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Treatment effects in multiple cognitive domains in Alzheimer's disease: a two-year cohort study.

ABSTRACT: Despite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer's disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort.A cohort of patients meeting the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for mild or moderate AD, including patients both on treatment with a cholinesterase inhibitor and untreated controls (treated?=?65, untreated?=?65), were recruited from the Cognitive Neurology Clinic at Sunnybrook Health Sciences Centre, as part of the Sunnybrook Dementia Study. Patients were followed for one to two years and underwent standardized neuropsychological assessments to evaluate global and domain-specific cognitive function. Associations between cholinesterase inhibitor use and global and domain-specific cognitive outcome measures at one and two years of follow-up were estimated using mixed model linear regression, adjusting for age, education, and baseline mini mental state examination (MMSE).At one year, treated patients showed significantly less decline in global cognitive function, and treatment and time effects across tests of executive and visuospatial function. At two years, there was a significant trend towards less decline in global cognition for treated patients. Moreover, treated patients showed significant treatment and time effects across tests of executive functioning, memory, and visuospatial function.The present study offers two important contributions to knowledge of the effectiveness of cholinesterase inhibitor treatment in patients with mild-moderate AD: 1) that second-generation cholinesterase inhibitors demonstrate long-term effectiveness for reducing global cognitive decline over one to two years of follow-up, and 2) that decline in function for cognitive domains, including executive function, memory, and visuospatial skill that are primarily mediated by frontal networks and by the cholinergic system, rather than memory, may be slowed by treatment targeting the cholinergic system.

SUBMITTER: Behl P

PROVIDER: S-EPMC4255390 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Treatment effects in multiple cognitive domains in Alzheimer's disease: a two-year cohort study.

Behl Pearl P Edwards Jodi D JD Kiss Alexander A Lanctot Krista L KL Streiner David L DL Black Sandra E SE Stuss Donald T DT

Alzheimer's research & therapy 20140818 4

<h4>Introduction</h4>Despite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer's disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or modera ...[more]

PMID: 25484926

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Project description:OBJECTIVE:Selective serotonin reuptake inhibitors (SSRIs) have increased cognitive performance in some clinical studies of Alzheimer's disease (AD), but it is has been difficult to dissociate whether this is due to direct effects on cognition (neurochemical or disease-modifying) or a secondary effect of mood stabilization. We performed a systematic review for preclinical and human clinical trial evidence to support the use of SSRIs specifically for the management of cognitive decline in AD. DATA SOURCES:(1) PUBMED without language restrictions from 1950s until 2004 and updated August 2006, terms: "serotonin uptake inhibitors"[MeSH] AND ("Alzheimer disease"[MeSH] OR "Cognition Disorders"[MeSH]) NOT "Parkinson disease"[MeSH] AND (Clinical Trial[ptyp] OR Letter[ptyp] OR Meta-Analysis[ptyp] OR Randomized Controlled Trial[ptyp]) AND "alzheimer disease" [MESH] OR "Alzheimer*" combined with AND to "ssri*" OR "serotonin reuptake inhibitors" [MESH] NOT Review[ptyp]. (2) Cochrane Database of Systematic Reviews, keywords "SSRI" and "Alzheimer's". STUDY SELECTION:The PubMed search yielded 57 hits. Of these, 23 were included in this review for their specificity to SSRI use in AD or indications on efficacy beyond depressive symptoms. The other 34 citations were excluded because: (1) depression or other mood or behavioral disturbance severity was the reported outcome measure, (2) effects of SSRIs on cognition were confounded by concomitant use of other drugs, (3) subjects described were young adults, and/or (4) subjects had traumatic brain injury. The Cochrane Database of Systematic Reviews, 3rd Quarter 2006, yielded six citations related to SSRIs. DATA EXTRACTION:Data extracted from clinical trials included name of SSRI tested, cognitive outcome measures, and adverse events reported, which could include cognitive worsening. DATA SYNTHESIS:Preclinical evidence for use of SSRIs to enhance cognition in AD includes an effect at the hippocampus through carbonic anhydrase activation or stimulation of hippocampal neurogenesis. The chemical structure of paroxetine, and not intrinsic SSRI activity, may also affect APP ectodomain expression to reduce amyloid plaque formation. Clinical trials in AD generally have not assessed cognitive outcomes independently from mood or behavior stabilization. Currently, clinical studies in AD only indirectly support the use of SSRIs for disease modification by confirming a serotonergic deficit during the course of illness. CONCLUSIONS:Lack of supportive evidence for SSRIs as cognition enhancers or disease modifiers in AD is the result of omissions in clinical trial design, as opposed to reporting of negative outcomes. The preclinical evidence warrants the study of SSRIs in AD using mood, behavior, cognition, neurochemistry, and possibly neuroimaging as outcome variables.

Project description:Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. So far, there is no effective treatment for this condition. Tetramethylpyrazine (TMP) is an alkaloid extracted from traditional Chinese medicine chuanxiong, which is mainly used in the treatment of ischemic stroke some related diseases. In this study, we studied the potential effects of TMP on AD progression by using two AD mouse models. 8-month-old 3xTg-AD mice received TMP treatment (10mg/kg/d) for 1 month, and 4-month-old APP/PS1-AD mice received TMP treatment (10mg/kg/d) for 2 months. The behavioral tests by step-down passive avoidance test (SDA), new object recognition (NOR) and Morris water maze (MWM) showed that TMP significantly improved the learning and memory impairment of two AD transgenic mice. In addition, TMP reduced Aß levels and tau phosphorylation. Venny analysis showed that 116 differentially expressed proteins were commonly changed in 3xTg mice vs WT mice and TMP treated mice vs untreated mice. The same, 130 differentially expressed proteins were commonly changed in APP/PS1 mice vs WT mice and TMP treated mice vs untreated mice. The functions of the common proteins modified by TMP in the two models were mainly related to mitochondrial function, synaptic function, cytoskeleton, GTP binding, ATP binding. Mitochondrial omics analysis revealed 21 and 20 differentially expressed mitochondrial proteins modified by TMP in 3xTg-AD mice and APP/PS1 mice, respectively. These differential proteins were located in mitochondrial inner membrane, mitochondrial outer membrane, mitochondrial gap and mitochondrial matrix, and the function of some proteins is closely related to oxidative phosphorylation of (OXPHOS). Western-blot further validated that TMP changed the expression of OXPHOS complex proteins (sdhb, ndufa10, uqcrfs1, cox5b, atp5a) in the hippocampus of the two AD mice. Taken together, our study demonstrated that TMP improved the cognitive impairment and AD-like pathology, and modified hippocampal proteome in the two AD mice models. The improvement of the behavioral and pathology might be associated with modification of mitochondrial protein profile by TMP. Our study suggested that TMP had the potential for the treatment of AD.

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Treatment effects in multiple cognitive domains in Alzheimer's disease: a two-year cohort study.

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Treatment effects in multiple cognitive domains in Alzheimer's disease: a two-year cohort study.

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