and after 27.0 ± 6.1 days of amisulpride (25-50 mg) treatment (n = 4). D2/3 occupancy was calculated by percentage reduction in BPND between scanning sessions. Image data were re-analysed after reducing individual sampling times to 20 min. The protocol was tolerated well, apart from the final (40 min) session of the post-treatment scan in one participant. Higher occupancies were achieved in the striatum (caudate 47-70%, putamen 31-58%) and thalamus (54-76%) than in the inferior temporal gyrus (27-43%). There was high agreement between occupancy values derived using longer and shorter sampling times (mean absolute difference 6.1% in the inferior temporal gyrus; <2% all other regions). The protocol is feasible for use in AD and represents the first step towards establishing dose-occupancy relationships across older clinical populations.