Specific neuropsychiatric symptoms are associated with functional decline trajectories in Alzheimer's disease and Lewy body dementia: a five-year follow-up study.

Background: Neuropsychiatric symptoms (NPS) are often overlooked and under-identified symptoms associated with dementia, despite their significant impact on the prognosis of individuals living with the disease. The specific role of certain NPS in functional prognosis remains unclear. Aims: To determine the association of different NPS with functional decline in people living with Alzheimer's disease (AD) or Lewy body dementia (LBD). Methods: This is an analysis of data from the Dementia Study of Western Norway (DemVest) with 196 patients included of which 111 had AD and 85 LBD. The Neuropsychiatric Inventory (NPI) and the Rapid Disability Rating Scale (RDRS-2) for activities of daily living were administered annually for 5 years. NPI total score and individual items with RDRS-2 trajectories were analyzed with linear mixed models. Results: The LBD group exhibited higher levels of functional impairment and a greater burden of NPS at baseline. Over the 5-year follow-up, hallucinations, aggression, depression, anxiety, apathy, disinhibition, aberrant motor behavior, nighttime behavior disturbances, and abnormal eating patterns were significantly associated with the decline in functional abilities in individuals with AD, as well as irritability and aberrant motor behavior in those with LBD. Discussion: These results highlight the relevance of early detection and intervention of these particularly relevant NPS, due to its potential of also impacting physical function. Better detection and management of these NPS could improve functional prognosis in people living with dementia. Conclusion: Specific NPS demonstrate relevant distinct associations with Longitudinal trajectories of functional decline in AD and LBD.

Specific depressive symptoms are related with different patterns of alcohol use in community-dwelling older adults.

OBJECTIVES: To explore how individual depressive symptoms might contribute to different patterns of alcohol consumption in Colombian older adults living in the community. METHODS: A Secondary analysis from a nationally representative cross-sectional study of more than 23,000 older adults, with data from 19,004 participants. Drinking frequency, and level (moderate or heavy drinking) were used to assess alcohol use and depressive symptoms explored with the 15 items-GDS., using bivariate and multivariate adjusted regression models. RESULTS: Lower weekly drinking frequency and a higher number of drinks per serving were associated with total GDS score. For individual symptoms, higher drinking frequency was associated with dropping activities and a preference to stay at home. Lower drinking frequency was associated with low mood, unhappiness, feelings of emptiness, worthlessness, hopelessness, and a lack of vigour. Lower number of drinks per serving was associated with withdrawal/apathy related symptoms; these also related to higher frequency of weekly alcohol consumption. Higher number of drinks per serving was associated with feelings of emptiness, worthlessness, boredom, helplessness, worthlessness. not wanting to be alive, thinking that other people are better off in their mood, being afraid that something bad will happen and subjective memory problems. Moderate drinkers had a higher likelihood of reporting lack of vigour. CONCLUSION: There were diverse patterns of alcohol use according to individual depressive symptoms. This has implications for interventions to reduce alcohol related harm in older people across a range of depressive symptoms with different patterns of alcohol use.

Differentiating traits and states identifies the importance of chronic neuropsychiatric symptoms for cognitive prognosis in mild dementia.

INTRODUCTION: Neuropsychiatric symptoms (NPS) in dementia are associated with poor cognitive outcomes in longitudinal studies. Whether this is due to differences in symptom burden between persons (BP) or changes within persons (WP) is unknown. METHODS: Patients with mild Alzheimer's disease (AD, n = 111) and Lewy-body dementia (LBD, n = 85) were assessed annually for 8 years. We modelled the association between NPS assessed by the Neuropsychiatric Inventory (NPI) and Mini-Mental State Examinations (MMSE) using Tobit mixed-effects model with NPS as individual means over time (BP) and its deviance (WP). RESULTS: The association between higher NPS and poorer cognitive outcomes was mostly due to BP differences for the NPI-total score, and in particular for delusions, hallucinations, agitation, aberrant motor behavior, and apathy scores. DISCUSSION: The NPS trait (BP) effect on cognitive decline is considerably stronger than the state effect (WP). Clinically, long-term rather than episodic NPS better identifies patients with poor cognitive outcomes.

The Truth behind the Zeros: A New Approach to Principal Component Analysis of the Neuropsychiatric Inventory.

Psychiatric syndromes in dementia are often derived from the Neuropsychiatric Inventory (NPI) using principal component analysis (PCA). The validity of this statistical approach can be questioned, since the excessive proportion of zeros and skewness of NPI items may distort the estimated relations between the items. We propose a novel version of PCA, ZIBP-PCA, where a zero-inflated bivariate Poisson (ZIBP) distribution models the pairwise covariance between the NPI items. We compared the performance of the method to classical PCA under zero-inflation using simulations, and in two dementia-cohorts (N = 830, N = 1349). Simulations showed that component loadings from PCA were biased due to zero-inflation, while the loadings of ZIBP-PCA remained unaffected. ZIBP-PCA obtained a simpler component structure of "psychosis," "mood" and "agitation" in both dementia-cohorts, compared to PCA. The principal components from ZIBP-PCA had component loadings as follows: First, the component interpreted as "psychosis" was loaded by the items delusions and hallucinations. Second, the "mood" component was loaded by depression and anxiety. Finally, the "agitation" component was loaded by irritability and aggression. In conclusion, PCA is not equipped to handle zero-inflation. Using the NPI, PCA fails to identify components with a valid interpretation, while ZIBP-PCA estimates simple and interpretable components to characterize the psychopathology of dementia.

Benzodiazepines and antidepressants: Effects on cognitive and functional decline in Alzheimer's disease and Lewy body dementia.

OBJECTIVES: We aim to study the effects of the prescription of benzodiazepines and antidepressants on cognitive and functional decline in older adults living with Alzheimer's disease (AD) and Lewy body dementia (LBD) over a 5-year follow-up. METHODS: This is a longitudinal analysis of a Norwegian cohort study entitled "The Dementia Study of Western Norway" (DemVest). We included 196 patients newly diagnosed with AD (n = 111) and LBD (n = 85), followed annually for 5 years. Three prescription groups were defined: only benzodiazepines (BZD), only antidepressants (ADep), and the combination of benzodiazepines and antidepressants (BZD-ADep). Linear mixed-effects models were conducted to analyze the effect of the defined groups on the outcomes. The outcomes were functional decline, measured by the Rapid Disability Rating Scale-2, and cognition measured with the Mini-Mental State Examination. RESULTS: Prescription of the combination of benzodiazepines and antidepressants in LBD was associated with faster functional decline. In AD, the prescription of BZD and BZD-ADep was associated with greater functional deterioration. ADep alone did not show positive or negative significant associations with the studied outcomes. CONCLUSIONS: BZD and especially the combination of BZD and ADep are associated with functional decline in AD and LBD and should be used cautiously.

Hippocampal subfields and decline in activities of daily living in Alzheimer's disease and dementia with Lewy bodies.

Background: Hippocampal atrophy is presented in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Cognition, dual-tasks, muscular function, goal-related behaviors and neuropsychiatric symptoms are linked to hippocampal volumes and may lead to functional decline in activities of daily living. We examined the association between baseline hippocampal subfield volumes (HSv) in mild AD and DLB, and functional decline. Materials & methods: 12 HSv were computed from structural magnetic resonance images using Freesurfer 6.0 segmentation. Functional decline was assessed using the rapid disability rating scale score. Linear regressions were conducted. Results: In AD, HSv were smaller bilaterally. However, HSv were not associated with functional decline. Conclusion: Functional decline does not depend on HSv in mild AD and DLB.

Neuropsychiatric Symptoms and Functional Decline in Alzheimer's Disease and Lewy Body Dementia.

BACKGROUND/OBJECTIVES: Functional status is one of the most important markers of well-being in older adults, but the drivers of functional decline in dementia are not well known. The aim of our work was to study the association of neuropsychiatric symptoms (NPSs) with functional decline over 5 years in newly diagnosed people with Alzheimer´s disease (AD) and Lewy body dementia (LBD). DESIGN: Secondary analysis of the Dementia Study of Western Norway longitudinal cohort study. SETTING: Multicenter study conducted in memory clinics in western Norway. PARTICIPANTS: We included a total of 196 patients newly diagnosed with AD (n = 111) and LBD (n = 85), followed up annually for 5 years. MAIN OUTCOMES AND MEASURES: The outcome was the rapid disability rating scale (items 1-13). Linear mixed-effects models were used for analysis with the total score of the Norwegian Neuropsychiatric Inventory (NPI) as a predictor measured either at baseline or longitudinally, adjusted for potential confounders, including cognition. Effect modification was checked by introducing interactions with NPI score and stratifying by diagnosis. RESULTS: The total NPI score longitudinal course was associated with functional decline in both AD and LBD. At baseline, the total NPI score predicted functional decline in AD. CONCLUSION: NPSs were associated with the rate of functional decline in people with AD and LBD, independent of cognitive impairment. These results highlight the relevance of early detection and intervention of NPSs, which may also reduce functional decline. J Am Geriatr Soc 68:2257-2263, 2020.

The individual course of neuropsychiatric symptoms in people with Alzheimer's and Lewy body dementia: 12-year longitudinal cohort study.

INTRODUCTION: Understanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals. METHOD: Primary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia). RESULTS: We found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms. CONCLUSIONS: We observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.

Serum Potassium Is Associated with Cognitive Decline in Patients with Lewy Body Dementia.

BACKGROUND: Epidemiological studies link serum potassium (K+) to cognitive performance, but whether cognitive prognosis in dementia is related to K+ levels is unknown. OBJECTIVE: To determine if K+ levels predict cognitive prognosis in dementia and if this varies according to diagnosis or neuropathological findings. METHODS: This longitudinal cohort study recruited 183 patients with mild Alzheimer's disease or Lewy body dementia (LBD). Serum K+ and eGFR were measured at baseline and medications which could affect K+ registered. The Mini-Mental State Examination (MMSE) was measured annually over 5 years, and mortality registered. Association between K+ and √(30 -MMSE) was estimated overall, and according to diagnosis (joint model). Associations between MMSE-decline and K+ were assessed in two subgroups with neuropathological examination (linear regression) or repeated measurements of K+ over 3 years (mixed model). RESULTS: Serum K+ at baseline was associated with more errors on MMSE over time (Estimate 0.18, p = 0.003), more so in LBD (p = 0.048). The overall association and LBD interaction were only significant in the 122 patients not using K+ relevant medication. Repeated K+ measures indicated that the association with MMSE errors over time was due to a between-person effect (p < 0.05, n = 57). The association between the annual MMSE decline was stronger in patients with autopsy confirmed LBD and more α-synuclein pathology (all: p < 0.05, n = 41). CONCLUSION: Higher serum K+ predicts poorer cognitive prognosis in demented patients not using medications which affect K+, likely a between-person effect seen mainly in LBD.

Course of neuropsychiatric symptoms in dementia: 5-year longitudinal study.

OBJECTIVE: Neuropsychiatric symptoms (NPS) in dementia are frequent and challenging for patients, carers, and the health care system, but few long-term studies exist. We analyse the longitudinal course of NPS in patients with mild dementia. METHODS: A longitudinal cohort study of 223 patients with mild dementia and annual assessments using the Neuropsychiatric Inventory (NPI) for 5 years. RESULTS: A total 1043 NPI assessments, representing 97% of all possible measurements of living cohort members, were analysed. Neuropsychiatric symptoms were common at baseline, and only a moderate increase in total NPS score from 15 to 17 with no increase in the proportion with high NPI total scores. Ninety seven percent scored ≥16, and 49% scored ≥36 on NPI total score at least once during follow-up. Individual NPS fluctuated and often reappeared. The most common symptoms ever reported was apathy (83%), depression (63%), appetite (63%), and aberrant motor behavior (60%). Cognitive decline was associated with higher NPI total score and several NPI items, but only the frequency of apathy increased significantly with time. Lewy body dementia was associated with higher NPI total score and psychotic symptoms. Alzheimer's disease was associated with increase in apathy. CONCLUSIONS: Severe NPS are already common at time of dementia diagnosis, and the increase in overall severity over 5 years was moderate. Individual symptoms tend to fluctuate over time within patients and correspond to states rather than traits. These findings highlight the need to focus on, and plan for, NPS as part of dementia pathway, and are relevant for clinical trial design.

Antibodies to Multiple Receptors are Associated with Neuropsychiatric Symptoms and Mortality in Alzheimer's Disease: A Longitudinal Study.

BACKGROUND: Endogenous antibodies to signaling molecules and receptors (Abs) are associated with Alzheimer's disease (AD). OBJECTIVES: To investigate the association of 33 Abs to dopaminergic, serotoninergic, muscarinic, adrenergic, vascular, and immune receptors with cognitive, neuropsychiatric, and mortality outcomes. METHODS: Ninety-one patients with mild AD were followed annually for 5 years with the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI; composite outcomes: "psychosis" (item 1 + 2), "mood" (item 4 + 5 + 7), and "agitation" (item 3 + 8 + 9)). Abs were quantified in sera obtained at baseline by ELISA and reduced to principal components (PCs). Associations between Abs and outcomes were assessed by a mixed model (MMSE decline), zero-inflated fixed effects count models (composite NPI scores), and Cox regression (mortality). The resulting p-values were adjusted for multiple testing according to a false discovery rate of 0.05 (Benjamini-Hochberg). RESULTS: The measured levels of the 33 Abs formed four PCs. PC1 (dopaminergic and serotonergic Abs) was associated with increased mortality (Hazard ratio 2.57, p < 0.001), PC2 (serotonergic, immune, and vascular Abs) with decreased agitation symptoms (ß - 0.19, p < 0.001), and PC3 (cholinergic receptor Abs) with increased mood symptoms (ß 0.04, p = 0.002), over time. There were no associations between Abs and MMSE decline. CONCLUSION: The associations between Abs, mortality, and neuropsychiatric symptoms reported in this cohort are intriguing. They cannot, however, be generalized. Validation in independent sample sets is required.

Lipogenic effects of psychotropic drugs: focus on the SREBP system.

Antipsychotics, antidepressants and mood stabilizers are psychotropic drugs widely used in the treatment of psychiatric disorders, such as schizophrenia, bipolar disorder and major depressive disorder. Such drugs have been used since the early 1950s, and it is now well established that they target neurotransmitter receptors and/or transporters located on central nervous system (CNS) neurons. However, their mechanism of action is still not fully understood, and there is large inter-individual variation in therapeutic response. Psychotropic drugs are also associated with numerous adverse effects, of which weight gain and metabolic disturbances have gained increased focus during the last decade. Based on studies in cultured cells, we have demonstrated that several psychotropic drugs upregulate the expression of genes involved in cellular fatty acid and cholesterol biosynthesis, controlled by the SREBP transcription factors. Lipogenic effects were also observed in vivo, in rat liver and in lymphocytes from drug-treated patients. These results provide new insight into the molecular mechanisms of psychotropic drug action and could be relevant both for their therapeutic action and metabolic adverse effects.

Gene expression profiles in rat brain disclose CNS signature genes and regional patterns of functional specialisation.

BACKGROUND: The mammalian brain is divided into distinct regions with structural and neurophysiological differences. As a result, gene expression is likely to vary between regions in relation to their cellular composition and neuronal function. In order to improve our knowledge and understanding of regional patterns of gene expression in the CNS, we have generated a global map of gene expression in selected regions of the adult rat brain (frontomedial-, temporal- and occipital cortex, hippocampus, striatum and cerebellum; both right and left sides) as well as in three major non-neural tissues (spleen, liver and kidney) using the Applied Biosystems Rat Genome Survey Microarray. RESULTS: By unsupervised hierarchical clustering, we found that the transcriptome within a region was highly conserved among individual rats and that there were no systematic differences between the two hemispheres (right versus left side). Further, we identified distinct sets of genes showing significant regional enrichment. Functional annotation of each of these gene sets clearly reflected several important physiological features of the region in question, including synaptic transmission within the cortex, neurogenesis in hippocampus and G-protein-mediated signalling in striatum. In addition, we were able to reveal potentially new regional features, such as mRNA transcription- and neurogenesis-annotated activities in cerebellum and differential use of glutamate signalling between regions. Finally, we determined a set of 'CNS-signature' genes that uncover characteristics of several common neuronal processes in the CNS, with marked over-representation of specific features of synaptic transmission, ion transport and cell communication, as well as numerous novel unclassified genes. CONCLUSION: We have generated a global map of gene expression in the rat brain and used this to determine functional processes and pathways that have a regional preference or ubiquitous distribution within the CNS, respectively. The existence of shared specialised neuronal activities in CNS is interesting in a context of potential functional redundancy, and future studies should further explore the overall characteristics of CNS-specific versus region-specific gene profiles in the brain.

Zebrafish kidney marrow contains ABCG2-dependent side population cells exhibiting hematopoietic stem cell properties.

Zebrafish (Danio rerio) has emerged as a powerful genetic model for the study of vertebrate hematopoiesis. However, methods for detection and isolation of hematopoietic stem cells (HSCs) have not yet been reported. In mammals, the combination of Hoechst 33342 staining with flow cytometry can be used for separation of a bone marrow side population (SP), which is highly enriched for HSCs. We applied a similar procedure to hematopoietic kidney marrow cells from adult zebrafish, and identified a segregated cohort of SP cells, which demonstrate a set of features typical of stem cells. SP cells show extremely low scatter characteristics, and are small in size with a minimum of cytoplasm. Treatment of zebrafish kidney marrow cells with reserpine or fumitremorgin C, which inhibit the ABCG2 transporter responsible for Hoechst 33342 efflux, caused a clear reduction in the number of SP cells. Consistent with the quiescent state of HSCs, the SP cells are strongly resistant to the myelosuppressive agent 5-fluorouracil. In addition, SP cells specifically demonstrate higher expression of genes known to be markers of HSCs of mammals. Hence, our results show that the SP phenotype is conserved between mammals and teleosts, and the properties of the zebrafish SP cells indicate a significant enrichment for HSCs. These rapid flow cytometric methods for purification of HSCs from zebrafish may greatly facilitate genetic analysis of stem cells using the advantages of this vertebrate model.