Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

INTRODUCTION: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. METHODS: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. RESULTS: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. DISCUSSION: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration.

INTRODUCTION: Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. METHODS: We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. RESULTS: Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). DISCUSSION: Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

Arguing against the proposed definition changes of PD.

As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled "Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease." In particular, we suggest that the 1-year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, "PD (dementia with Lewy bodies subtype)," will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Improving dementia diagnosis and management in primary care: a cohort study of the impact of a training and support program on physician competency, practice patterns, and community linkages.

BACKGROUND: Primary care physicians routinely provide dementia care, but may lack the clinical skills and awareness of available resources to provide optimal care. We conducted a community-based pilot dementia training intervention designed to both improve clinical competency and increase utilization of local dementia care services. METHODS: Physicians (N = 29) and affiliated staff (N = 24) participated in a one-day training program on dementia screening, diagnosis and management that included direct engagement with local support service providers. Questionnaires about their dementia care competency and referral patterns were completed before and 6 months after the training intervention. RESULTS: Physicians reported significantly higher overall confidence in their dementia care competency 6 months post-training compared to pre-training. The largest reported improvements were in their ability to educate patients and caregivers about dementia and making appropriate referrals to community care services. Participants also reported markedly increased use of cognitive screening tools in providing care. Community service providers recorded approximately 160 physician-initiated referrals over a 2 year-period post-training, compared to few beforehand. CONCLUSIONS: Combining a targeted physician practice-based educational intervention with community service engagement improves dementia care competency in clinicians and promotes linkages between clinical and community dementia care providers.

Event-related functional magnetic resonance imaging changes during relational retrieval in normal aging and amnestic mild cognitive impairment.

The earliest cognitive deficits observed in amnestic mild cognitive impairment (aMCI) appear to center on memory tasks that require relational memory (RM), the ability to link or integrate unrelated pieces of information. RM impairments in aMCI likely reflect neural changes in the medial temporal lobe (MTL) and posterior parietal cortex (PPC). We tested the hypothesis that individuals with aMCI, as compared to cognitively normal (CN) controls, would recruit neural regions outside of the MTL and PPC to support relational memory. To this end, we directly compared the neural underpinnings of successful relational retrieval in aMCI and CN groups, using event-related functional magnetic resonance imaging (fMRI), holding constant the stimuli and encoding task. The fMRI data showed that the CN, compared to the aMCI, group activated left precuneus, left angular gyrus, right posterior cingulate, and right parahippocampal cortex during relational retrieval, while the aMCI group, relative to the CN group, activated superior temporal gyrus and supramarginal gyrus for this comparison. Such findings indicate an early shift in the functional neural architecture of relational retrieval in aMCI, and may prove useful in future studies aimed at capitalizing on functionally intact neural regions as targets for treatment and slowing of the disease course. (JINS, 2012, 18, 1-12).

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders.

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Dementia in Parkinson's disease.

OPINION STATEMENT: Dementia in Parkinson's disease encompasses a spectrum relating to motor, psychiatric, and cognitive symptoms that are classified as either Dementia with Lewy Bodies (DLB) (initial cognitive symptoms) or Parkinson's Disease Dementia (PDD) (initial motor signs preceding cognitive symptoms by at least a year). Anticholinergic and antipsychotic drugs have a high risk of adverse cognitive and/or motor effects, so their use should be minimized or avoided. Neuroleptic sensitivity is a severe psychomotor adverse reaction that is particularly associated with potent dopamine-blocking agents such as haloperidol. It occurs in up to 50% of individuals with PDD or DLB. Mild psychotic symptoms should first be addressed by reducing anticholinergic and/or dopaminergic agents, if possible. Patients with psychotic symptoms that threaten the safety of the patient or caregiver may benefit from treatment with quetiapine or, in refractory cases, clozapine. Cholinesterase inhibitors as a drug class have been shown to have beneficial effects on cognition in DLB and PDD, and may help to alleviate some psychiatric symptoms, such as apathy, anxiety, hallucinations, and delusions. Memantine may help to moderate cognitive symptoms in DLB and PDD, although current data suggest a more variable response, particularly in PDD. Parkinsonian motor signs that are accompanied by clinically significant cognitive impairment should be treated with carbidopa/levodopa only, as dopamine agonists and other antiparkinsonian medications generally carry a higher risk of provoking or exacerbating psychotic symptoms. Excessive daytime sleepiness and REM sleep behavior disorder are common associated features of PDD and DLB. Minimizing sedating medications during the day and promoting nocturnal sleep may help the daytime sleepiness; melatonin, clonazepam, gabapentin, and possibly memantine may be useful in treating REM sleep behavior disorder. Orthostatic hypotension can be managed with various nonpharmacologic interventions, and if needed, fludrocortisone and pyridostigmine. Midodrine should be used cautiously, if at all.

Constructing Connectome Atlas by Graph Laplacian Learning.

The recent development of neuroimaging technology and network theory allows us to visualize and characterize the whole-brain functional connectivity in vivo. The importance of conventional structural image atlas widely used in population-based neuroimaging studies has been well verified. Similarly, a "common" brain connectivity map (also called connectome atlas) across individuals can open a new pathway to interpreting disorder-related brain cognition and behaviors. However, the main obstacle of applying the classic image atlas construction approaches to the connectome data is that a regular data structure (such as a grid) in such methods breaks down the intrinsic geometry of the network connectivity derived from the irregular data domain (in the setting of a graph). To tackle this hurdle, we first embed the brain network into a set of graph signals in the Euclidean space via the diffusion mapping technique. Furthermore, we cast the problem of connectome atlas construction into a novel learning-based graph inference model. It can be constructed by iterating the following processes: (1) align all individual brain networks to a common space spanned by the graph spectrum bases of the latent common network, and (2) learn graph Laplacian of the common network that is in consensus with all aligned brain networks. We have evaluated our novel method for connectome atlas construction in comparison with non-learning-based counterparts. Based on experiments using network connectivity data from populations with neurodegenerative and neuropediatric disorders, our approach has demonstrated statistically meaningful improvement over existing methods.

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

OBJECTIVE: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. METHODS: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. RESULTS: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. CONCLUSIONS: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

Brain volumetric deficits in MAPT mutation carriers: a multisite study.

OBJECTIVE: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. METHODS: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. RESULTS: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. INTERPRETATION: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Lewy body dementia: caregiver burden and unmet needs.

Lewy body dementia (LBD) is a common cause of dementia but to date, little is known about caregiver burden. The Lewy Body Dementia Association (www.LBDA.org) conducted a web-based survey of 962 caregivers (mean age 56 y; 88% women). The most common initial symptoms were cognitive (48%), motor (39%), or both (13%). Caregivers expressed concerns about fear of future (77%), feeling stressed (54%), loss of social life (52%), and uncertainty about what to do next (50%). Caregivers reported moderate-to-severe burden; 80% felt the people around them did not understand their burden and 54% reported feelings of isolation with spousal caregivers reporting more burden than nonspousal caregivers. Only 29% hired in-home assistance, whereas less than 40% used respite or adult day care, geriatric case managers, or attended a support group meeting. Lack of service utilization occurred despite two-thirds of caregivers reporting medical crises requiring emergency services, psychiatric care, or law enforcement. Caregivers reported preferences for web-based information, directories of LBD expert providers, information on LBD research, and location of local support groups. These findings highlight significant unmet needs for LBD caregivers and provide targets for intervention to reduce caregiver burden. Community resources such as the Lewy Body Dementia Association may serve this end, while also providing practical information and support for caregivers.

An examination of Alzheimer's disease case definitions using Medicare claims and survey data.

BACKGROUND: The prevalence and expenditure estimates of Alzheimer's disease (AD) from studies using one data source to define cases vary widely. The objectives of this study were to assess agreement between AD case definitions classified with Medicare claims and survey data and to provide insight into causes of widely varied expenditure estimates. METHODS: Data were obtained from the 1999-2004 Medicare Current Beneficiary Survey linked with Medicare claims (n = 57,669). Individuals with AD were identified by survey, diagnosis, use of an AD prescription medicine, or some combination thereof. We also explored how much health care and drug expenditures vary by AD case definition. RESULTS: The prevalence of AD differed significantly by case definition. Using survey report alone yielded more cases (n = 1,994 or 3.46%) than diagnosis codes alone (n = 1,589 or 2.76%) or Alzheimer's medication use alone (n = 1,160 or 2.01%). Agreement between case definitions was low, with kappa coefficients ranging from 0.37 to 0.40. Per capita health expenditures ranged from $16,547 to $24,937, and drug expenditures ranged from $2,303 to $3,519, depending on how AD was defined. CONCLUSIONS: Different information sources yield widely varied prevalence and expenditure estimates. Although claims data provided a more objective means for identifying AD cases, survey report identified more cases, and pharmacy data also are an important source for case ascertainment. Using any single source will underestimate the prevalence and associated cost of AD. The wide range of AD cases identified by using different data sources demands caution interpreting cost-of-illness studies using single data sources.

Apathy rating scores and ß-amyloidopathy in patients with Parkinson disease at risk for cognitive decline.

OBJECTIVE: To determine whether ß-amyloidopathy correlates with apathy rating scores independently of mood changes and other neurodegenerative processes in Parkinson disease (PD). METHODS: In this cross-sectional study, patients with PD (n = 64, 48 male and 16 female, mean age 69.2 ± 6.7 years, Hoehn & Yahr stage 2.7 ± 0.5, Montreal Cognitive Assessment score 25.3 ± 3.0) underwent [11C]Pittsburgh compound B ß-amyloid, [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 (VMAT2), and [11C]methyl 4 piperidinyl propionate acetylcholinesterase brain PET imaging and clinical assessments, including the Marin Apathy Evaluation Scale, Clinician Version. Patients were recruited on the basis of having at least 1 risk factor for PD dementia, but they were excluded if they had dementia. RESULTS: Mean apathy rating score was 25.4 ± 6.4, reflecting predominantly subclinical apathy. Apathy rating scale scores correlated with amyloid binding, cognitive, depressive, and anxiety scores but not significantly with age, duration of disease, striatal VMAT2, or cholinergic binding. Multiple regression analysis model (p < 0.0001) showed significant regressor effects for global ß-amyloid burden (p = 0.0038) with significant covariate effects for global cognitive z scores (p = 0.028) and for anxiety (p = 0.038) but not with depressive scores. Voxel-based analysis showed robust correlation between apathy rating scale scores and ß-amyloid binding in bilateral nuclei accumbens, inferior frontal, and cingulate cortices (family-wise error rate-corrected p < 0.005). CONCLUSION: Apathy is independently associated with ß-amyloidopathy in patients with PD at risk of dementia. Regional brain findings are most robust for ß-amyloidopathy in the nuclei accumbens, inferior frontal, and cingulate regions. Findings may provide an explanation for the often treatment-refractory nature of apathy in advancing PD despite optimized dopaminergic and antidepressant pharmacotherapy. CLINICALTRIALSGOV IDENTIFIER: NCT01565473.

The concentration and persistence of health care expenditures and prescription drug expenditures in Medicare beneficiaries with Alzheimer disease and related dementias.

BACKGROUND: Alzheimer disease and related dementias (ADRD) have become a major concern for Medicare because of the increasing prevalence rate and the associated high cost of care. OBJECTIVES: This study investigated the extent of concentration and persistence in total health care expenditures and prescription drug expenditures among the elderly with ADRD, and identified characteristics associated with expenditure persistence that may provide targets for cost containment approaches. RESEARCH DESIGN: This retrospective cohort study analyzed cross-sectional Medicare Current Beneficiary Survey data to examine expenditure concentration by calculating the proportion of total and prescription drug expenditures incurred by the top 10%, top 25%, and top 50% of beneficiaries in each year. A transition probability matrix and logit models were estimated to predict expenditure persistence over a 2-year period. RESULTS: The top 10% of beneficiaries with ADRD accounted for nearly half of total health expenditures and one-third of drug expenditures. Inpatient care comprised the largest share of overall expenditures in the top 10% group, whereas physician visits and prescription medications were the cost drivers in the bottom 50% group. Expenditure persistence was very strong, especially for prescription drugs. Prior expenditures and comorbidity burdens were the strongest predictors of persistence. CONCLUSIONS: The results of our study highlight the challenges to reducing expenditure growth and persistence for high-cost ADRD beneficiaries with prominent comorbidities. It will be important to examine whether better care coordination and disease management tailored to high-cost beneficiaries with ADRD can effectively contain costs.

Culinary Medicine: Advancing a Framework for Healthier Eating to Improve Chronic Disease Management and Prevention.

Unsustainable increases in the prevalence and costs of chronic disease in the United States call for low-cost, high-impact interventions that can be readily incorporated into people's daily lives. Culinary medicine is one such intervention. As a practical discipline, culinary medicine integrates the art of preparing, cooking, and presenting food with the science of medicine to achieve desired health outcomes. This article describes how the underpinnings and components of culinary medicine enhance existing nutrition interventions. Evidence of improved well-being and reduced resource utilization as the result of culinary medicine interventions is compiled for easy reference by health care organizations, medical professionals, people living with or at risk for chronic disease, food industry specialists, and payers in both the public and private sectors. Suggestions for individual and organizational implementation of culinary medicine strategies are offered with a proposed lexicon for continued development of the field.

A computerized, self-administered test of verbal episodic memory in elderly patients with mild cognitive impairment and healthy participants: A randomized, crossover, validation study.

INTRODUCTION: Performance of "Revere", a novel iPad-administered word-list recall (WLR) test, in quantifying deficits in verbal episodic memory, was evaluated versus examiner-administered Rey Auditory Verbal Learning Test (RAVLT) in patients with mild cognitive impairment and cognitively normal participants. METHODS: Elderly patients with clinically diagnosed mild cognitive impairment (Montreal Cognitive Assessment score 24-27) and cognitively normal (Montreal Cognitive Assessment score ≥28) were administered RAVLT or Revere in a randomized crossover design. RESULTS: A total of 153/161 participants (Revere/RAVLT n = 75; RAVLT/Revere n = 78) were randomized; 148 (97%) completed study; 121 patients (mean [standard deviation] age: 70.4 [7.84] years) were included for analysis. Word-list recall scores (8 trials) were comparable between Revere and RAVLT (Pearson's correlation coefficients: 0.12-0.70; least square mean difference [Revere-RAVLT]: -0.84 [90% CI, -1.15; -0.54]). Model factor estimates indicated trial (P < .001), period (P < .001) and evaluation sequence (P = .038) as significant factors. Learning over trials index and serial position effects were comparable. DISCUSSION: Participants' verbal recall performance on Revere and RAVLT were equivalent.

Residential care/assisted living staff may detect undiagnosed dementia using the minimum data set cognition scale.

OBJECTIVES: To estimate the sensitivity, specificity, and reliability of the Minimum Data Set Cognition Scale (MDS-COGS) in screening for undetected dementia when completed by direct care staff in residential care/assisted living (RC/AL) facilities and secondarily to determine the prevalence of dementia in the sample. DESIGN: A cross-sectional study in which staff were trained to complete the MDS-COGS. Research interviewers and a neuropsychologist obtained information on each participant. Two neurologists reviewed the data and examined the participant, rendering a probable diagnosis of dementia/non-dementia diagnosis. MDS-COGS results were compared with the neurologists' determination. SETTING: Fourteen RC/AL facilities in North Carolina. PARTICIPANTS: Data were collected from 50 staff on 166 residents without a diagnosis of dementia. MEASUREMENTS: In addition to the MDS-COGS, measures included a comprehensive neuropsychological battery. Depression and other neuropsychiatric symptoms were also assessed. RESULTS: Neurologists determined that 38% of participants had probable dementia. An MDS-COGS cutpoint of 2 was highly specific (0.97) but not very sensitive (0.49) for dementia. Test-retest and interrater agreement for a negative screen were high (88% and 93%, respectively). CONCLUSION: The MDS-COGS is a simple, brief screen that RC/AL staff can complete. It will identify with high specificity a subset of residents with undetected dementia, allowing rapid identification of those likely to need dementia care. Caution needs to be exercised in light of its low sensitivity, because some with milder dementia will not be detected. Further work is needed to determine whether staff can and will use the MDS-COGS as a trigger for more-thorough assessment and to guide care and improve outcomes.

Functional outcomes of drug treatment in Alzheimer's disease: A systematic review and meta-analysis.

BACKGROUND: Patient functioning is an important outcome in Alzheimer's disease, but treatment-related improvements in patient function are difficult to quantify because a number of different scales are used in its measurement. OBJECTIVE: To evaluate systematically the evidence relating to patient functioning as an outcome measure in the drug treatment of Alzheimer's disease. Data were obtained by searching MEDLINE, EMBASE, The Cochrane Library and the International Pharmaceutical Abstracts from 1980 through to December 2005 for studies assessing functional outcomes with donepezil, galantamine, rivastigmine and memantine in Alzheimer's disease. Reference lists were searched manually and pharmaceutical manufacturers were invited to submit dossiers. Trained reviewers abstracted data and assessed the internal validity (quality) of trials using predefined criteria. Standardised effect sizes (i.e. Cohen's standardised mean difference [d]) for various functional outcome scales and pooled mean incidence and 95% CIs for adverse events were calculated and summarised qualitatively and quantitatively. Meta regression was used to explore potential heterogeneity. RESULTS: Overall, the standardised effect size for functional outcome measures was small (d = 0.1-0.4) among included studies. However, effect sizes consistently favoured drug treatment over placebo. For all drugs, pooled standardised effect sizes were consistent in both short (<24 weeks; d = 0.25; 95% CI 0.13, 0.37) and long trials (>or=24 weeks; d = 0.29; 95% CI 0.22, 0.36). The pooled effect size was not significantly affected by parameters such as disease severity, age, gender and drug dose. Adverse events were generally limited to gastrointestinal problems, weight loss and dizziness, all of which were reported in <20% of patients on average. CONCLUSIONS: Standardised estimates of effect size across diverse functional outcome measures for drug treatment in patients with Alzheimer's disease were small and the data reflect only a modest trend favouring active treatment over placebo. However, given the current lack of other effective treatments for Alzheimer's disease, this trend supports the clinical benefits of these treatments with regard to this important health outcome.

Effect of Trospium Chloride on Cognitive Function in Women Aged 50 and Older: A Randomized Trial.

OBJECTIVES: This study aimed to investigate the effect of trospium chloride on cognitive function in postmenopausal women treated for overactive bladder (OAB). METHODS: Randomized double-blind placebo-controlled trial conducted from April 2013 to April 2015. Women aged 50 years or older seeking treatment for OAB were randomized to either trospium chloride XR 60 mg daily or placebo. Baseline cognitive function was assessed via Hopkins Verbal Learning Test-Revised (HVLT-R), Mini Mental Status Exam, Mini Mental Status X, Digit Span, Trails A, Trails B, and Epworth Sleepiness Scale. Cognitive function was reassessed at week 1 and week 4. A priori power analysis determined that 21 subjects were needed per group. RESULTS: Although 59 women were enrolled and randomized (28 trospium and 31 placebo), 45 completed assessment (21 trospium and 24 placebo). Mean age was 68 years, 78% were white, and 44% had previously taken OAB medication. For the primary outcome, there was no difference in HVLT-R total score between trospium and placebo groups at week 4 (P = 0.29). There were also no differences based on the other cognitive tests. There was a correlation between age and the following week-4 tests: HVLT-R total score (r = -0.3, P = 0.02), HVLT-R total recall subscale (r = -0.4, P = 0.007), Trails A (r = 0.4, P = 0.002), and Trails B (r = 0.4, P = 0.004). A linear regression model found that HVLT-R total score decreased by 0.372 points for each increased year of age. CONCLUSIONS: In women aged 50 years and older, there were no changes in cognitive function between those taking trospium and placebo. Cognitive function was correlated with age.