Psychosis in Alzheimer's disease is associated with frontal metabolic impairment and accelerated decline in working memory: findings from the Alzheimer's Disease Neuroimaging Initiative.

OBJECTIVE: An ascendant body of evidence suggests that Alzheimer disease with psychosis (AD+P) is a distinct variant of illness with its own genetic diathesis and a unique clinical course. Impaired frontal lobe function has been previously implicated in AD+P. The current exploratory study, presented in two parts, evaluates both the regional brain metabolic and psychometric correlates of psychosis in a longitudinal sample of subjects with AD, made available by the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: In Part 1 of the study, 21 ADNI participants with AD who developed psychotic symptoms during the study but were not psychotic at baseline were matched with 21 participants with AD who never became psychotic during the study period, and mean brain [F(18)]fluorodeoxyglucose positron emission tomography (FDG-PET) Cerebral metabolic rate for glucose (CMRgl) by regions of interest (ROIs) were compared Additionally, 39 participants with active psychosis at the time of image acquisition were matched with 39 participants who were never psychotic during the study period, and mean brain FDG-PET CMRgl by sROI were compared. In Part 2 of the study, 354 ADNI participants with AD who were followed for 24 months with serial psychometric testing were identified, and cognitive performance and decline were evaluated for correlation with psychotic symptoms. RESULTS: Part 1: There were no regional brain metabolic differences between those with AD destined to become psychotic and those who did not become psychotic. There was a significant reduction in mean orbitofrontal brain metabolism in those with active psychosis. Part 2: Over the course of study follow-up, psychosis was associated with accelerated decline in functional performance as measured by the Functional Assessment Questionnaire, the Mini-Mental State Examination, and Forward Digit Span. CONCLUSION: In a sample drawn from the ADNI dataset, our exploratory FDG-PET findings and longitudinal cognitive outcomes support the hypofrontality model of AD+P. Focal frontal vulnerability may mediate the accelerated decline seen in AD+P.

Medical outcome of patients with dementia in a free-standing psychiatric hospital.

BACKGROUND: The hospital outcome of patients with dementia is significantly worse than that of cognitively intact persons of the same age admitted to medical or surgical units but has not been investigated in psychiatric settings. AIM OF STUDY: To determine the medical outcome of patients with dementia admitted for behavioral disturbance to a free-standing psychiatric hospital. METHODS: Emergency transfers from the psychiatric setting to a general hospital were used as proxies for medical deteriorations occurring among the 71 patients with dementia (age 78.4 ± 10.4 years; 40.1% males) and 71 age- and gender-matched nondementia control patients. The patients were identified in a cohort of 1000 patients consecutively admitted to a free-standing mental health institution. Logistic regression was used to determine the clinical and laboratory variables independently associated with medical deteriorations. RESULTS: A total of 30 patients with dementia and 25 nondementia patients were transferred to a general hospital after an acute medical deterioration (42.3% vs 35.2%, P = .38). Febrile illnesses and falls with head trauma were the most common reasons for transfers in the dementia group, in which they constituted more than half of medical deteriorations, a proportion significantly higher than in the control group (P = .011). Admission hemoglobin levels were the only independent predictor of medical deterioration in this geriatric sample. CONCLUSIONS: Although nearly 50% of patients with dementia admitted for behavioral disturbance to a free-standing psychiatric institution required transfer to a general hospital, their rate of medical deteriorations was similar to age-matched nondementia control patients.

Relationships between behavioral syndromes and cognitive domains in Alzheimer disease: the impact of mood and psychosis.

OBJECTIVES: Behavioral disturbances occur in nearly all Alzheimer disease (AD) patients together with an array of cognitive impairments. Prior investigations have failed to demonstrate specific associations between them, suggesting an independent, rather than shared, pathophysiology. The objective of this study was to reexamine this issue using an extensive cognitive battery together with a sensitive neurobehavioral and functional rating scale to correlate behavioral syndromes and cognitive domains across the spectrum of impairment in dementia. DESIGN: Cross-sectional study of comprehensive cognitive and behavioral ratings in subjects with AD and mild cognitive impairment. SETTING: Memory disorders research center. PARTICIPANTS: Fifty subjects with AD and 26 subjects with mild cognitive impairment; and their caregivers. MEASUREMENTS: Cognitive rating scales administered included the Mini-Mental State Examination; the Modified Mini-Mental State Examination; the Boston Naming Test; the Benton Visual Retention Test; the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychology Assessment; the Controlled Oral Word Test; the Wechsler Memory Scale logical memory I and logical memory II task; the Wechsler Memory Scale-Revised digit span; the Wechsler Adult Intelligence Scale-Revised digit symbol task; and the Clock Drawing Task together with the Clinical Dementia Rating Scale and the Neuropsychiatric Inventory. RESULTS: Stepwise regression of cognitive domains with symptom domains revealed significant associations of mood with impaired executive function/speed of processing (Δr = 0.22); impaired working memory (Δr = 0.05); impaired visual memory (Δr = 0.07); and worsened Clinical Dementia Rating Scale (Δr = 0.08). Psychosis was significantly associated with impaired working memory (Δr = 0.13). CONCLUSIONS: Mood symptoms appear to impact diverse cognitive realms and to compromise functional performance. Among neuropsychological indices, the unique relationship between working memory and psychosis suggests a possible common underlying neurobiology.

CALHM1 P86L polymorphism modulates CSF Aß levels in cognitively healthy individuals at risk for Alzheimer's disease.

The calcium homeostasis modulator 1 (CALHM1) gene codes for a novel cerebral calcium channel controlling intracellular calcium homeostasis and amyloid-ß (Aß) peptide metabolism, a key event in the etiology of Alzheimer's disease (AD). The P86L polymorphism in CALHM1 (rs2986017) initially was proposed to impair CALHM1 functionally and to lead to an increase in Aß accumulation in vitro in cell lines. Recently, it was reported that CALHM1 P86L also may influence Aß metabolism in vivo by increasing Aß levels in human cerebrospinal fluid (CSF). Although the role of CALHM1 in AD risk remains uncertain, concordant data have now emerged showing that CALHM1 P86L is associated with an earlier age at onset of AD. Here, we have analyzed the association of CALHM1 P86L with CSF Aß in samples from 203 AD cases and 46 young cognitively healthy individuals with a positive family history of AD. We failed to detect an association between the CALHM1 polymorphism and CSF Aß levels in AD patients. Our data, however, revealed a significant association of CALHM1 P86L with elevated CSF Aß42 and Aß40 in the normal cohort at risk for AD. This work shows that CALHM1 modulates CSF Aß levels in presymptomatic individuals, strengthening the notion that CALHM1 is involved in AD pathogenesis. These data further demonstrate the utility of endophenotype-based approaches focusing on CSF biomarkers for the identification or validation of risk factors for AD.

Atypical (second generation) antipsychotic treatment response in very late-onset schizophrenia-like psychosis.

INTRODUCTION: Symptom amelioration in older patients with very late onset schizophrenia-like psychosis (VLOSLP) is often difficult, with limited psychotropic response reports yielding variable findings. Information about atypical (second generation) antipsychotic use in this population is scant. METHODS: A consecutive sample of geriatric psychiatry outpatients and inpatients with psychotic disorders were retrospectively identified over a 31-month period based on systematic information abstraction from an electronic medical record (e-record). After exclusion criteria were applied, 8/138 outpatients and 13/362 inpatients met inclusion criteria for VLOSLP and had been naturalistically treated with an atypical antipsychotic during hospitalization or nine months of outpatient care. Mandatorily completed e-record standardized symptom severity response ratings were converted into positive treatment response thresholds. RESULTS: 38% of outpatients and 77% of inpatients (mean age = 76 years for both groups; mean age of onset of psychosis = 70 years for outpatients and 74 years for inpatients) met criteria for positive treatment response to an atypical antipsychotic (either aripiprazole, olanzapine, quetiapine, or risperidone) with sign/symptom amelioration, rather than eradication. CONCLUSIONS: Various atypical antipsychotics at geriatric doses yielded a positive treatment response in nearly two-thirds of VLOSLP patients. Patients with less chronic, more severe symptoms responded at a higher rate. Prospective, double-blind, placebo-controlled trials with representative subject samples are needed to validate these preliminary findings.

A Model for Incident Review Committees in Behavioral Health Settings.

Despite the fact that incident review committees have been a key component of quality improvement in behavioral health settings for decades, specific models of how these committees are structured and operate are not well described. We present a model for an incident review committee that has been implemented in 2 large, academic acute care psychiatric hospitals. We believe the model not only permitted us to efficiently and effectively review untoward incidents, but that it also provided an approach to calibrating standards of care for the institution, engaging physicians in an interdisciplinary effort, promulgating a culture of quality review and improvement throughout the organization, promoting continuity and sustainability of the incident review process, and, most importantly, driving beneficial change in clinical practice. Demonstration of the effectiveness of this model requires formal investigation.

Haloperidol inactivates AMPK and reduces tau phosphorylation in a tau mouse model of Alzheimer's disease.

INTRODUCTION: The use of antipsychotic medications in Alzheimer's disease has been associated with an increased risk of mortality in clinical trials. However, an older postmortem literature suggests that those with schizophrenia treated in an era of exclusively conventional antipsychotic medications had a surprisingly low incidence of tau pathology. No previously published studies have investigated the impact of conventional antipsychotic exposure on tau outcomes in a tau mouse model of AD. METHODS: In two experiments, transgenic rTg (tauP301L) 4510 tau mice were treated with either haloperidol or vehicle and phosphotau epitopes were quantified using high-sensitivity tau ELISA. RESULTS: After treatments of 2 and 6 week's duration, mice treated with haloperidol evidenced a significant reduction in tau phosphorylation associated with an inactivation of the tau kinase AMPK. DISCUSSION: The data suggest that D2 receptor blockade reduces tau phosphorylation in vivo. Future studies are necessary to investigate the impact of this reduction on tau neuropathology.

Geriatric psychiatry versus general psychiatry inpatient treatment of the elderly.

OBJECTIVE: The authors compared the clinical treatment given older psychiatric inpatients on a geriatric psychiatry unit and a general psychiatry unit. METHOD: The charts of 50 randomly selected general psychiatry inpatients over the age of 65 years and 50 inpatients from the geriatric psychiatry unit who were matched for age, gender, and primary diagnosis were reviewed. RESULTS: Significantly greater percentages of older inpatients treated on the geriatric psychiatry unit received complete organic medical workups, structured cognitive assessment, aging-sensitive aftercare referral, and monitoring of psychopharmacological side effects and blood levels than comparable patients on a general psychiatry unit. CONCLUSIONS: Geriatric psychiatry subspecialty inpatient care appears to be associated with distinct clinically relevant assessment and treatment advantages. Continuing geropsychiatric education of general psychiatrists is indicated.

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.

Psychotic Alzheimer's disease is associated with gender-specific tau phosphorylation abnormalities.

Converging evidence suggests that psychotic Alzheimer's disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD - P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of α-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration.

Frontal signal hyperintensities in mania in old age.

OBJECTIVE: Signal hyperintensities (SH) on magnetic resonance (MR) imaging have been associated with increased age and with mood disorders. Frontal and subcortical neuropathology has been implicated in the pathophysiology of mania and bipolar disorders. The authors assessed frontal and subcortical SH in elderly bipolar manic patients and the comparison group, and hypothesized that SH scores would be greater in the patient group. METHOD: MR imaging was performed in patients aged > or = 60 years with bipolar disorder, mania, and in a same-aged community comparison group. SH were rated blindly using the Boyko system. Frontal deep white matter and basal ganglia SH were assessed in the left and right hemispheres. RESULTS: SH scores were significantly greater in patients (N = 40) than the comparison group (N = 15) in frontal deep white matter (left: p = 0.003; right: p = 0.023) based on Mann-Whitney two-sample exact tests. The SH scores in the subcortical gray regions overlapped in these groups. In patients, higher right frontal SH scores were associated with later age at onset of mania. CONCLUSIONS: Frontal deep white matter SH may be increased in elders with bipolar disorder. Further study of the relationship of SH to age at onset in elders is warranted.