Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians.

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

Delusions in Alzheimer Disease are Associated With Decreased Default Mode Network Functional Connectivity.

OBJECTIVE: Approximately one-third of patients with Alzheimer disease (AD) develop delusions. Delusions have been linked to numerous adverse outcomes, including worsened cognitive and functional decline, increased caregiver burden, and higher mortality rates. Previous studies have indicated that both AD and neuropsychiatric symptoms within AD are associated with abnormal functional connectivity of the resting brain, but no studies have focused on how delusions alter resting-state functional connectivity. The authors' objective was to test for differences in resting brain function between delusional and non-delusional patients with AD. The authors hypothesized that patients with AD with delusions would exhibit reduced connectivity of the default mode network (DMN) compared with patients with AD without delusions. METHODS: Resting-state functional magnetic resonance imaging was used to investigate differences in functional connectivity between 15 patients with AD with delusions and 15 comparable patients with AD without delusions. A group-level principal component analysis was used to identify functional networks accounting for greatest variability over all subjects, and the DMN was selected for between-group analysis. Dual regression was used to reconstruct individual subject component maps, and a two-sample t test was used to compare groups with and without delusion, adjusted at a false discovery rate of 0.05. RESULTS: The two cohorts were comparable demographically and cognitively. The patients with delusions showed significantly reduced connectivity of the left inferior parietal lobule (IPL) with the rest of the DMN. CONCLUSION: Delusions in AD are associated with reduced connectivity within the DMN, specifically the left IPL. The authors' findings provide insight into the underlying neuropathophysiology of delusions in AD.

Gray Matter Changes Associated With the Development of Delusions in Alzheimer Disease.

OBJECTIVE: Delusions affect approximately a third of Alzheimer disease (AD) patients and are associated with poor outcomes. Previous studies investigating the neuroanatomic correlates of delusions have yet to reach a consensus, with findings of reduced volume across all lobes, particularly in frontal regions. The current study examined the gray matter (GM) differences associated with delusions in AD. METHODS: Using voxel-based morphometry, we assessed GM in 23 AD patients who developed delusions (AD+D) and 36 comparable AD patients who did not (AD-D) at baseline and follow-up. Analysis of variance was used to identify consistent differences between AD+D and AD-D patients across time points (main effect of group), consistent changes from baseline to follow-up (main effect of time), and differential changes between AD+D and AD-D over time (interaction of group and time). All data were obtained from the National Alzheimer's Coordinating Center database. RESULTS: The AD+D group had consistently lower frontal GM volume, although both groups showed decreased GM in frontotemporal brain regions over time. An interaction was observed between delusions and longitudinal change, with AD+D patients having significantly elevated GM in predominantly temporal areas at baseline assessment, becoming significantly lower than the AD-D group at follow-up. CONCLUSION: These findings suggest that, there are specific volumetric markers that distinguish patients with delusions from those without, before, and after the onset of delusions. Specifically, the decline of GM in temporal areas that had elevated levels prior to the onset of delusions may be involved in the manifestation of delusions.

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.

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.

Anti N-methyl-D-aspartate receptor encephalitis: a game-changer?

INTRODUCTION: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an inflammatory disorder of the brain that has garnered significant interest within the medical and lay communities. There is a need for formal guidelines to assist physicians in identifying patients who should undergo testing for NMDAR encephalitis, recognizing the high potential for this potentially treatable disease to mimic more common disorders, and consequently remain undiagnosed. AREAS COVERED: This review highlights the impact of the discovery of NMDAR encephalitis on the fields of neurology and psychiatry, and discusses the steps that are necessary to improve recognition and treatment of NMDAR encephalitis. Expert commentary: While much progress has been made in our understanding of NMDAR encephalitis, much work remains to be done to delineate the underlying disease mechanisms and their relevance to brain function.

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.

The VASOGRADE: A Simple Grading Scale for Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Patients are classically at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. We validated a grading scale-the VASOGRADE-for prediction of DCI. METHODS: We used data of 3 phase II randomized clinical trials and a single hospital series to assess the relationship between the VASOGRADE and DCI. The VASOGRADE derived from previously published risk charts and consists of 3 categories: VASOGRADE-Green (modified Fisher scale 1 or 2 and World Federation of Neurosurgical Societies scale [WFNS] 1 or 2); VASOGRADE-Yellow (modified Fisher 3 or 4 and WFNS 1-3); and VASOGRADE-Red (WFNS 4 or 5, irrespective of modified Fisher grade). The relation between the VASOGRADE and DCI was assessed by logistic regression models. The predictive accuracy of the VASOGRADE was assessed by receiver operating characteristics curve and calibration plots. RESULTS: In a cohort of 746 patients, the VASOGRADE significantly predicted DCI (P<0.001). The VASOGRADE-Yellow had a tendency for increased risk for DCI (odds ratio [OR], 1.31; 95% CI, 0.77-2.23) when compared with VASOGRADE-Green; those with VASOGRADE-Red had a 3-fold higher risk of DCI (OR, 3.19; 95% CI, 2.07-4.50). Studies were not a significant confounding factor between the VASOGRADE and DCI. The VASOGRADE had an adequate discrimination for prediction of DCI (area under the receiver operating characteristics curve=0.63) and good calibration. CONCLUSIONS: The VASOGRADE results validated previously published risk charts in a large and diverse sample of subarachnoid hemorrhage patients, which allows DCI risk stratification on presentation after subarachnoid hemorrhage. It could help to select patients at high risk of DCI, as well as standardize treatment protocols and research studies.

Effect of aneurysmal subarachnoid hemorrhage on word generation.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) survivors commonly exhibit impairment on phonemic and semantic fluency tests; however, it is unclear which of the contributing cognitive processes are compromised in aSAH patients. One method of disentangling these processes is to compare initial word production, which is a rapid, semiautomatic, frontal-executive process, and late phase word production, which is dependent on more effortful retrieval and lexical size and requires a more distributed neural network. METHODS: Seventy-two individuals with aSAH and twenty-five control subjects were tested on a cognitive battery including the phonemic and semantic fluency task. Demographic and clinical information was also collected. RESULTS: Compared to control subjects, patients with aSAH were treated by clipping and those with multiple aneurysms were impaired across the duration of the phonemic test. Among patients treated by coiling, those with anterior communicating artery aneurysms or a neurological complication (intraventricular hemorrhage, vasospasm, and edema) showed worse output only in the last 45 seconds of the phonemic test. Patients performed comparably to control subjects on the semantic test. CONCLUSIONS: These results support a "diffuse damage" hypothesis of aSAH, indicated by late phase phonemic fluency impairment. Overall, the phonemic and semantic tests represent a viable, rapid clinical screening tool in the postoperative assessment of patients with aSAH.

Impact of socioeconomic status on initial clinical presentation to a memory disorders clinic.

BACKGROUND: Dementia affects 15% of Canadians 65 and older, and the prevalence is expected to double over the next two decades. Low socioeconomic status (SES) can increase the risk of Alzheimer's disease (AD) and the precursor mild cognitive impairment (MCI), but it is unknown what the relationship of SES is on initial clinical presentation to a memory disorders clinic. METHODS: Data from 127 AD and 135 MCI patients who presented to our Memory Disorders Clinic from 2004 to 2013 were analyzed retrospectively. We examined the relationship between SES (measured using Hollingshead two-factor index) and (1) diagnosis of either AD or MCI; (2) age when first presented to clinic; (3) objective cognitive tests to indicate clinical severity; and (4) the use of cognitive enhancers, medication for treating mild-to-moderate AD patients. RESULTS: AD patients had lower SES than MCI patients (p < 0.001, r = 0.232). Lower SES was associated with a greater age at initial time of diagnosis (χ2 = 11.5, p = 0.001). In MCI patients, higher SES individuals outperformed lower SES individuals on the BNA after correcting for the effect of age (p = 0.004). Lower SES was also associated with decreased use of cognitive enhancers in AD patients (p < 0.001, r = 0.842). CONCLUSION: Individuals with lower SES come into memory clinic later when the disease has progressed to dementia, while higher SES individuals present earlier when the disease is still in its MCI stage. There were more higher SES individuals who presented to our memory clinic. Higher SES is associated with better cognitive functioning and increased use of cognitive enhancers. The health policy implication is that we need to better engage economically disadvantaged individuals, perhaps at the primary care level.

CD86 gene variants and susceptibility to pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. CD86 (B7-2) is a costimulatory molecule on antigen-presenting cells and plays critical roles in tumor immunity. It has been reported that polymorphisms in CD86 gene can be involved in the development of various cancers. Here, we investigated the association of two CD86 polymorphisms, +1057G/A (rs1129055) and +2379G/C (rs17281995), with pancreatic cancer in the Chinese population. METHODS: The two polymorphisms were identified in 369 pancreatic cancer patients and 412 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data were analyzed by chi-square test and adjusted for body mass index, smoking, drinking, and diabetes status. RESULTS: Results showed that the frequency of the +1057A allele was significantly higher in pancreatic cancer cases than in controls (59.8 vs. 52.8 %, p = 0.021). Comparison of genotype frequencies showed that +1057GA and +1057AA genotypes were significantly increased in the pancreatic cancer group (odds ratio (OR) = 1.52; 95 % confidence interval (CI), 1.09-2.38; p = 0.026; and OR = 1.90; 95 % CI, 1.21-3.01; p = 0.007). We did not find any association between the +2379G/C polymorphism and pancreatic cancer. Analysis of haplotypes indicated that the AG (+1057, +2379) haplotype was correlated with the susceptibility to this disease (p = 0.019). CONCLUSIONS: These results suggest that the CD86 +1057G/A polymorphism and AG (+1057, +2379) haplotype are genetic risk factors for pancreatic cancer.