The Association Between Biomarkers and Neuropsychiatric Symptoms Across the Alzheimer's Disease Spectrum

ObjectiveTo investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms.MethodsData from two large cohort studies, the Dutch Parelsnoer Institute – Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aβ₄₂, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses.ResultsAlzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aβ₄₂, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aβ₄₂ and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning.ConclusionThe association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning.     

以精神行为异常为主要症状的非痴呆型血管性认知障碍临床研究

目的 分析以精神行为异常为主要症状的非痴呆型血管认知障碍（vascular cognitive impairment no
dementia,VCIND）的精神行为特点和认知功能特征。
方法 本研究为横断面研究,收集2011年6月～2013年12月广州市脑科医院以精神行为异常为主要
症状就诊的VCIND18例、伴有精神行为异常的血管性痴呆（vascular dementia,VaD）16例和无认知功能
障碍（no cognitive impairment,NCI）18例作为对照组。采用神经精神科问卷（Neuropsychiatric Inventory,
NPI）和简易精神状态检查量表（Mini-Mental State Examination,MMSE）及蒙特利尔认知评估量表
（Montreal Cognitive Assessment,MoCA）分别评定精神行为和认知状态,并比较各组间精神行为及认
知状态的差异。
结果 VCIND组最多见的精神行为异常表现为易激惹/情绪不稳（66.7%）,睡眠障碍（61.1%）,其
次为激越/攻击行为（55.6%）,幻觉/妄想（44.4%）。VaD组焦虑/抑郁症状与VCIND组相比较多见,差
异具有显著性（75% vs 16.7%;P =0.001）。VCIND组各认知评分介于VaD组和NCI组之间,与NCI组
相比,在视空间/执行能力（2.78±0.73 vs 4.50±0.51）、注意（4.61±0.61 vs 5.33±0.48）、语言
（2.11±0.47 vs 2.67±0.49）、抽象［1（0,1）vs 2（1,2）］、延迟记忆［2（2,3）vs 4（4,4）］方面差异
均具有显著性（P <0.001）。
结论 VCIND可以以精神行为异常为主要表现,尤其是急起的易激惹/情绪不稳、睡眠障碍及激越/
攻击行为。     

Association of Hearing Loss With Neuropsychiatric Symptoms in Older Adults With Cognitive Impairment

Neuropsychiatric symptoms (NPS) in persons with dementia (PWD) are common and can lead to poor outcomes, such as institutionalization and mortality, and may be exacerbated by sensory loss. Hearing loss is also highly prevalent among older adults, including PWD.ObjectiveThis study investigated the association between hearing loss and NPS among community- dwelling patients from a tertiary memory care center.Design, Setting, and ParticipantsParticipants of this cross-sectional study were patients followed at the Johns Hopkins Memory and Alzheimer's Treatment Center who underwent audiometric testing during routine clinical practice between October 2014 and January 2017.Outcome MeasurementsIncluded measures were scores on the Neuropsychiatric Inventory–Questionnaire and the Cornell Scale for Depression in Dementia.ResultsParticipants (n = 101) were on average 76 years old, mostly female and white, and had a mean Mini-Mental State Examination score of 23. We observed a positive association between audiometric hearing loss and the number of NPS (b = 0.7 per 10 dB; 95% confidence interval [CI]: 0.2, 1.1; t = 2.86; p = 0.01; df = 85), NPS severity (b = 1.3 per 10 dB; 95% CI: 0.4, 2.5; t = 2.13; p = 0.04; df = 80), and depressive symptom severity (b = 1.5 per 10 dB; 95% CI: 0.4, 2.5; t = 2.83; p = 0.01; df = 89) after adjustment for demographic and clinical characteristics. Additionally, the use of hearing aids was inversely associated with the number of NPS (b = ?2.09; 95% CI ?3.44, ?0.75; t = ?3.10; p = 0.003; df = 85), NPS severity (b = ?3.82; 95% CI ?7.19, ?0.45; t = ?2.26; p = 0.03; df = 80), and depressive symptom severity (b = ?2.94; 95% CI: ?5.93, 0.06; t = 1.70; p = 0.05; df = 89).ConclusionAmong patients at a memory clinic, increasing severity of hearing loss was associated with a greater number of NPS, more severe NPS, and more severe depressive symptoms, while hearing aid use was associated with fewer NPS, lower severity, and less severe depressive symptoms. Identifying and addressing hearing loss may be a promising, low-risk, non-pharmacological intervention in preventing and treating NPS.     

The Independent Contributions of Cognitive Impairment and Neuropsychiatric Symptoms to Everyday Function in Older Adults

The everyday functional capacities of older adults are determined by multiple factors. The primary goal of the present study was to evaluate whether apathy and depression have unique influences on degree of functional impairment, independent of the effects of specific cognitive impairments. Participants included 344 older adults (199 normal, 87 with MCI, 58 with dementia). The Everyday Cognition (ECog) scales were used to measure both global and domain-specific functional abilities. Neuropsychiatric symptoms of depression and apathy were measured by the Neuropsychiatric Inventory (NPI), and specific neuropsychological domains measured included episodic memory and executive functioning. Results indicated that worse memory and executive function, as well as greater depression and apathy, were all independent and additive determinants of poorer functional abilities. Apathy had a slightly more restricted effect than the other variables across the specific functional domains assessed. Secondary analysis suggested that neuropsychiatric symptoms may be more strongly associated with everyday function within cognitively normal and MCI groups, while cognitive impairment is more strongly associated with everyday function in dementia. Thus, a somewhat different set of factors may be associated with functional status across various clinical groups.     

Neuropsychiatric Symptoms as Predictor of Poor Clinical Outcome in Patients With Vascular Cognitive Impairment

ObjectiveExamine the association between neuropsychiatric symptoms (NPS) and clinical outcome in memory clinic patients with vascular brain injury.Design/SettingTRACE-VCI prospective memory clinic cohort with follow-up (2.1 ± 0.5 years).ParticipantsFive hundred and seventy-five memory clinic patients with vascular brain injury on MRI (i.e. possible Vascular Cognitive Impairment [VCI]). Severity of cognitive impairment ranged from no objective cognitive impairment to mild cognitive impairment (MCI) and dementia.MeasurementsWe used Neuropsychiatric Inventory (total score and score on hyperactive, psychotic, affective, and apathetic behavior domains) to measure NPS. We assessed the association between NPS and institutionalization, mortality and cognitive deterioration (increase ≥0.5 on Clinical Dementia Rating scale) with Cox proportional hazards models and logistic regression analyses.ResultsNPS were present in 89% of all patients, most commonly in the hyperactive and apathetic behavior domain. Across the whole cohort, affective behavior was associated with institutionalization (HR: 1.98 [1.01-3.87]), mainly driven by the dementia subgroup (HR: 2.06 [1.00–4.21]). Apathetic behavior was associated with mortality and cognitive deterioration (HR: 2.07 [1.10–3.90],OR: 1.67 [1.12–2.49], respectively), mainly driven by the MCI subgroup (HR: 4.93 [1.07–22.86],OR: 3.25 [1.46–7.24], respectively). Conversely, hyperactive behavior was related to lower mortality (HR: 0.54 [0.29–0.98]), again particularly driven by the MCI subgroup (HR:0.17 [0.04–0.75]). Psychotic behavior was associated with cognitive deterioration in patients with no objective cognitive impairment (OR: 3.10 [1.09–8.80]) and with institutionalization in MCI (HR: 12.45 [1.28–121.14]).ConclusionNPS are common and have prognostic value in memory clinic patients with possible VCI. This prognostic value depends on the severity of cognitive impairment.     

Role of Donepezil in the Management of Neuropsychiatric Symptoms in Alzheimer's Disease and Dementia with Lewy Bodies

Alzheimer's disease (AD) is a progressive condition that affects cognition, function, and behavior. Approximately 60–90% of patients with AD develop neuropsychiatric symptoms (NPS) such as hallucinations, delusions, agitation/aggression, dysphoria/depression, anxiety, irritability, disinhibition, euphoria, apathy, aberrant motor behavior, sleep disturbances, appetite and eating changes, or altered sexual behavior. These noncognitive behavior changes are thought to result from anatomical and biochemical changes within the brain, and have been linked, in part, to cholinergic deficiency. Cholinesterase inhibitors may reduce the emergence of NPS and have a role in their treatment. These agents may delay initiation of, or reduce the need for, other drugs such as antipsychotics. This article summarizes the effects of donepezil, a cholinesterase inhibitor, on the NPS of dementia with emphasis on AD and dementia with Lewy bodies.     

Poststroke Neuropsychiatric Symptoms and Pseudoseizures: A Discussion

LESSONS LEARNED AT THE INTERFACE OF MEDICINE AND PSYCHIATRY: The Psychiatric Consultation Service at Massachusetts General Hospital (MGH) sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. Such consultations require the integration of medical and psychiatric knowledge. During their thrice-weekly rounds, Dr. Huffman and Dr. Stern discuss the diagnosis and management of conditions confronted. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.     

An Exploration of Subgroups of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Their Risks of Conversion to Dementia or Death

ObjectiveTo explore the heterogeneity of neuropsychiatric symptom (NPS) complexes in individuals with mild cognitive impairment (MCI) and assess the relative risks of converting to dementia or dying.DesignLatent class analysis using 7,971 participants with MCI.SettingParticipants in the Uniform Data Set (UDS) from 39 NIH Alzheimer's Disease Centers.ParticipantsPersons with a diagnosis of MCI at initial visit from each center and with either a Mini-Mental State Examination (MMSE) score of 22 or greater or an equivalent education-adjusted Montreal Cognitive Assessment (MoCA) score of 16 or greater.MeasurementsNeuropsychiatric Inventory Questionnaire (NPI-Q) administered at initial visit.ResultsIn addition to a subgroup with mild or no NPS (relative frequency, 50%), three empirically-based subgroups of NPS were identified: 1) an “affect” or “negative mood” subgroup (27%) with depression, anxiety, apathy, nighttime disturbance, and change in appetite; 2) a “hyperactive” subgroup (14%) with agitation, irritability, and disinhibition; and 3) a “psychotic with additional severe NPS” subgroup (9%) with the highest risk of delusions and hallucinations, as well as highest risk of all other NPS. Each of these three subgroups had significantly higher risk of converting to dementia than the “mild NPS” class, with the “psychotic with additional severe NPS” subgroup possessing a 64% greater risk. The subgroups did not differ in their risks of death without dementia.ConclusionOur findings of three NPS subgroups in MCI characterized by affect, hyperactive, or psychotic features are largely consistent with a previous 3-factor model of NPS found in a demented population. The consistency of these findings across studies and samples, coupled with our results on the associated risks of converting to dementia, suggests that the NPS structure is robust, and warrants further consideration in classification models of MCI.     

Differences in Assessment of Everyday Preferences Between People With Cognitive Impairment and Their Care Partners: The Role of Neuropsychiatric Symptoms

ObjectiveAs cognitive impairment progresses, people with dementia increasingly rely on surrogate decision-makers for everyday activities. Yet, little is known about concordance on everyday preferences between persons with cognitive impairment and their care partners.MethodsThe sample included 69 dyads of persons with cognitive impairment (Clinical Dementia Rating Scale ≥0.5) and their care partners. We used the Preferences for Everyday Living Inventory (PELI) to assess preferences for activities and lifestyle choices among persons with cognitive impairment. The PELI was concurrently but separately administered to care partners, who answered as surrogate decision-makers. Factor analysis was used to ascertain factor structure of the PELI; reliability measures were computed within the sample. Paired sample t-tests were used to estimate differences in scores of corresponding PELI items for each factor. Multiple regression models were used to relate predictors, including neuropsychiatric symptoms, to agreement levels.ResultsFour factors were identified from the PELI: autonomous choice, social engagement, personal growth, and keeping a routine. Significant participant-care partner discrepancy was found in “social engagement” preferences (e.g., regular contact with family, meeting new people, volunteering). Geriatric Depression Scale-15 score and care partner sex were significantly associated with participant-care partner discrepancies in “social engagement” preferences.ConclusionThis study yields new insights regarding the most important preferences for persons with cognitive impairment and clarifies a path to optimizing surrogate decision-making around everyday preferences by highlighting areas of apparent disagreement and identifying potential predictors of discrepancy.     

Brain Regional Glucose Metabolism,Neuropsychiatric Symptoms,and the Risk of Incident Mild Cognitive Impairment: The Mayo Clinic Study of Aging

ObjectiveThe authors conducted a prospective cohort study to examine the risk of incident mild cognitive impairment (MCI) as predicted by baseline neuropsychiatric symptoms (NPS) and brain regional glucose metabolic dysfunction.MethodsAbout 1,363 cognitively unimpaired individuals (52.8% males) aged ≥50 years were followed for a median of 4.8 years to the outcome of incident MCI. NPS were assessed using Beck Depression and Anxiety Inventories and Neuropsychiatric Inventory Questionnaire. Glucose hypometabolism was measured by fluorodeoxyglucose positron emission tomography and defined as standardized uptake value ratio ≤ 1.47 in regions typically affected in Alzheimer disease. Cox proportional hazards models were adjusted for age, sex, education, and APOE ε4 status.ResultsParticipants with regional glucose hypometabolism and depression (Beck Depression Inventory-II ≥13) had a more than threefold increased risk of incident MCI (hazard ratio [95% confidence interval], 3.66 [1.75, 7.65], p <0.001, χ² = 11.83, degree of freedom [df] = 1) as compared to the reference group (normal regional glucose metabolism and no depression), and the risk was also significantly elevated (7.21 [3.54, 14.7], p <0.001, χ² = 29.68, df = 1) for participants with glucose hypometabolism and anxiety (Beck Anxiety Inventory ≥10). Having glucose hypometabolism and ≥1 NPS (3.74 [2.40, 5.82], p <0.001, χ² = 34.13, df = 1) or ≥2 NPS (3.89 [2.20, 6.86], p <0.001, χ² = 21.92, df = 1) increased the risk of incident MCI by more than three times, and having ≥3 NPS increased the risk by more than four times (4.12 [2.03, 8.37], p <0.001, χ² = 15.39, df = 1).ConclusionCombined presence of NPS with regional glucose hypometabolism is associated with an increased risk of incident MCI, with fluorodeoxyglucose positron emission tomography appearing to be a stronger driving force of cognitive decline than NPS.     

Longitudinal Changes in Neuropsychiatric Symptoms: Impact of Discrepancy in Everyday Preferences Between Persons With Cognitive Impairment and Their Care Partners

ObjectivesNeuropsychiatric symptoms (NPS) of dementia are common and may be driven by inability of persons with cognitive impairment (CI) to communicate needs. We addressed the relevance of this unmet-needs model to burden of NPS among persons with milder CI.MethodsThe sample included 48 dyads of persons with CI and their care partners. NPS were measured at baseline and follow-up (mean 486 days +/-107 SD). Mixed random and fixed effects longitudinal models were used to evaluate impact of discrepancies between persons with CI and their care partners in everyday preferences (baseline) on changes in NPS over time.ResultsHigher levels of underestimation of “social engagement” preferences of persons with CI by care partners were associated with a higher average burden of NPS across all follow-up.ConclusionsThis study suggests that unmet-needs may be a useful construct for understanding etiology for NPS across the spectrum of severity of cognitive impairment.     

Neuropsychiatric differences between Parkinson's disease with dementia and Alzheimer's disease

OBJECTIVE: To compare the profile of neuropsychiatric symptoms in patients with Parkinson's disease with dementia (PDD) and patients with Alzheimer's disease (AD). DESIGN: Cross-sectional survey of a population-based sample of patients with PDD and AD patients matched for age, sex, and Mini-Mental State Examination (MMSE) score. METHOD: Patients were diagnosed according to published criteria for PD and AD. The diagnosis of dementia in PD was made according to DSM-III-R, and was based on clinical interview of the patient and a relative, psychometric testing (including MMSE, Dementia Rating Scale and tests assessing memory, executive functions and visuospatial functioning) and physical examination. The Neuropsychiatric Inventory (NPI) was administered to all patients. RESULTS: One or more psychiatric symptoms was reported in 95% of AD and 83% of PDD patients. Hallucinations were more severe in PD patients, while aberrant motor behavior, agitation, disinhibition, irritability, euphoria, and apathy were more severe in AD. In PDD, apathy was more common in mild Hoehn and Yahr stages, while delusions increased with more severe motor and cognitive disturbances. In PDD, only delusions correlated with the MMSE score. CONCLUSIONS: Neuropsychiatric symptoms are common and severe in patients with PDD, with important implications for the management of these patients. AD and PDD patients have different neuropsychiatric profiles, suggesting different underlying mechanisms. Cognitive impairment, psychopathology, and motor features progress independently in PDD patients Copyright 2001 John Wiley & Sons, Ltd.     

Neuropsychiatric profiles in patients with Alzheimer's disease and vascular dementia

Background/Aims:

The aim of the following study is to compare the behavioral and psychological symptoms of dementia (BPSD) in patients of Alzheimer disease (AD) and vascular dementia (VaD).

Materials and Methods:

We used National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer''s Disease and Related Disorders Association criteria for diagnosing AD and National Institute of Neurological Disorders and Stroke-Association International pour la Recherche et l’Enseignement en Neurosciences Criteria for diagnosing VaD. VaD cohort was further subcategorized into small vessel and large vessel disease. The severity of cognitive impairment and the BPSD were studied by means of the Clinical Dementia Rating Scale (CDR) and the Neuropsychiatric Inventory respectively.

Results:

We studied 50 AD and 50 VaD patients of whom 38 were small vessels and 12 were large vessels VaD. The severity of dementia was comparable in both groups. The agitation/aggression, depression/dysphoria, anxiety, apathy/indifference, irritability, aberrant motor behavior, appetite and eating behavior and night-time behaviors occurred significantly more frequently in patients with VaD than AD. We found a weak positive correlation between the CDR score and the number of neuropsychiatric symptoms per patient in both cohorts. Elation/euphoria, agitation/aggression was significantly more frequent in patients with large vessel in comparison to small vessel VaD.

Conclusions:

BPSD are common in both types of dementia and they are more severe in VaD than AD when the groups have similar levels of cognitive impairment.     

Neuropsychiatric profiles in patients with Alzheimer's disease and vascular dementia

OBJECTIVE: To explore the neuropsychiatric manifestations in patients with Alzheimer's disease (AD) and cortical and subcortical vascular dementia (VaD). METHODS: We investigated consecutive patients with dementia. All the participants received brain computed tomography. The diagnosis of dementia was confirmed by clinical criteria and the imaging findings. Only patients with probable AD, and subcortical and cortical VaD were included. The Mini Mental State Examination (MMSE) was used to evaluate global cognitive function, and the Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. RESULTS: Of the 536 participants with dementia, 320 (59.7%) had AD, 161 (30%) had subcortical VaD, 35 (6.4%) had cortical VaD, and 16 (2.9%) had mixed cortical and subcortical VaD. Cortical VaD patients had the highest mean composite NPI scores in all domains and AD patients had the lowest composite scores in most domains. The mean composite scores of the apathy and sleep disturbance domains in patients with cortical VaD were significantly higher than those in the patients with AD after controlling for years of education and MMSE score (p < 0.01). CONCLUSIONS: There were few differences among the patients with AD, subcortical VaD and cortical VaD. The most consistent differences were the high sleep disturbance scores in those with cortical VaD.     

Cognitive and Neuropsychiatric Impairments in Alzheimer's Disease: Current Treatment Strategies

Late life depression is a complex disease associated with a number of contributing neurobiological factors, including cerebrovascular disease, neurodegeneration, and inflammation, which also contribute to its longitudinal prognosis and course. These factors create a context in which the brain is more vulnerable to the impact of stress, and thus, to depression. At the same time, some individuals are protected from late life depression and its consequences, even in the face of neurobiological vulnerability, through benefitting from one or more attributes associated with resilience, including social support, engagement in physical and cognitive activities, and brain reserve. Enhanced understanding of how neurobiological and environmental factors interact in predicting vulnerability and resilience is needed to predict onset and course of depression in late life and develop more effective interventions.