Preclinical Evidence Supporting Early Initiation of Citalopram Treatment in Machado-Joseph Disease

Spinocerebellar ataxias are dominantly inherited neurodegenerative disorders with no disease-modifying treatment. We previously identified the selective serotonin reuptake inhibitor citalopram as a safe and effective drug to be repurposed for Machado-Joseph disease. Pre-symptomatic treatment of transgenic (CMVMJD135) mice strikingly ameliorated mutant ataxin-3 (ATXN3) pathogenesis. Here, we asked whether citalopram treatment initiated at a post-symptomatic age would still show efficacy. We used a cohort of CMVMJD135 mice that shows increased phenotypic severity and faster disease progression (CMVMJD135hi) compared to the mice used in the first trial. Groups of hemizygous CMVMJD135hi mice were orally treated with citalopram. Behavior, protein analysis, and pathology assessment were performed blindly to treatment. Our results show that even when initiated after symptom onset, treatment of CMVMJD135hi mice with citalopram ameliorated motor coordination and balance, attenuating disease progression, albeit to a lesser extent than that seen with pre-symptomatic treatment initiation. There was no impact on ATXN3 aggregation, which contrasts with the robust reduction in ATXN3-positive inclusions observed in CMVMJD135 mice, when treated pre-symptomatically. Post-symptomatic treatment of CMVMJD135hi mice revealed, however, a limited neuroprotective effect by showing a tendency to repair cerebellar calbindin staining, and to increase the number of motor neurons and of NeuN-positive cells in certain brain regions. While supporting that early initiation of treatment with citalopram leads to a marked increase in efficacy, these results strengthen our previous observation that modulation of serotonergic signaling by citalopram is a promising therapeutic approach for Machado-Joseph disease even after symptom onset.European Regional Development Funds (FEDER), through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. This article has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the FEDER. This work was also supported by FCT and COMPETE through the projects [PTDC/SAU-GMG/112617/2009] (to PM) and [EXPL/BIM-MEC/0239/2012] (to AT-C), by FCT through the project [POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)] (to PM), by National Ataxia foundation (to PM and to AT-C), and by Ataxia UK (to PM). SE, SD-S, SO, and AT-C were supported by the FCT individual fellowships, SFRH/BD/78554/2011, SFRH/BD/78388/2011, PD/BD/127818/2016, and SFRH/BPD/102317/2014, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa, and EU/FSEinfo:eu-repo/semantics/publishedVersio

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension

BACKGROUND: Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. METHODS AND RESULTS: Four hundred seventy‐seven patients with mild‐to‐moderate Alzheimer disease were randomized to the calcium‐channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH‐related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow‐up visits. Mean age of the study population was 72.2±8.2 years and mean Mini‐Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by −7.8/−3.9 mm Hg for nilvadipine and by −0.4/−0.8 mm Hg for placebo (P<0.001). Across the 78‐week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8–1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH‐related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. CONCLUSIONS: This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild‐to‐moderate Alzheimer disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340

Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: Data from NILVAD

Background: Previous evidence suggests that slower gait speed is longitudinally associated with cognitive impairment, dementia and falls in older adults. Despite this, the longitudinal relationship between gait speed, cognition and falls in those with a diagnosis of dementia remains poorly explored. We sought to assess this longitudinal relationship in a cohort of older adults with mild to-moderate Alzheimer Disease (AD). Methods: Analysis of data from NILVAD, an 18-month randomised-controlled trial of Nilvadipine in mild to moderate AD. We examined: (i) the cross-sectional (baseline) association between slow gait speed and cognitive function, (ii) the relationship between baseline slow gait speed and cognitive function at 18 months (Alzheimer Disease Assessment Scale, Cognitive Subsection: ADAS-Cog), (iii) the relationship between baseline cognitive function and incident slow gait speed at 18 months and finally (iv) the relationship of baseline slow gait speed and incident falls over the study period. Results: Overall, one-tenth (10.03%, N = 37/369) of participants with mild-to-moderate AD met criteria for slow gait speed at baseline and a further 14.09% (N = 52/369) developed incident slow gait speed at 18 months. At baseline, there was a significant association between poorer cognition and slow gait speed (OR 1.05, 95% CI 1.01-1.09, p = 0.025). Whilst there was no association between baseline slow gait speed and change in ADAS-Cog score at 18 months, a greater cognitive severity at baseline predicted incident slow gait speed over 18 months (OR 1.04, 1.01-1.08, p = 0.011). Further, slow gait speed at baseline was associated with a significant risk of incident falls over the study period, which persisted after covariate adjustment (IRR 3.48, 2.05-5.92, p < 0.001). Conclusions: Poorer baseline cognition was associated with both baseline and incident slow gait speed. Slow gait speed was associated with a significantly increased risk of falls over the study period. Our study adds further evidence to the complex relationship between gait and cognition in this vulnerable group and highlights increased falls risk in older adults with AD and slow gait speed. Trial registration: Secondary analysis of the NILVAD trial (Clincaltrials.gov NCT02017340; EudraCT number 2012-002764-27). First registered: 20/12/2013

The impact of anticholinergic burden in Alzheimer's Dementia-the Laser-AD study

Objective: to examine the effect of medications with anticholinergic effects on cognitive impairment and deterioration in Alzheimer's dementia (AD). Methods: cognitive function was measured at baseline and at 6- and 18-month follow-up using the Mini-Mental State Exam (MMSE), the Severe Impairment Battery (SIB) and the Alzheimer's Disease Assessment Battery, Cognitive subsection (ADAS-COG) in a cohort study of 224 participants with AD. Baseline anticholinergic Burden score (ABS) was measured using the Anticholinergic Burden scale and included all prescribed and over the counter medication. Results: the sample was 224 patients with Alzheimer's dementia and 71.4% were women. Their mean age was 81.0 years [SD 7.4 (range 55–98)]. The mean number of medications taken was 3.6 (SD 2.4) and the mean anticholinergic load was 1.1 (SD 1.4, range 0–7). The total number of drugs taken and anticholinergic load correlated (rho = 0.44; P < 0.01). There were no differences in MMSE and other cognitive functioning at either 6 or 18 months after adjusting for baseline cognitive function, age, gender and use of cholinesterase inhibitors between those with, and those without high anticholinergenic load. Conclusions: medications with anticholinergic effect in patients with AD were not found to effect deterioration in cognition over the subsequent 18 months. Our study did not support a continuing effect of these medications on people with AD who are established on them