Determining the impact of psychosis on rates of false-positive and false-negative diagnosis in Alzheimer's disease.

INTRODUCTION: The rate of clinical misdiagnosis of Alzheimer's disease (AD) and how psychosis impacts that clinical judgment is unclear. METHODS: Using data from National Alzheimer's Coordinating Center, we compared the clinical and neuropathologic diagnosis in patients with a diagnosis of AD with autopsy and in neuropathology-confirmed AD cases (n = 961). We determined the rate of true positives, false positives, and false negatives in patients with and without psychosis. RESULTS: A total of 76% received a correct AD diagnosis, 11.9% had a false-negative diagnosis, and 12.1% had a false-positive diagnosis of AD. Psychotic patients had a higher rate of false-negative diagnosis and a lower rate of false-positive diagnosis of AD compared with nonpsychotic patients. DISCUSSION: Patients with psychosis were five times more likely to be misdiagnosed as dementia with Lewy bodies, whereas patients without psychosis were more likely to be falsely diagnosed with AD when vascular pathology is the underlying neuropathologic cause of dementia.

Prevalence of Depression in Patients With Mild Cognitive Impairment: A Systematic Review and Meta-analysis.

IMPORTANCE: Depression is common in individuals with mild cognitive impairment (MCI) and may confer a higher likelihood of progression to dementia. Prevalence estimates of depression in those with MCI are required to guide both clinical decisions and public health policy, but published results are variable and lack precision. OBJECTIVE: To provide a precise estimate of the prevalence of depression in individuals with MCI and identify reasons for heterogeneity in the reported results. DATA SOURCES: A search of literature from database inception to March 2016 was performed using Medline, Embase, and PsycINFO. Hand searching of all included articles was performed, including a Google Scholar search of citations of included articles. STUDY SELECTION: Articles were included if they (1) were published in English, (2) reported patients with MCI as a primary study group, (3) reported depression or depressive symptoms using a validated instrument, and (4) reported the prevalence of depression in patients with MCI. DATA EXTRACTION AND SYNTHESIS: All abstracts, full-text articles, and other sources were reviewed, with data extracted in duplicate. The overall prevalence of depression in patients with MCI was pooled using a random-effects model. Heterogeneity was explored using stratification and random-effects meta-regression. MAIN OUTCOMES AND MEASURES: The prevalence of depression in patients with MCI, reported as a percentage with 95% CIs. Estimates were also stratified by population source (community-based or clinic-based sample), method of depression diagnosis (clinician-administered, informant-based, or self-report), and method of MCI diagnosis (cognitive vs global measure and amnestic vs nonamnestic). RESULTS: Of 5687 unique abstracts, 255 were selected for full-text review, and 57 studies, representing 20 892 patients, met all inclusion criteria. The overall pooled prevalence of depression in patients with MCI was 32% (95% CI, 27-37), with significant heterogeneity between estimates (I2 = 90.7%). When stratified by source, the prevalence of depression in patients with MCI in community-based samples was 25% (95% CI, 19-30) and was 40% (95% CI, 32-48) in clinic-based samples, which was significantly different (P < .001). The method used to diagnose depression did not significantly influence the prevalence estimate, nor did the criteria used for MCI diagnosis or MCI subtype. CONCLUSIONS AND RELEVANCE: The prevalence of depression in patients with MCI is high. A contributor to heterogeneity in the reported literature is the source of the sample, with greater depression burden prevalent in clinic-based samples.

Gray matter atrophy in patients with mild cognitive impairment/Alzheimer's disease over the course of developing delusions.

OBJECTIVE: We conducted a neuroimaging analysis to understand the neuroanatomical correlates of gray matter loss in a group of mild cognitive impairment and early Alzheimer's disease patients who developed delusions. METHODS: With data collected as part of the Alzheimer's Disease Neuroimaging Initiative, we conducted voxel-based morphometry to determine areas of gray matter change in the same Alzheimer's Disease Neuroimaging Initiative participants, before and after they developed delusions. RESULTS: We identified 14 voxel clusters with significant gray matter decrease in patient scans post-delusional onset, correcting for multiple comparisons (false discovery rate, p < 0.05). Major areas of difference included the right and left insulae, left precuneus, the right and left cerebellar culmen, the left superior temporal gyrus, the right posterior cingulate, the right thalamus, and the left parahippocampal gyrus. CONCLUSIONS: Although contrary to our initial predictions of enhanced right frontal atrophy, our preliminary work identifies several neuroanatomical areas, including the cerebellum and left posterior hemisphere, which may be involved in delusional development in these patients.

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

BACKGROUND: 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. OBJECTIVE: To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD. METHOD: 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. RESULTS: 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. METHOD: Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.

Grey matter atrophy in mild cognitive impairment / early Alzheimer disease associated with delusions: a voxel-based morphometry study.

OBJECTIVES: Grey matter atrophy in the right hemisphere has been shown to be more severe in dementia patients with delusions, suggesting a neuroanatomical localization that may be pertinent to impending neurodegeneration. Delusional symptoms may arise when atrophy in these areas reduces the regulatory functions of the right hemisphere, in tandem with asymmetric neuropathology in the left hemisphere. We hypothesized that delusional patients with either amnestic mild cognitive impairment (MCI) or early Alzheimer Disease (AD) would experience more pronounced grey matter atrophy in the right frontal lobe compared with matched patients without delusions. METHODS: We used neuroimaging and clinical data obtained from the Alzheimer's Disease Neuroimaging Initiative. A comparison group of twenty-nine nondelusional MCI/early AD participants were compared with twenty-nine delusional participants using voxel-based morphometry, matched at baseline by age, sex, education, and Mini-Mental State Exam score. All included participants were diagnosed with amnestic MCI at study baseline. RESULTS: Fifteen voxel clusters of decreased grey matter in participants with delusions were detected. Prominent grey matter decrease was observed in the right precentral gyrus, right inferior frontal gyrus, right insula, and left middle occipital gyrus, areas that may be involved in control of thought and emotions. CONCLUSION: Greater right fronto-temporal grey matter atrophy was observed in MCI or early AD participants with delusions compared to matched patients without delusions. Consistent with our predictions, asymmetric grey matter atrophy in the right hemisphere may contribute to development of delusions through loss of executive inhibition.

Verbal fluency component analysis in adults with HIV/AIDS.

The present study examined the impact of HIV disease severity, depressed mood, and highly-active antiretroviral therapy (HAART) on verbal fluency components in a sample of adults with HIV-infection. Switching and clustering have been identified as dissociable components that contribute to performance on tests of phonemic and semantic verbal fluency. Advanced HIV-infection was predicted to differentially impair switching. Switching has been shown to be reduced in disorders affecting frontal-striatal systems (e.g., Parkinson's disease). Verbal fluency protocols (FAS and Animals) of 217 adults with HIV-infection were scored for total switches and average cluster size following the method of Troyer, et al. (1998). Component scores were compared to published norms. Analysis of variance (ANOVA) was used to examine the impact on switching and clustering performance of (1) HIV disease severity (presence of AIDS diagnosis) and depressed mood, and (2) AIDS diagnosis and medication status (current HAART therapy). FAS switching was more often impaired in participants with AIDS. Depressed mood did not affect switching. Neither AIDS diagnosis nor depressed mood was associated with clustering performance. Participants with an AIDS diagnosis who were receiving HAART showed better performance on FAS switching relative to participants with AIDS who were not taking antiretroviral medication. FAS switching appears to be sensitive to cognitive changes associated with advanced HIV-infection. Further research is needed to determine if switching is a specific marker of frontal-striatal dysfunction in this population.

Fatigue in HIV/AIDS is associated with depression and subjective neurocognitive complaints but not neuropsychological functioning.

Fatigue and depressive symptoms are common in HIV-infection. The relationship between these symptoms and neuropsychological functioning is poorly understood, particularly in symptomatic infection/AIDS. This study examined the associations among fatigue, depressive symptoms, subjective neurocognitive complaints, and objective neuropsychological performance in HIV/AIDS. Sixty-eight men with HIV-infection (27 adults with HIV-infection but not AIDS and 41 with AIDS diagnosis) completed a neuropsychological test battery and self-report measures of fatigue (Fatigue Severity Scale), depressive symptoms (Beck Depression Inventory), and subjective neurocognitive complaints (Patient's Assessment of Own Functioning). High levels of fatigue were endorsed by participants. Fatigue severity was related to depressive symptoms but not to AIDS diagnosis or medication status. Verbal learning and motor function was worse in participants with AIDS, but neuropsychological functioning was not significantly correlated with fatigue or depressive symptoms. Subjective neurocognitive complaints were predicted by both depressive symptoms and fatigue. Our results suggest that adults with fatigue and HIV-infection (with or without AIDS) should be screened for depression. Neither fatigue nor depressive symptoms appear to affect neuropsychological functioning in HIV/AIDS. Future research is needed to develop and evaluate instruments and methods to differentiate depression-related fatigue from fatigue that may reflect underlying medical disease. Such research will further the development of effective treatments for fatigue associated with HIV-infection.