Higher Neuropsychiatric Inventory Scores Research Articles

Comparison of clinicopathologic features of Limbic and Diffuse Transactive Response DNA‐binding Protein 43 pathology in Alzheimer’s disease neuropathologic spectrum

AbstractBackgroundIncreasing evidence suggests that transactive response DNA‐binding protein 43 (TDP‐43) pathology in Alzheimer’s Disease (AD), or AD‐TDP, can be diffuse or limbic‐predominant. Understanding whether diffuse AD‐TDP has genetic, clinical, and pathological features that differ from limbic AD‐TDP could have clinical and research implications. We aimed to better characterize the clinicopathologic features of diffuse AD‐TDP and differentiate it from limbic‐predominant AD‐TDP pathology.MethodThree hundred sixty‐three participants were prospectively recruited and followed in the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group and died between May 1999 and August 2021. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. At postmortem evaluation, they showed Alzheimer’s disease neuropathologic changes and TDP‐43‐immunoreactive inclusions. The distribution of TDP‐43 pathology was assessed using the Josephs 6‐stage scheme. Participants with TDP‐43 stages 1‐3 were classified as Limbic, while those with stages 4‐6 were classified as Diffuse. Neuropathologically defined frontotemporal lobar degeneration cases were excluded. Multivariable logistic regression was used to identify clinicopathological features that predicted diffuse TDP‐43 pathology at postmortem. We hypothesized that the Diffuse group would show impairment in cognitive domains beyond episodic memory and more hippocampal sclerosis.ResultsThe cohort was 61% female and old at onset (median:76 years [IQR:70‐82]) and death (median:88 years [IQR:82‐92]). Fifty‐four percent (n = 197) were classified as Limbic and 46% (n = 166) as Diffuse. A “clinical” multivariate logistic regression fit to 85 participants with all clinical variables of interest showed that later age at onset (OR:1.09, 95%CI:1.01‐1.19;P = 0.03), longer disease duration (OR:1.17, 95%CI:1.02‐1.36;P = 0.03) and higher Neuropsychiatric Inventory scores (OR:1.14, 95%CI:1.01‐1.28;P = 0.03) all independently increased the odds of being Diffuse, while higher Trails Making Test‐B (OR:0.99, 95%CI:0.98‐0.99;P = 0.02) and Block Design Test scores (OR:0.91, 95%CI:0.85‐0.99;P = 0.023) independently decreased the odds of being Diffuse. A “pathology” multivariate logistic regression fit to 233 cases with all neuropathological data revealed that widespread amyloid‐β pathology corresponding to Thal phases 3‐5 all significantly decreased the odds of diffuse pathology by 80‐90%, while hippocampal sclerosis increased it sixfold (OR:6.18, 95% CI:2.93‐13.03;P<0.001).ConclusionsDiffuse AD‐TDP shows clinicopathological features that differ from Limbic AD‐TDP, which could have public health implications relating to treatment and research on AD and dementia.

Comparison of Clinical, Genetic, and Pathologic Features of Limbic and Diffuse Transactive Response DNA-Binding Protein 43 Pathology in Alzheimer's Disease Neuropathologic Spectrum.

Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer's disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications. To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP. 363 participants from the Mayo Clinic Study of Aging, Alzheimer's Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1-3 were classified as Limbic, those 4-6 as Diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology. The cohort was 61% female and old at onset (median: 76 years [IQR:70-82]) and death (median: 88 years [IQR:82-92]). Fifty-four percent were Limbic and 46% Diffuse. Clinically, ∼10-20% increases in odds of being Diffuse associated with 5-year increments in age at onset (p = 0.04), 1-year longer disease duration (p = 0.02), and higher Neuropsychiatric Inventory scores (p = 0.03), while 15-second longer Trailmaking Test-B times (p = 0.02) and higher Block Design Test scores (p = 0.02) independently decreased the odds by ~10-15%. There was evidence for association of APOEɛ4 allele with limbic AD-TDP and of TMEM106B rs3173615 C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3-5) decreased the odds of diffuse TDP-43 pathology by 80-90%, while hippocampal sclerosis increased it sixfold (p < 0.001). Diffuse AD-TDP shows clinicopathologic and genetic features different from limbic AD-TDP.

Brain free‐water increases in mild behavioral impairment

AbstractBackgroundMild behavioural impairment (MBI) is proposed as a diagnostic construct to identify dementia‐free individuals with sustained neuropsychiatric symptoms as an early manifestation of dementia. Our previous study has demonstrated that MBI predicts faster cognitive decline and progression to dementia. Other studies have shown that MBI was associated with Alzheimer’s disease biomarkers for Aβ and tau. However, cerebrovascular disease (CeVD), which is another critical pathology in dementia, has not been investigated in MBI. Here, we sought to test brain free‐water (FW) alterations, a marker for CeVD, in MBI compared with non‐MBI participants and their associations with longitudinal changes in cognition, function, and neuropsychiatric symptoms.MethodLongitudinal global cognitive scores, clinical dementia rating sum‐of‐boxes (CDR‐SoB), neuropsychiatric inventory (NPI) scores, over 5 years were reported in 281 dementia‐free participants (40 MBI and 241 non‐MBI). MBI was diagnosed using established criteria. All participants underwent T1‐weighted structural and diffusion MRI at baseline. FW imaging method was applied to derive individual‐level white matter (WM) and grey matter (GM) FW maps from diffusion MRI. We compared baseline GM‐FW and WM‐FW between non‐MBI and MBI subjects. We then tested the associations of MBI‐related FW increase with baseline and longitudinal changes in global cognition, CDR‐SB, and NPI scores using linear regression models.ResultMBI had greater GM‐FW in executive control (prefrontal), motor sensory (precentral), attention (insula) and memory (left temporal and right cingulate and cuneus) networks and widespread higher WM‐FW compared with non‐MBI (Fig‐1). Both higher GM‐FW and WM‐FW were associated with lower global cognition, higher CDR‐SB, and higher NPI scores across all participants at baseline (Table‐1). There was no interaction effect of MBI status on such association. Moreover, higher baseline GM‐FW and WM‐FW were associated with longitudinal worsening in global cognition, CDR‐SB, and NPI scores (Table‐2). Interestingly, such associations were greater in MBI than in non‐MBI (Fig‐2).ConclusionThis study demonstrated that MBI was associated with increased brain FW, which may have contributed to the relationship between persistent neuropsychiatric disturbances and clinical and cognitive outcomes. Early detection of cerebrovascular‐related FW alteration may allow for timely management of MBI individuals before development of dementia.

Neuropsychiatric symptoms impact associations between plasma neurofilament light and cognition in individuals with Lewy body pathology, but not in Alzheimer’s disease.

AbstractBackgroundLewy body disease (LBD) is one of the most prevalent causes of dementia following Alzheimer’s disease (AD). Plasma neurofilament light chain (NfL) is a marker of neuroaxonal degeneration associated with cognitive decline in LBD, AD, and other neurodegenerative disorders. Neuropsychiatric symptoms are often present in both LBD and AD and can affect quality of life and cognitive performance. Therefore, we investigated whether the association between plasma NfL and cognition was moderated by the severity of neuropsychiatric symptoms in LBD and AD.MethodParticipants from the UCSD Shiley‐Marcos Alzheimer’s Disease Research Center with data for the informant‐reported Neuropsychiatric Inventory (NPI), plasma NfL, and AD and/or LBD neuropathology at autopsy were included (n = 204). General linear models examined whether the influence of neuropsychiatric symptoms on the association between plasma NfL and cognition at the last assessment prior to death varied by neuropathology. Participants with LBD only (n = 22), LBD+AD (n = 59) and AD only (n = 123) were included. Covariates included: age, education, sex, APOE ε4 carrier status, cognitive classification (unimpaired, MCI, or dementia), and time from last assessment to death. Given similar patterns of results for the LBD and LBD+AD pathology groups, they were combined for the final analyses. The Dementia Rating Scale (DRS) was used as the cognitive outcome measure.ResultThe three‐way NfL x NPI x pathology interaction was significant (p = .019, η p 2 = .029). In the LBD+AD group, neuropsychiatric symptoms moderated the relationship between plasma NfL and DRS total score (p = .013, η p 2 = .084) such that higher NPI scores had a more negative association between NfL and DRS (total score as well as attention, initiative/perseveration, and memory subscales). Although there was an association between NfL and DRS total score in the AD‐only group, this was not moderated by NPI score (p = .460, η p 2 = .005).ConclusionThese results highlight the importance of considering neuropsychiatric symptoms when examining the relationship between NfL and cognition, particularly in patients with suspected LBD pathology. Neuropsychiatric symptoms differ in LBD and AD, so future work will examine whether specific symptoms that are more prevalent in LBD, such as apathy, are driving the observed relationships.

Neuropsychiatric Symptoms Exacerbate the Cognitive Impairments in Patients With Late-Life Depression.

Background: Neuropsychiatric symptoms (NPS) and cognitive impairments are both common in patients with late-life depression (LLD). However, the relationship between NPS and cognitive functions in LLD patients remains unclear. The current study aims to explore the effects of NPS on cognitive impairments in LLD patients.Methods: Two hundred and sixty-two LLD patients and 141 normal controls (NC) were recruited. Exploratory factor analysis was used to extract factors from the Neuropsychiatric Inventory (NPI). Correlation, mediation, and moderation analyses were used to explore whether NPS exacerbated the cognitive impairments in LLD and whether NPS exhibited different effects on cognitive impairments in acute-state LLD (aLLD) and recovery-state LLD (rLLD).Results: Three main factors were extracted from the NPI, including emotional, behavioral, and psychotic factors. The patients with LLD exhibited worse cognition and higher NPI scores, and the scores of NPI-total and three extracted factors were negatively associated with cognitive scores. The mediation analyses exhibited that NPI-total and behavioral factor scores increase the difference in cognition scores between LLD and NC groups. The mediation analyses exhibited that behavioral factor score played a greater effect on impairing MMSE in the rLLD group than in the aLLD group. Additionally, behavioral factor score was in a trend to be negatively associated with Mini-Mental State Examination (MMSE) score changes at a one-year follow-up (p = 0.051).Conclusions: NPS, especially behavioral symptoms, exacerbate cognitive impairments in LLD and may contribute to residual cognitive impairment in rLLD patients. Early intervention for behavioral symptoms in LLD patients may be beneficial to their long-term clinical prognosis.

Phenotyping Neuropsychiatric Symptoms Profiles of Alzheimer's Disease Using Cluster Analysis on EEG Power.

Background: There has been an increasing interest in studying electroencephalogram (EEG) as a biomarker of Alzheimer’s disease but the association between EEG signals and patients’ neuropsychiatric symptoms remains unclear. We studied EEG signals of patients with Alzheimer’s disease to explore the associations between patients’ neuropsychiatric symptoms and clusters of patients based on their EEG powers.Methods: A total of 69 patients with mild Alzheimer’s disease (the Clinical Dementia Rating = 1) were enrolled and their EEG signals from 19 channels/electrodes were recorded in three sessions for each patient. The EEG power was calculated by Fourier transform for the four frequency bands (beta: 13–40 Hz, alpha: 8–13 Hz, theta: 4–8 Hz, and delta: <4 Hz). We performed K-means cluster analysis to classify the 69 patients into two distinct groups by the log-transformed EEG powers (4 frequency bands × 19 channels) for the three EEG sessions. In each session, both clusters were compared with each other to assess the differences in their behavioral/psychological symptoms in terms of the Neuropsychiatric Inventory (NPI) score.Results: While EEG band powers were highly consistent across all three sessions before clustering, EEG band powers were different between the two clusters in each session, especially for the delta waves. The delta band powers differed significantly between the two clusters in most channels across the three sessions. Patients’ demographics and cognitive function were not different between both clusters. However, their behavioral/psychological symptoms were different between the two clusters classified based on EEG powers. A higher NPI score was associated with the clustering of higher EEG powers.Conclusion: The present study suggests that EEG power correlates to behavioral and psychological symptoms among patients with mild Alzheimer’s disease. The clustering approach of EEG signals may provide a novel and cost-effective method to differentiate the severity of neuropsychiatric symptoms and/or predict the prognosis for Alzheimer’s patients.

COVID-19 and the forgotten pandemic: follow-up of neurocognitive disorders during lockdown in Argentina

IntroductionHealth systems in numerous countries around the world are suffering a serious burden as a consequence of the COVID-19 pandemic. As a result of this situation, the follow-up of such chronic diseases as dementia may be at risk. Similarly, neuropsychiatric complications related to lockdown measures may also be neglected; Argentina’s lockdown has been the longest implemented in Latin America. This study aims to determine the frequency of the different types of medical consultations for neurocognitive disorders and the predictors for requiring consultation since the beginning of the lockdown. MethodsWe performed a descriptive, observational, cross-sectional study based on data collected through an online survey. ResultsData were collected on 324 participants, with 165 (50.9%) having had at least one medical consultation. Consultations were held by telephone in 109 cases (33.6%), by e-mail in 62 (19.1%), by video conference in 30 (9.3%), and at the emergency department in 23 (7.1%). Predictors of requiring consultation were Clinical Dementia Rating scores ≥1 (P < .001) and diagnosis of Alzheimer disease (P = .017). Higher Neuropsychiatric Inventory scores were found in the group of respondents who did require medical consultation (P < .001), but no significant differences were found between groups for Zarit Burden Interview scores. ConclusionWe identified a high prevalence of behavioural disorders and caregiver burden during lockdown. Nevertheless, only 50% of respondents had sought medical consultation (by telephone or email in 52.7% of cases). Care of people with dementia must be emphasised, guaranteeing follow-up of these patients.

Relationship between comprehensive geriatric assessment and amyloid PET in older persons with MCI

BackgroundThe association between amyloid deposition and cognitive, behavioral and physical performance in mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) has been poorly investigated, especially in older persons.MethodsWe studied the in vivo correlation between the amyloid deposition at Positron Emission Tomography (amyloid-PET) and the presence of memory loss, reduced executive function, neuropsychiatric symptoms and physical performance in older persons with MCI. Amyloid-PET was performed with 18F-flutemetamol and quantitatively analyzed.ResultsWe evaluated 48 subjects, 21 men and 27 women. We performed in each patient a comprehensive geriatric assessment (CGA) including Mini Mental State Examination (MMSE), Clock Drawing Test (CDT), Activity Daily Living (ADL), Instrumental Activity of Daily Living (IADL), Neuropsychiatric inventory (NPI) questionnaire, 15 Geriatric Depression Scale (GDS), Short Physical Performance Battery (SPPB) and Hand Grip strength. Then, each patient underwent amyloid-PET. Mean age of the enrolled subjects was 74.6 ± 7.8 years. All of these subjects showed preserved cognitive function at MMSE > 24, while 29 of 48 subjects (61.0%) had altered CDT.Mean NPI score was 6.9 ± 5.9. The mean value of SPPB score was 9.0 ± 2.6, while the average muscle strength of the upper extremities measured by hand grip was 25.6 ± 7.7 Kg. CT/MRI images showed cortical atrophic changes in 26 of the 48 examined subjects (54.0%), while cerebrovascular modifications were present in 31 subjects (64.5%). Pathological burden of amyloid deposits was detected in 25 of 48 (52.0%) patients with a mean value of global z-score of 2.8 (subjects defined as MCI due to AD).After stratifying subjects in subclasses of clinical alterations, more probability of pathological amyloid deposition was found in subjects with impaired CDT and higher NPI score (O.R. = 3.45 [1.01–11.2], p = 0.04), with both impaired CDT and low physical performance (O.R. = 5.80 [1.04–32.2], p = 0.04), with altered CDT and high NPI score (O.R. = 7.98 [1.38–46.0], p = 0.02), and finally in those subjects with altered CDT, high NPI and low physical performance (O.R. = 5.80 [1.05–32.2], p = 0.04).ConclusionOur findings support the recent hypothesis that amyloid deposition could be associated with multiple cerebral dysfunction, mainly affecting executive, behavioral and motor abilities.

COVID-19 y la pandemia olvidada: el seguimiento de las enfermedades neurocognitivas durante la cuarentena en Argentina

IntroductionHealth systems in numerous countries around the world are suffering a serious burden as a consequence of the COVID-19 pandemic. As a result of this situation, the follow-up of such chronic diseases as dementia may be at risk. Similarly, neuropsychiatric complications related to lockdown measures may also be neglected; Argentina's lockdown has been the longest implemented in Latin America. This study aims to determine the frequency of the different types of medical consultations for neurocognitive disorders and the predictors for requiring consultation since the beginning of the lockdown. MethodsWe performed a descriptive, observational, cross-sectional study based on data collected through an online survey. ResultsData were collected on 324 participants, with 165 (50.9%) having had at least one medical consultation. Consultations were held by telephone in 109 cases (33.6%), by e-mail in 62 (19.1%), by video conference in 30 (9.3%), and at the emergency department in 23 (7.1%). Predictors of requiring consultation were Clinical Dementia Rating scores ≥1 (P<.001) and diagnosis of Alzheimer disease (P=.017). Higher Neuropsychiatric Inventory scores were found in the group of respondents who did require medical consultation (P<.001), but no significant differences were found between groups for Zarit Burden Interview scores. ConclusionWe identified a high prevalence of behavioural disorders and caregiver burden during lockdown. Nevertheless, only 50% of respondents had sought medical consultation (by telephone or email in 52.7% of cases). Care of people with dementia must be emphasised, guaranteeing follow-up of these patients.

Neuropsychiatric Correlates of Small Vessel Disease Progression in Incident Cognitive Decline: Independent and Interactive Effects.

Cerebral small vessel disease (SVD) and neuropsychiatric symptoms (NPS) independently increase the risk of cognitive decline. While their co-existence has been reported in the preclinical stage of dementia, longitudinal data establishing the prognosis of their associations, especially in an Asian context remains limited. This study investigated the role of SVD and NPS progressions on cognitive outcomes over 2 years in a dementia-free elderly cohort. 170 dementia-free elderly with baseline and 2-year neuropsychological assessments and MRI scans were included in this study. White matter hyperintensities (WMH), lacunes, and microbleeds (CMBs) were graded as markers of SVD. The Neuropsychiatric Inventory (NPI) was used to measure NPS. Generalized estimating equations modelling evaluated the relationship between NPI change and SVD progression. Logistic regression evaluated the risk of incident cognitive decline with both SVD and NPS. All models were adjusted for demographics, baseline cerebrovascular diease, and medial temporal lobe atrophy. Higher NPI scores were associated with higher SVD burden at baseline. Subjects with WMH progression had greater increase in total NPI (β[SE] = 0.46[0.19], p = 0.016), driven by hyperactivity subsyndrome (β[SE] = 0.88[0.34], p = 0.007). Subjects with incident CMBs had greater increase in psychosis subsyndrome (β[SE] = 0.89[0.30], p < 0.001). Subjects with progressions in both SVD and NPS were more likely to develop cognitive decline over 2 years (OR[95% CI] = 4.17[1.06-16.40], p < 0.05). Our findings support worsening of NPS as a clinical indicator of SVD progression and are associated with cognitive decline over 2 years. Early detection of NPS and targeted interventions on SVD burden may improve NPS outcomes.

Association Between Neuropsychiatric Symptom Trajectory and Conversion to Alzheimer Disease.

Neuropsychiatric symptoms (NPS) are both common in mild cognitive impairment and Alzheimer disease (AD). Studies have shown that some NPS such as apathy and depression are a key indicator for progression to AD. We compared Neuropsychiatric Inventory (NPI) total score and NPI subdomain score between mild cognitive impairment-converters (MCI-C) and mild cognitive impairment-nonconverters (MCI-NC) longitudinally for 6 years using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In addition to the NPI, Mini-Mental State Examination (MMSE) scores were also compared to find out if MMSE scores would differ between different NPI groups. Lastly, a linear regression model was done on MMSE and NPI total score to establish a relationship between MMSE and NPI total score. The results in this study showed that NPI total scores between MCI-C and MCI-NC differed significantly throughout 6 years. MCI-C subjects had a higher mean NPI total score and lower MMSE score compared with MCI-NC subjects. In addition, MMSE scores were significantly different between the 3 groups of NPI total score. Subjects who have a high NPI score have the lowest mean MMSE score, thus demonstrating that NPI scores do indeed affect MMSE scores. Further analyses using a regression model revealed that a unit change in NPI total score lead to 0.1 to 0.3 decrease in MMSE. On the basis of the findings, this study showed evidence that increase in NPS burden (reflected by increase in NPI) over time predicts conversion to AD, whereas stability of symptoms (reflected by stable NPI score) favors nonconversion. Further study should investigate the underlying mechanisms that drive both NPS burden and cognitive decline.

Feasibility of Home-Based Neurologic Music Therapy for Behavioral and Psychological Symptoms of Dementia: A Pilot Study.

Family caregivers often feel ill-equipped to handle bothersome behavioral and psychological symptoms of dementia, such as agitation, apathy, and sleep disturbances, leading to increased caregiver distress and nursing home placement for people with dementia. Therapies for such symptoms are currently limited and non-pharmacological options are preferred, given potential side effects of medications. Neurologic music therapy (NMT) could provide an additional treatment option for managing behavioral and psychological symptoms for community-dwelling people with dementia and their caregivers. This pilot study sought to evaluate the feasibility, acceptability, and effectiveness of home-based NMT for behavioral and psychological symptoms of dementia. Eighteen persons with dementia-caregiver dyads were enrolled to receive one-hour weekly sessions of home-based NMT for 6 weeks. Demographic, quality of life, neuropsychiatric symptom, and caregiver burden and self-efficacy information was collected at baseline, 6 weeks, and 12 weeks. Seven dyads (38.9%) withdrew from therapy before completing all sessions; these participants had higher Neuropsychiatric Inventory scores and were of older age at baseline. For those who completed therapy, neuropsychiatric symptom scores improved at 6 weeks, an effect that was sustained at 12 weeks. No other outcome measures changed significantly after therapy. Initiating NMT too late in the course of dementia, when behavioral symptoms are already present, may be impractical for people with dementia and increase caregiver stress, even when provided within the home. Introducing and incorporating the principles of NMT earlier in the course of dementia could allow for increased comfort and benefit for people with dementia and their caregivers.

Author response: Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

We thank Landin-Romero and Kumfor for the comments. Our regression techniques showed an association between neuropsychiatric inventory (NPI) scores and [18F]fluorodeoxyglucose (FDG) uptake in preclinical Alzheimer disease (AD).1 We did not find posterior cingulate cortex (PCC) hypermetabolism, but higher PCC-FDG uptake was found in patients with preclinical AD with higher NPI scores at baseline. We did not find hypermetabolism even when we contrasted the mean FDG uptake at the local maxima within the cluster.

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

Objective:To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).Methods:We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.Results:Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.Conclusions:The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.

Gender difference in the association and presentation of visual hallucinations in dementia with Lewy bodies: a cross-sectional study.

Visual hallucinations (VHs) are among the most striking features of dementia with Lewy bodies (DLB). We investigated gender differences in the association and presentation of VHs in DLB. A cross-sectional analysis of baseline data from a prospective, longitudinal study on dementia was performed. Cumulative frequency, 1-month frequency, and phenomenology of VHs were summarized and compared between female and male patients with DLB. Gender differences in the factors associated with VHs were investigated in patients with and without hallucinations. A total of 152 patients including 65 (42.8%) women and 87 (57.2%) men were analyzed. The cumulative and 1-month frequencies of VHs were 60% and 55.4%, respectively, in women and 44.8% and 41.4%, respectively, in men. Adjusting for age and disease severity resulted in the inclusion of more women in the VH group [odds ratio (OR)=2.33, p=0.028)] than in the non-VH group. In female participants, older age (OR=9.16, p=0.003) and higher neuropsychiatric inventory score (OR=4.89, p=0.009) were associated with VHs, whereas in male participants, more severe dementia stage (clinical dementia rating 2-3 versus clinical dementia rating 0.5, OR=6.22, p=0.008) and higher rates of using antipsychotics (OR=9.64, p=0.047) were associated with VHs. The frequencies of 1-month and cumulative VHs were high in DLB, which indicated a high prevalence as well as a high persistency of VHs in DLB. The patterns of factors associated with VHs differed between female and male patients. Copyright © 2017 John Wiley & Sons, Ltd.

IMPACT OF CO-MORBID AMYLOID PATHOLOGY ON CLINICAL PHENOTYPE OF PATIENTS WITH VASCULAR COGNITIVE DISORDERS

Cerebrovascular disease is an important cause of cognitive impairment and dementia, and vascular cognitive disorders (VCD) are conceptually distinct from Alzheimer's disease (AD). However, cerebrovascular and amyloid pathology may be co-morbid, particularly in older patients. Amyloid-beta biomarkers can detect amyloid pathology in vivo. Our aim was to investigate the impact of co-morbid amyloid pathology on the clinical phenotype of patients with VCD. From the Amsterdam Dementia Cohort we included 218 patients with VCD who fulfilled the 2014 VASCOG criteria (66 with Major VCD and 152 with Mild VCD). As a reference group we included 120 patients with (prodromal) AD (85 with MCI and 35 with dementia due to AD). All subjects underwent a diagnostic work-up including brain MRI and lumbar puncture. We defined presence of amyloid pathology (A+) as CSF Abeta-42 <638ng/L. VCD patients were termed V+, patients in the reference group V-. This resulted in 116 A+V+, 102 A-V+, and 120 A+V- patients. We used linear regression analysis to compare MMSE scores, z-scores for neuropsychological test performance in five cognitive domains, and scores on the neuropsychiatric inventory (NPI), adjusting for age, sex and education. The table gives the subject characteristics according to study group. Amyloid-negative VCD patients were younger than those who were amyloid-positive. Mean MMSE scores did not differ between study groups. The figure shows the association of VCD diagnosis and amyloid status with neuropsychological test performance. Greatest memory impairment was found in the A+V- group (p<0.05). In VCD patients (V+), co-morbid amyloid-positivity was associated with worse memory performance (A+V+ < A-V+, p<0.05). Conversely, amyloid-negative VCD patients had greater attentional and executive deficits (A-V+ < A+V+, p<0.05), as well as higher NPI scores (A-V+ [15.3±14.0] > A+V+ [9.8±10.5]; p<0.05). The association of VCD diagnosis and amyloid status with neuropsychological test performance.

Sleep disturbances are key symptoms of very early stage Alzheimer disease with behavioral and psychological symptoms: a Japan multi-center cross-sectional study (J-BIRD).

Sleep disturbances in Alzheimer disease (AD) may affect behavioral and psychological symptoms of dementia (BPSD). Our aim was to elucidate the associations between sleep disturbances and other BPSD at different stages of AD. This investigation was part of a multicenter-retrospective study in Japan (J-BIRD). Eligible for final analyses were 684 AD patients. Global severity of dementia was estimated using the Clinical Dementia Rating (CDR) scale. BPSD were assessed using the Neuropsychiatric Inventory (NPI). We analyzed the relationships between sleep disturbances and BPSD at different stages of AD according to the CDR score. Among the 684 AD patients, 146 (21.3%) had sleep disturbances. Patients with very early AD (CDR 0.5) and sleep disturbances had significantly more BPSD than those without sleep disturbances, as indicated by the higher prevalence of the following four NPI items: anxiety, euphoria, disinhibition, and aberrant motor behavior. In AD at CDR 2, (moderate AD) only one NPI item (irritability) was affected, while none was affected at CDR 1 (mild AD) and 3 (severe AD). Multiple regression analyses were performed in those with AD having various CDR scores. At CDR 0.5, the presence of sleep disturbances was associated with a high total NPI score (β = 0.32, p < 0.001). However, other factors, including cognitive decline, age, gender, and years of education, were not significantly associated with the NPI score. At CDR 1 and 2, no factor was significantly related to BPSD. Sleep disturbances were strongly associated with other BPSD in the very early stage of AD. Copyright © 2016 John Wiley & Sons, Ltd.

A neurophysiological profile in Parkinson’s disease with mild cognitive impairment and dementia in China

Mild cognitive impairment (MCI) and dementia (D) are frequent features of Parkinson’s disease (PD) but widely disparate criteria have been used. Our understanding of the prevalence and cognitive profile of Chinese PD patients remains limited. In order to determine the frequency and pattern of cognitive dysfunction and identify risk factors for cognitive dysfunction in the Chinese Han PD population we performed a cross-sectional study in a cohort of 330 PD patients and 163 healthy controls. Five cognitive domains (executive function, attention, praxis and visuospatial function, memory, and language) and mood/behavior were evaluated. According to the Movement Disorder Society Task Force consensus criteria, up to 29.1% of PD patients were classified as PD-MCI and 32.1% as PD-D. Impairments occur in a range of cognitive domains with dysexecutive profile predominating. Healthy controls also outperformed cognitively preserved PD patients in tasks of executive function and attention. Logistic regression indicated that PD-MCI may be predicted by lower educational level and apathy. Additionally, later disease onset, longer disease duration, more severe motor symptoms and higher neuropsychiatric inventory score were associated with a faster transition from PD-MCI to PD-D. These findings suggest that all PD patients should undergo routine cognitive screening. For high-risk patients early recognition and therapeutic intervention is imperative.

Neuropsychiatric symptoms in people screened positive for dementia in primary care.

Neuropsychiatric symptoms are major determinants for caregiver distress and institutionalization in dementia. Little is known about the prevalence of neuropsychiatric symptoms and their association with use of medication, caregiver distress, and resource utilization in primary care. We assessed frequency of neuropsychiatric symptoms in a sample retrieved from a primary care intervention study. Patients were screened for dementia by their primary care physicians. A study nurse assessed neuropsychiatric symptoms in 176 patients using the neuropsychiatric inventory (NPI) through face-to-face interviews by proxy during home visits. In addition, data on global cognition (MMSE), quality of life (QoL-AD), resource utilization in dementia (RUD), caregiver distress (BIS), and use of psychotropic medication in patients were obtained. We used linear mixed effect models taking into account the clustering of patients within general physician practices. Clinically relevant neuropsychiatric symptoms (NPI score ≥ 4) occurred in about 53% of the patients. Higher NPI scores were significantly associated with more severe cognitive impairment, higher caregiver distress, and higher utilization of caregiver resources by patients but not with a formal diagnosis of dementia from the primary care physician. Use of antipsychotics was associated with higher NPI scores, particularly in non-psychotic domains. Neuropsychiatric symptoms in a primary care cohort screened positive for dementia were associated with resource utilization and distress of caregivers. In contrast to guideline recommendations, the use of antipsychotics was associated with non-psychotic domains of behavioral symptoms. These findings underscore the relevance of neuropsychiatric symptoms for the design of future interventions in primary care.

Risk factors and characteristics of the recurrence of behavioral and psychological symptoms of Alzheimer's disease

BackgroundThere is limited data on the risk factors and characteristics of the recurrence of behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease (AD). MethodsOne hundred and two AD patients complaining of BPSD were followed-up for 12 months after being well controlled. Potential risk factors for the recurrence of BPSD were evaluated. The severity of BPSD was measured using the Neuropsychiatric Inventory (NPI). NPI syndromes were categorized into affective impairments, psychotic symptoms, and lack of control disorders. Characteristics of the recurrent BPSD were compared with those of the former onset. ResultsForty-five of the patients presented recurrent BPSD within 12 months. Risk factors of recurrence included change of environment (RR = 5.42, p < 0.001), failure to maintain antipsychotic medication (RR = 3.13, p < 0.001), and high NPI score (RR = 1.06, p = 0.023) at the former onset. Both the number of symptoms and the affective subscores were correlated (r = 0.93, p = 0.011; r = 0.79, p = 0.016, respectively) and showed no significant difference between the two adjacent onsets of BPSD. The NPI total score (18.29 ± 2.06 vs. 20.80 ± 3.78, p = 0.031) and the psychotic subscore (6.49 ± 1.80 vs. 7.73 ± 1.92, p = 0.033) were significantly lower in the recurrent onset than those in the former and the two values showed no significant correlation between the two onsets. Subscores of lack of control of the two onsets were neither correlated nor different statistically from each other. ConclusionChange of environment, failure to maintain antipsychotic medication, and high NPI score at the former onset are risk factors for the recurrence of BPSD. Profiles of two onsets in the same patient are not always the same. The severity of BPSD and its psychotic symptoms show a tendency to ameliorate with the progression of AD. Affective impairments appear to be consistent. Lack of control disorders may be variable.