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Objectives We aim to study the effects of the prescription of benzodiazepines and antidepressants on cognitive and functional decline in older adults living with AD (Alzheimer's disease) and LBD (Lewy body dementia) over a five-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. 3 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 didn't 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. This article is protected by copyright. All rights reserved.

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

Background: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline. Objective: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia. Methods: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer’s disease (AD) (n = 103), Lewy body dementia (LBD) (n = 74), and other dementias (OD) (n = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models. Results: At baseline, the prevalence of general malnutrition was 28.7%; 17.3% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline. Conclusion: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis.

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. publishedVersion

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.

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.

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 (β - 0.19, p < 0.001), and PC3 (cholinergic receptor Abs) with increased mood symptoms (β 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.

IntroductionUnderstanding 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.MethodPrimary 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).ResultsWe 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.ConclusionsWe 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.

Introduction: The aim of the study is to describe the frequency of frailty in people with a new diagnosis of mild dementia due to Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Methods: This is a secondary analysis of the Dementia Study of Western Norway (Demvest). For this study, we analysed a sample of 186 patients, 116 with AD and 70 with DLB. Subjects were included at a time in which mild dementia was diagnosed according to consensus criteria after comprehensive standardized assessment. Frailty was evaluated retrospectively using a frailty index generated from existing data. The cut-off value used to classify an older adult as frail was 0.25. Results: The prevalence of frailty was 25.81% (n = 48). In the DLB group, 37.14% (n = 26) were classified as frail, compared to 18.97% (n = 22) of those with AD (p < 0.001). The adjusted multivariate analysis revealed an OR of 2.45 (1.15–5.23) for being frail in those with DLB when using AD as the reference group. Conclusion: Frailty was higher than expected in both types of dementia. The prevalence of frailty was higher in those with DLB compared to AD. This new finding underscores the need for a multi-systems approach in both dementias, with a particular focus on DLB.

Psychotic symptoms may occur in any dementia, including Alzheimer’s disease (AD), but are particularly common in Lewy body dementia (LBD). The mechanisms of psychotic symptoms are largely unknown. Psychosis has been found to be associated with more severe AD and Lewy body pathology in patients with AD and cerebrovascular disease-related vasculopathy.1 One form of vascular pathology, cerebral amylod angiopathy (CAA), is defined as deposits of amyloid in the vessel walls that increase risk of haemorrhage and ischaemia. CAA contributes to neurodegeneration, but its relation to clinical symptoms and course in dementia is not fully understood.2 The aim of this study was to investigate the postmortem pathological correlates of severe psychotic symptoms in moderate AD and LBD, which were followed annually from the time of diagnosis until death. This is a 12-year prospective follow-up study of dementia ending in neuropathological examination. The 223 patients of the dementia study in Western Norway (Demvest) were diagnosed as mild dementia and followed annually with standardised clinical assessments until death. Patient were diagnosed according to standardised clinical criteria for AD3 and DLB4 or Parkinson's disease dementia (PDD) (both combined as LBD) and mild dementia defined as Mini Mental Status Examination (MMSE) score of at least 20 or a Clinical Dementia Rating scale(CDR) global score=1. The procedures are described in detail elsewhere.5 All comparisons are between groups are based on pathological defined diagnosis. The validated Norwegian 12-item Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. Presence of severe psychosis was based on the first 5 years after diagnosis and MMSE value above 10. NPI score of >4 on either item 1 (delusions) or 2 (hallucinations) was used as clinical significant cut-off. …

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.

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.