Mild behavioral impairment: measurement and clinical correlates of a novel marker of preclinical Alzheimer’s disease

Abstract Background Late-life onset neuropsychiatric symptoms are established risk factors for dementia. The mild behavioral impairment (MBI) diagnostic framework was designed to standardize assessment to determine dementia risk better. In this Mini Review, we summarize the emerging clinical and biomarker evidence, which suggests that for some, MBI is a marker of preclinical Alzheimer’s disease. Main MBI is generally more common in those with greater cognitive impairment. In community and clinical samples, frequency is around 10–15%. Mounting evidence in cognitively normal samples links MBI symptoms with known AD biomarkers for amyloid, tau, and neurodegeneration, as well as AD risk genes. Clinical studies have found detectable differences in cognition associated with MBI in cognitively unimpaired people. Conclusion The emerging evidence from biomarker and clinical studies suggests MBI can be an early manifestation of underlying neurodegenerative disease. Future research must now further validate MBI to improve identification of those at the very earliest stages of disease.

Download Full-text

Frontal Behavior Syndromes in Idiopathic Normal Pressure Hydrocephalus as a Function of Alzheimer’s Disease Biomarker Status

Journal of the International Neuropsychological Society ◽

10.1017/s1355617720000387 ◽

2020 ◽

Vol 26 (9) ◽

pp. 883-893

Author(s):

Madison Niermeyer ◽

Chad Gaudet ◽

Paul Malloy ◽

Irene Piryatinsky ◽

Stephen Salloway ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Normal Pressure Hydrocephalus ◽

Neuropsychiatric Symptoms ◽

Executive Dysfunction ◽

Normal Pressure ◽

Idiopathic Normal Pressure Hydrocephalus ◽

Future Research ◽

Positron Emission ◽

Neuropsychiatric Manifestations

AbstractObjectives:Cognitive impairment and apathy are well-documented features of idiopathic normal pressure hydrocephalus (iNPH). However, research examining other neuropsychiatric manifestations of iNPH is scant, and it is unknown whether the neuropsychiatric presentation differs for iNPH patients with comorbid Alzheimer’s disease (AD) versus iNPH without AD. This study aims to advance our understanding of neuropsychiatric syndromes associated with iNPH.Methods:Fifty patients from Butler Hospital’s Normal Pressure Hydrocephalus Clinic met inclusion criteria. Caregiver ratings on the Frontal Systems Behavior Scale (FrSBe) were examined to appraise changes in apathy, executive dysfunction, and disinhibition. Patients also completed cognitive tests of global cognition, psychomotor speed, and executive functioning. AD biomarker status was determined by either amyloid-beta (Aβ) positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) total tau to Aβ-42 ratio.Results:Results revealed clinically significant elevations on the FrSBe’s apathy and executive dysfunction scales and modest correlations among these scales and cognitive measures. Of the 44 patients with available neuroimaging or CSF draw data, 14 presented with comorbid AD. Relative to the iNPH-only group, the iNPH + AD group showed a larger increase from pre-illness to current informant ratings on the executive dysfunction scale, but not the apathy or disinhibition scales.Conclusions:These results replicate and extend prior research by identifying apathy and executive dysfunction as prominent neuropsychiatric symptoms of iNPH and suggest comorbid AD exacerbates dysexecutive behaviors. Future research is warranted to examine the effects of comorbid AD pathology in response to shunt surgery for iNPH, neuropsychiatric symptom changes, and resultant caregiver burden.

Download Full-text

Affective Neuropsychiatric Symptoms as Early Signs of Dementia Risk in Older Adults

Journal of Alzheimer s Disease ◽

10.3233/jad-200190 ◽

2020 ◽

Vol 77 (3) ◽

pp. 1195-1207

Author(s):

Jung Yun Jang ◽

Jean K. Ho ◽

Anna E. Blanken ◽

Shubir Dutt ◽

Daniel A. Nation ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Latent Class ◽

Neuropsychiatric Symptoms ◽

Community Dwelling ◽

Dementia Risk ◽

Increased Risk ◽

Risk Of Progression

Background: Affective neuropsychiatric symptoms (aNPS: depression, anxiety, apathy, irritability) have been linked to increased dementia risk. However, less is known whether this association is independent of Alzheimer’s disease (AD) pathophysiology. Objective: To investigate the contribution of early aNPS to dementia risk in cognitively normal (CN) older adults and mild cognitive impairment (MCI) patients, with and without AD biomarker abnormality. Methods: Participants included 763 community-dwelling, stroke-free older adults identified as CN and 617 with MCI at baseline, drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Baseline assessments included a neuropsychological battery, the Neuropsychiatric Inventory (NPI), and apolipoprotein E ɛ4 (ApoE4) genotyping. A participant subset completed cerebrospinal fluid (CSF) AD biomarker assessment. Time to progression to dementia was measured based on months at follow-up when an individual was diagnosed with dementia, over the follow-up period of 48 months. Results: Latent class analysis identified 3 subgroups of older adults in CN and MCI, indicated by the baseline profiles of neuropsychiatric symptoms (NPS). Subgroups with higher aNPS were at increased risk of progression to dementia in both CN (HR = 3.65, 95% CI [1.80, 7.40]) and MCI (HR = 1.52, 95% CI [1.16, 2.00]; HR = 1.86 [1.05, 3.30]) groups, adjusting for age, sex, global cognition, and ApoE4, compared with their counterparts with minimal NPS. There was no difference between higher aNPS and minimal NPS subgroups in their CSF AD biomarker profiles. Conclusion: Findings suggest that aNPS may represent a neurobiological vulnerability that uniquely contribute to the dementia risk, independent of AD biomarker profiles.

Download Full-text

A-1 Neuropsychiatric Symptoms over Time in Autopsy-Confirmed Alzheimer’s Disease, Lewy Body Disease, and Mixed Pathology

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab062.02 ◽

2021 ◽

Vol 36 (6) ◽

pp. 1022-1022

Author(s):

Jeff Schaffert ◽

Will Goette ◽

Anne Carlew ◽

Allison Parker ◽

Saranya Patel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lewy Body ◽

Neuropsychiatric Symptoms ◽

Depression Scale ◽

Lewy Body Disease ◽

Cognitive Status ◽

Future Research ◽

Final Visit ◽

Over Time

Abstract Objective Neuropsychiatric symptoms (NPS) are common in neurodegenerative disease, but longitudinal studies using large autopsy-confirmed samples are lacking. Our primary aim was to investigate progression of NPS over time in autopsy-confirmed Alzheimer’s disease (ad), Lewy body disease (LBD), and mixed (ad+LBD) cohorts. Methods Data on individuals (age > =50) with autopsy-confirmed ad (N = 1568), ad+LBD (N = 349), and LBD (N = 142) was obtained from the National Alzheimer’s Coordinating Center (Mean visits = 2.61). Neuropsychiatric Inventory Questionnaire (NPI-Q) and 15-item Geriatric Depression Scale (GDS) scores were used to measure NPS. Multilevel zero-inflated binomial regression models were used to assess if NPI-Q and GDS scores differed among ad, ad+LBD, and LBD groups over time. Covariates included: years from baseline to final visit, cognitive status at baseline (i.e., normal, MCI, or dementia), demographic characteristics, MMSE, Functional Activities Questionnaire, and psychotropic treatment of psychiatric conditions. Results Higher NPI-Q and GDS scores were observed at baseline in the LBD group compared to ad (p’s < 0.001). NPI-Q scores increased over time in the LBD group compared to ad+LBD and ad groups (90% CI). GDS scores differed among all groups at baseline (95% CI), with more rapid increase in the LBD group vs. ad and ad+LBD groups. Conclusions Overall, the course of NPS differs among disease pathologies. Those with pure LBD appear to have more severe NPS over time compared to those with ad and ad+LBD. Depressive symptoms increased more in LBD and ad+LBD compared to ad over time. Future research examining clinical outcomes related to NPS burden (care needs, caregiver burden, and life expectancy) is needed.

Download Full-text

401 - The Costs of Agitation: A Literature Review

International Psychogeriatrics ◽

10.1017/s1041610220002549 ◽

2020 ◽

Vol 32 (S1) ◽

pp. 117-117

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Literature Review ◽

Service Use ◽

Neuropsychiatric Symptoms ◽

Unmet Need ◽

Cochrane Library ◽

Future Research ◽

The Cost ◽

The Impact

PRESENTING AUTHOR:Mary Michael, Vice President, Patient Advocacy and Stakeholder Management, Otsuka America Pharmaceutical, Inc.OBJECTIVE:To evaluate the extent to which the cost of both treated and untreated agitation in Alzheimer’s disease has been studied in order to inform future research and development of predictive models of the cost of untreated agitation in Alzheimer’s disease.BACKGROUND:There is inadequate understanding of the costs of agitation in Alzheimer’s disease in the scientific and academic literature. Agitation in Alzheimer’s disease contributes to negative social and financial outcomes for people with the condition, their care partners, and health systems. When left untreated, the impact of these outcomes is exacerbated, yet the scale of this impact is unknown. This gap in the literature both reflects and perpetuates the broader under-recognition of agitation as a serious unmet need in the Alzheimer’s community. Conversely, a better understanding of the costs can help elevate agitation within the global Alzheimer’s dialogue.METHODS:We used MEDLINE, PubMed, PsychINFO the Cochrane Library and Google Scholar databases to identify relevant articles published between 2000 until May 2020. We also reviewed reliable literature published outside of these databases. Keywords utilized in the search include agitation in Alzheimer’s, neuropsychiatric symptoms of Alzheimer’s, cost of informal and formal care, Medicare and Medicaid costs, economic costs associated to delirium, among others. Only articles in English were included. Inclusion and exclusion criteria were determined by study design, data source and population studied, number of cases included in analysis, source of health service use or cost data, statistical methods and agitation in Alzheimer’s attributable and/or incremental costs.RESULTS:Results will describe the breadth and depth to which costs of treated and untreated agitation in Alzheimer’s have been examined, indicating data and statistical methodology used.CONCLUSIONS:This literature review serves as the basis for understanding global costs of agitation in Alzheimer’s disease. From our analysis, we recommend that further cost modeling activities be conducted. We also urge the greater community to use these findings to elevate agitation to the top of the Alzheimer’s agenda.

Download Full-text

Behavioral and Psychological Symptoms in Alzheimer’s Disease

BioMed Research International ◽

10.1155/2014/927804 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 28

Author(s):

Xiao-Ling Li ◽

Nan Hu ◽

Meng-Shan Tan ◽

Jin-Tai Yu ◽

Lan Tan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Psychiatric Symptoms ◽

Psychological Symptoms ◽

Neuropsychiatric Symptoms ◽

Treatment Success ◽

Future Research ◽

Brain Changes ◽

Specific Symptoms

Neuropsychiatric symptoms (NPS) such as depression, apathy, aggression, and psychosis are now recognized as core features of Alzheimer’s disease (AD), and there is a general consensus that greater symptom severity is predictive of faster cognitive decline, loss of independence, and even shorter survival. Whether these symptoms result from the same pathogenic processes responsible for cognitive decline or have unique etiologies independent of AD-associated neurodegeneration is unclear. Many structural and metabolic features of the AD brain are associated with individual neuropsychiatric symptoms or symptom clusters. In addition, many genes have been identified and confirmed that are associated with symptom risk in a few cases. However, there are no single genes strongly predictive of individual neuropsychiatric syndromes, while functional and structural brain changes unique to specific symptoms may reflect variability in progression of the same pathological processes. Unfortunately, treatment success for these psychiatric symptoms may be lower when comorbid with AD, underscoring the importance of future research on their pathobiology and treatment. This review summarizes some of the most salient aspects of NPS pathogenesis.

Download Full-text

Provisional research criteria for the behavioral variant of Alzheimer’s disease A systematic review and meta-analysis

10.1101/2021.09.08.21263253 ◽

2021 ◽

Author(s):

R. Ossenkoppele ◽

E.H. Singleton ◽

C. Groot ◽

Anke A. Dijkstra ◽

Willem S. Eikelboom ◽

...

Keyword(s):

Systematic Review ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Meta Analysis ◽

Neuropsychiatric Symptoms ◽

Behavioral Symptoms ◽

Future Research ◽

Clinical Criteria ◽

Meta Analyses ◽

Research Criteria

ABSTRACTImportanceThe behavioral variant of Alzheimer’s disease (bvAD) is characterized by early and predominant behavioral deficits caused by AD pathology. This AD phenotype is insufficiently understood and lacks standardized clinical criteria, limiting reliability and reproducibility of diagnosis and scientific reporting.ObjectiveTo perform a systematic review and meta-analysis of the bvAD literature, and use the outcomes to propose provisional research criteria for this syndrome.Data sourcesA systematic literature search in PubMed/Medline and Web-of-Science databases (from inception through April 7th, 2021, performed in duplicate) led to the assessment of 83 studies, including 13 suitable for meta-analysis.Study selectionStudies reporting on behavioral, neuropsychological or neuroimaging features in bvAD, and, when available, providing comparisons with “typical” amnestic-predominant AD (tAD) or behavorial variant frontotemporal dementia (bvFTD).Data extraction and synthesisWe performed random-effects meta-analyses on group-level study results of clinical data, and systematically reviewed the neuroimaging literature.Main outcome and measuresBehavioral symptoms (neuropsychiatric symptoms and bvFTD core clinical criteria), cognitive function (global cognition, episodic memory and executive functioning) and neuroimaging features (structural MRI, [18F]FDG-PET, perfusion SPECT, amyloid-PET and tau-PET).ResultsData were collected for 591 patients with bvAD. There was moderate-to-substantial heterogeneity and moderate risk of bias across studies. bvAD showed more severe behavioral symptoms compared to tAD (standardized mean difference [SMD, 95% confidence interval]: 1.16[0.74–1.59], p<0.001), and a trend towards less severe behavioral symptoms compared to bvFTD (SMD:-0.22[-0.47–0.04], p=0.10). Meta-analyses of cognitive data indicated worse executive performance in bvAD versus tAD (SMD:-1.03[-1.74–-0.32], p<0.01), but not compared to bvFTD (SMD:-0.61[-1.75–0.53], p=0.29). bvAD showed a trend towards worse memory performance compared to bvFTD (SMD:-1.31[-2.75–0.14], p=0.08), but did not differ from tAD (SMD:0.43[-0.46–1.33], p=0.34). The neuroimaging literature revealed two distinct bvAD neuroimaging-phenotypes: an “AD-like” posterior-predominant pattern and a “bvFTD-like” anterior-predominant pattern, with the former being more prevalent.Conclusions and relevanceOur data indicate that bvAD is clinically most similar to bvFTD, while it shares most pathophysiological features with tAD. Based on these insights, we propose provisional research criteria for bvAD aimed at improving the consistency and reliability of future research and aiding the clinical assessment of this AD phenotype.KEY POINTSQuestionHow does the behavioral variant of Alzheimer’s disease (bvAD) relate to typical AD (tAD) and to behavioral variant frontotemporal dementia (bvFTD) in terms of clinical presentation and neuroimaging signatures?FindingsIn this systematic review and meta-analysis, we found that, at time of diagnosis, bvAD showed more severe neuropsychiatric symptoms and other behavioral deficits compared to tAD. Two distinct neuroimaging phenotypes were observed across reported bvAD cases: an “AD-like” posterior-predominant pattern and a “bvFTD-like” anterior-predominant pattern, with the posterior-predominant neuroimaging phenotype being the most prevalent across reported bvAD cases.MeaningbvAD is clinically most reminiscent of bvFTD, while it shares most pathophysiological features with tAD. The provisional research criteria are aimed at improving the consistency and reliability of future research, and potentially aid in the clinical assessment of bvAD.

Download Full-text