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Author(s): Brian Lawlor 1,2,*, Ricardo Segurado 3,4, Sean Kennelly 5,6, Marcel G. M. Olde Rikkert 7, Robert Howard 8, Florence Pasquier 9, Anne Börjesson-Hanson 10, Magda Tsolaki 11, Ugo Lucca [...], Background This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. Methods and findings NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of [greater than or equal to]12 and Conclusions The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. Trial registration Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Background: Older adults are frequently prescribed medications with sedative effects, which are associated with numerous adverse consequences. However, the prevalence and longitudinal associations of sedative medication use in community-dwelling older adults with mild–moderate Alzheimer's disease (AD) has not been explored to date. Objectives: Our objective was to assess the prevalence of sedative medication use in community-dwelling older adults with mild–moderate AD and examine the longitudinal association between sedative medication use and adverse events (AEs). Methods: The association between baseline sedative load (SL) and AEs, unscheduled healthcare utilisation, delirium and falls was assessed in older adults with mild–moderate AD over 18 months using secondary analysis of NILVAD trial data (collected from 2014 to 2016). Baseline medication use was assessed, and the SL model was applied to each participant's medication individually. The SL model classifies medications into one of four categories: (1) primary sedatives, (2) medications with a sedating component or prominent side effect, (3) medications with sedation as a potential adverse reaction and (4) all other medications with no known sedative side effects. Medications in group 1 were assigned an SL score of 2, those in group 2 were assigned an SL score of 1, and those in categories 3 and 4 an SL score of 0. SL scores for each medication participants were taking were summed and the total SL calculated as an arithmetic sum of individual medications score. A total SL score ≥ 3 was classed as high. Statistical analysis was conducted using Poisson regression and mixed-effects linear regression, with adjustment for important clinical covariates. We also assessed the impact of SL on dementia progression and cognitive decline. Results: Over half (55.7% [284/510]) of those with mild–moderate AD (age 72.8 ± 8.3 years, 61.9% female) were prescribed a regular medication with sedation as a primary effect or prominent side effect, with 22.2% (113/510) having a high SL (≥ 3). The most common medications contributing to SL were antidepressants, antipsychotics, anxiolytics and hypnotics. Over 18 months, increasing baseline SL was associated with incident AEs (incidence rate ratio [IRR] 1.15; 95% confidence interval [CI] 1.11–1.19; p < 0.001), serious AEs (IRR 1.23; 95% CI 1.11–1.36; p < 0.001) and unscheduled general practitioner visits (IRR 1.23; 95% CI 1.13–1.34; p < 0.001). Further, increasing SL was associated with a greater likelihood of incident delirium (IRR 1.30; 95% CI 1.11–1.53; p < 0.001) and falls (IRR 1.20; 95% CI 1.03–1.42; p = 0.02). Associations persisted after robust covariate adjustment. SL was not associated with accelerated cognitive decline or AD progression. Conclusions: In the current study, over half of older adults with mild–moderate AD were prescribed at least one drug with a sedative effect, and a significant minority had a high SL. Increasing baseline SL was associated with a greater likelihood of incident AEs, delirium and falls, highlighting the need for optimal prescribing in this potentially vulnerable cohort. [ABSTRACT FROM AUTHOR]

We examined the effects of a dihydropyridine calcium channel blocker nilvadipine with anti-inflammatory properties on cognition and cerebrospinal fluid (CSF) biomarkers by baseline Alzheimer's disease (AD) severity. Exploratory analyses were performed on the dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in AD subjects stratified by baseline AD severity into very mild (MMSE ≥ 25), mild (MMSE 20-24) and moderate AD (MMSE < 20). The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS). Cerebrospinal fluid biomarkers Aβ38, Aβ40, Aβ42, neurofilament light chain (NFL), neurogranin, YKL-40, total tau and P181 tau (ptau) were measured in a subset of samples (n = 55). Regression analyses were adjusted for confounders to specifically examine the influence of nilvadipine and baseline AD severity on cognitive outcomes over 78-weeks. Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed a greater cognitive decline on the ADAS-Cog 12 test and the ADCOMS. A lower decline was observed after nilvadipine treatment for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. Cerebrospinal fluid Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Among moderate AD subjects, levels of ptau, total tau, neurogranin and YKL-40 increased in subjects treated with nilvadipine compared to placebo. These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients. Trial Registration: NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340 EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27 [ABSTRACT FROM AUTHOR]

Background: The p75 neurotrophin receptor (p75NTR) modulates pro‐ and anti‐apoptotic pathways as well as neurite and neuritic spine integrity. This receptor is expressed in cells vulnerable to aging and disease, including basal forebrain cholinergic neurons and hippocampal pyramidal neurons. It is also expressed by glial cells under pathological conditions. Pharmacological modulation of the p75NTR with LM11A‐31 alters both age‐ and disease‐related neuronal dysfunction. For example, LM11A‐31 reverses neuritic pathology in aged mice and reduces amyloid‐induced tau phosphorylation in mouse models of Alzheimer's disease (AD). In this proof‐of‐concept study, we examined the effects of LM11A‐31 treatment on longitudinal neuroimaging and CSF biomarkers in humans with mild to moderate Alzheimer's disease. Based on our preclinical work, we hypothesized that age and disease may interact to predict response to LM11A‐31 treatment in humans. Therefore, we additionally conducted subgroup analyses of drug effect in older and younger individuals. Method: Participants with mild to moderate AD (MMSE score = 18‐26; age 55‐85 years) were enrolled in a 26‐week placebo‐controlled phase 2a safety and exploratory endpoint trial of LM11A‐31. Exploratory outcome measures included structural MRI, CSF AD core biomarkers, and CSF biomarkers related to pathological processes affected in mouse studies including synaptic integrity and inflammation. For placebo and drug, age subgroups were defined using a median‐split: younger (<72 years) and older (> = 72 years). Result: Whole brain structural MRI analyses revealed that 26‐week treatment with LM11A‐31 reduced longitudinal grey matter degeneration in AD‐vulnerable brain regions including the inferior temporal gyrus, insula, frontal operculum and retrosplenial cortex. Furthermore, drug treatment, compared to placebo, prevented longitudinal increases of CSF tau, the presynaptic biomarker SNAP25, and the inflammatory biomarker YKL‐40. Median split analyses demonstrated that drug effects for structural MRI and CSF measures were consistently stronger in younger individuals. Conclusion: This investigation highlights that biomarkers may demonstrate age‐dependency in response to therapeutic interventions in the context of mild‐moderate AD. Our results may inform biomarker selection and design of future studies of LM11A‐31 in human AD. [ABSTRACT FROM AUTHOR]

Background: Low cerebrospinal fluid (CSF) levels of Aβ42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Aβ interacts with different brain pathologies early in the disease process is limited. We examined how CSF Aβ markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old.Objective: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia.Methods: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aβ42 and Aβ40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed.Results: In 85-year-olds without dementia, lower levels of both CSF Aβ42 and CSF Aβ40 were associated with WMLs. CSF Aβ42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aβ42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs.Conclusions: Our findings may suggest that there is an interrelationship between Aβ and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aβ42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Aβ deposition than cortical degeneration. [ABSTRACT FROM AUTHOR]

Background: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking.Objective: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aβ42, T-tau, P-tau181, and CSF: serum albumin ratio.Methods: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Aβ42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria.Results: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p = 0.022) and the subtype AD (OR 1.38 CI [1.06-1.82), p = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r = 0.88, p <  0.001), P-tau181 (r = 0.619, p <  0.001), and CSF:serum albumin ratio (r = 0.233, p = 0.031), but not with Aβ42 (r = -0.08, p = 0.444)CONCLUSION:CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aβ metabolism. [ABSTRACT FROM AUTHOR]

Background Frontotemporal dementia (FTD) is believed to be rare in the elderly, and the influence of different criteria on the prevalence of FTD is unclear. Methods Population-based samples of 70- to 95-year-olds (n = 2462) in Gothenburg, Sweden, underwent neuropsychiatric examinations. Behavioral variant FTD (bvFTD) was diagnosed according to the International Behavioural Variant FTD Criteria Consortium (FTDC), the Frontotemporal Lobe Degeneration Consensus criteria, and the Lund-Manchester Research Criteria. A subset (n = 1074) underwent computerized tomography (CT) of the brain. Results The prevalence of bvFTD varied between 0.2% and 0.5% at age 70 to 79 years, between 2.5% and 3.6% at age 80 to 89 years, and between 1.7% and 2.2% at age 90 to 95 years. The agreement between different criteria was low to moderate (κ = 0.20–0.42). Among those with bvFTD according to FTDC, 93.3% had frontal and/or temporal lobar atrophy on CT, compared with 12.6% of those without bvFTD ( P < .001). Conclusions The prevalence of bvFTD was higher than expected in this population. To a large extent, different criteria captured different individuals. [ABSTRACT FROM AUTHOR]

Objective: To examine the occurrence of past month suicidal feelings in extreme old age. Further, to identify factors associated with such feelings. Design: Cross-sectional population-based study. Setting: Gothenburg, Sweden. Participants: 269 adults (197 women, 72 men) without dementia born in 1901-1909 who participated in a psychiatric examination. Main outcome measures: Death thoughts and suicidal feelings. The latter were rated in accordance with the Paykel questions (life not worth living, death wishes, thoughts of taking own life, seriously considered taking own life, attempted suicide) during the past month. Results: One quarter of the sample (26.7%) reported that they thought about their own death at least once a month. Past month thoughts that life was not worth living were acknowledged by 7.9% of the total sample, death wishes by 10.5% and thoughts of taking life by 3.8%. Few had serious thoughts of taking own life (0.8%) and none had attempted suicide. In all, 11.5% acknowledged some level of suicidal feelings. Most (77.4%) of those who reported such feelings fulfilled criteria for neither major nor minor depression. Neither poor perceived health nor disability (hearing, vision and motor function) was associated with suicidal feelings. Problematic sleep and deficient social contacts were also related to suicidal feelings after adjustment for depression. Conclusions: Suicidal feelings may occur outside the context of depression and disability in this age group. Results can inform clinicians who care for persons who reach extreme old age. [ABSTRACT FROM AUTHOR]

Background: The prevalence of psychotropic drug use is high among the elderly, but research on how psychotropic drugs are used among individuals aged 90 years and older is limited. An increased knowledge on this topic may contribute to improved prescribing patterns in this vulnerable population. The aim of this study was to assess the use of psychotropic drugs in relation to mental disorders and institutionalization among 95-year-olds and to identify use of potentially inappropriate psychotropic drugs.Methods: All 95-year-olds born in 1901–1903 living in nursing homes or community settings in Gothenburg, Sweden were invited to participate. The response rate was 65% and 338 95-year-olds were examined (263 women, 75 men). Psychotropic drug use in relation to mental disorders and institutionalization was assessed. Information on drug use was collected primarily from multi-dose drug dispensing lists. Participants were examined by trained psychiatrists using the Comprehensive Psychopathological Rating Scale and a battery of cognitive tests. Dementia, depression, anxiety and psychotic disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R).Results: Sixty percent of the 95-year-old participants used psychotropic drugs; hypnotics were most common (44%). Potentially inappropriate psychotropics were observed in one third (33%). Antidepressants were used by 7% of the participants without dementia who fulfilled criteria for a depressive disorder, while 56% used hypnotics and 30% used anxiolytics.Conclusions: The high prevalence of psychotropic drug use and the nonspecific nature of these treatments among 95-year-olds indicate a need for improvement in prescribing patterns. [ABSTRACT FROM AUTHOR]

Psychotic symptoms are common in elderly persons with dementia. These symptoms affect a person’s ability to function in daily life and put strain on the caregiver. Most studies focus on psychotic symptoms in clinical samples with Alzheimer disease (AD). Thus, their prevalence and relation with dementia subtype and severity in very old populations is unclear. We assessed a representative sample of 85-year-old individuals living in Gothenburg, Sweden (n = 494) using neuropsychiatric examinations, key informant interviews, and medical record reviews; 147 had dementia. Dementia and its severity were diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders (Third Edition, Revision [DSM-III-R]) criteria. Alzheimer disease according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria was diagnosed in 64 persons and vascular dementia (VaD) according to Erkinjuntti criteria was observed in 69. Fourteen had dementia due to other causes. Psychotic symptoms were classified according to DSM-III-R. The prevalence of psychotic symptoms in this very old population was 36% among AD cases compared to 54% in VaD cases (P = .04). Proportions with psychotic symptoms increased with increasing dementia severity in individuals with AD. No such association could be shown in those with VaD. This finding of a high proportion of psychotic symptoms also in individuals with mild severity of VaD should alert health professionals to evaluate dementia in very old patients who present with hallucinations or delusions. [ABSTRACT FROM AUTHOR]

We used data from two population-based longitudinal studies to estimate time of onset and rate of accelerated decline across cognitive domains before dementia diagnosis. The H70 includes an age-homogeneous sample (127 cases and 255 non-cases) initially assessed at age 70 with 12 follow-ups over 30 years. The Kungsholmen Project (KP) includes an age-heterogeneous sample (279 cases and 562 non-cases), with an average age of 82 years at initial assessment, and 4 follow-ups spanning 13 years. We fit mixed linear models to the data and determined placement of change points by a profile likelihood method. Results demonstrated onset of accelerated decline for fluid (speed, memory) versus crystallized (verbal, clock reading) abilities occurring approximately 10 and 5 years before diagnosis, respectively. Although decline before change points was greater for fluid abilities, acceleration was more pronounced for crystallized abilities after the change points. This suggests that onset and rate of acceleration vary systematically along the fluid-crystallized ability continuum. There is early onset in fluid abilities, but these changes are difficult to detect due to substantial age-related decline. Onset occurred later and acceleration was greater in crystallized abilities, suggesting that those markers may provide more valid identification of cases in later stages of the prodromal phase. (JINS, 2011, 17, 000–000) [ABSTRACT FROM PUBLISHER]

We used data from two population-based longitudinal studies to estimate time of onset and rate of accelerated decline across cognitive domains before dementia diagnosis. The H70 includes an age-homogeneous sample (127 cases and 255 non-cases) initially assessed at age 70 with 12 follow-ups over 30 years. The Kungsholmen Project (KP) includes an age-heterogeneous sample (279 cases and 562 non-cases), with an average age of 82 years at initial assessment, and 4 follow-ups spanning 13 years. We fit mixed linear models to the data and determined placement of change points by a profile likelihood method. Results demonstrated onset of accelerated decline for fluid (speed, memory) versus crystallized (verbal, clock reading) abilities occurring approximately 10 and 5 years before diagnosis, respectively. Although decline before change points was greater for fluid abilities, acceleration was more pronounced for crystallized abilities after the change points. This suggests that onset and rate of acceleration vary systematically along the fluid-crystallized ability continuum. There is early onset in fluid abilities, but these changes are difficult to detect due to substantial age-related decline. Onset occurred later and acceleration was greater in crystallized abilities, suggesting that those markers may provide more valid identification of cases in later stages of the prodromal phase. (JINS, 2011, 17, 000–000) [ABSTRACT FROM AUTHOR]