Real-world effects of anti-dementia treatment on mortality in patients with Alzheimer´s dementia.

To examine the real-world effects of the cholinesterase inhibitors (AChEI) on all-cause mortality. A nationwide, retrospective cohort study. Participants were diagnosed with incident AD in Denmark from January 1, 2000 to December 31, 2011 with follow-up until December 31, 2012. A total of 36,513 participants were included in the current study with 22,063 deaths during 132,426 person-years of follow-up. At baseline, patients not treated with AChEI (n = 28,755 [9961 males (35%)]) had a mean age ±â€…standard deviation (SD) of 80.33 ±â€…7.98 years (78.97 ±â€…8.26 for males and 81.04 ±â€…7.98 for females), as compared to 79.95 ±â€…7.67 (78.87 ±â€…7.61 for males and 80.61 ±â€…7.63 for females) in the group exposed at baseline. Patients treated with AChEI had a beneficial hazard ratio (HR) of 0.69, 95% confidence interval (CI) (0.67-0.71) for all-cause mortality as compared to patients not treated, with donepezil (HR 0.80, 95% CI [0.77-0.82]) and galantamine (HR 0.93,95% CI [0.89-0.97]) having beneficial effects on mortality rate as compared to non-treatment, whereas rivastigmine (HR 0.99, 95% CI [0.95-1.03]) was associated with a mortality rate comparable to non-treatment with AChEI. Patients were primarily exposed to donepezil (65.8%) with rivastigmine (19.8%) and galantamine (14.4%) being used less often. These findings underscore the effect of AChEI on not only reducing speed of cognitive decline but also directly prolonging life, which could result in changes in treatment recommendation for when to stop treatment.

The role of physical and cognitive function in performance of activities of daily living in patients with mild-to-moderate Alzheimer's disease - a cross-sectional study.

BACKGROUND: Several factors may play a role in the ability of patients with Alzheimer's disease to perform activities of daily living (ADL). The aim of this study was to examine the impact of different aspects of physical performance and cognitive functions on ADL in patients suffering from mild-to-moderate Alzheimer's disease. METHODS: We conducted secondary analyses on cross-sectional baseline data from the randomized controlled multicentre study "Preserving quality of life, physical health and functional ability in Alzheimer's Disease: The effect of physical exercise" (ADEX). In total, 185 AD patients (76 women and 109 men), with a mean age on 70,4 years, were included. Data from physical performance tests (Astrand cycle test, Timed up & Go (TUG), Sit to Stand test (STS)) and cognitive tests (Mini Mental Status Examination (MMSE), Symbol Digit Modalities Test (SDMT), Stroop Color and Word test (Stroop)) were used. Their associations with ADL, measured on the ADCS-ADL scale was assessed in multivariable regression analyses. RESULTS: SDMT and MMSE had significant, moderate correlations with total ADL (SDMT: r = 0.33, MMSE: r = 0.42) and instrumental ADL (SDMT: r = 0.31, MMSE: r = 0.42), but not with basic ADL. Adjusting for age and sex, the associations between SDMT and MMSE to total ADL and instrumental ADL persisted. No significant associations were found between Astrand, TUG, STS or Stroop and total ADL, basic ADL or instrumental ADL. CONCLUSION: Total ADL and instrumental ADL are associated with cognitive functions, including executive function. No significant association between examined physical performance parameters and ADL functions was observed, and consequently does not support an impact of physical function on ADL functions in patients with mild-to-moderate Alzheimer's disease and relatively well-preserved physical function. Strategies aimed to improve cognition may be better suited to improve ADL function in patients with mild-to-moderate Alzheimer's disease. TRIAL REGISTRATION: NCT01681602 . Registered 10 September 2012, retrospectively registered.

Transcranial pulsed electromagnetic fields for treatment-resistant depression: A multicenter 8-week single-arm cohort study.

BACKGROUND: The efficacy of antidepressant treatment is fair, but the efficacy is considerably lower in patients failing two or more trials underscoring the need for new treatment options. Our study evaluated the augmenting antidepressant effect of 8-weeks transcranial pulsed electromagnetic field (T-PEMF) therapy in patients with treatment-resistant depression. METHODS: A multicenter 8-week single-arm cohort study conducted by the Danish University Antidepressant Group. RESULTS: In total, 58 participants (20 men and 38 women) with a moderate to severe depression as part of a depressive disorder according to ICD-10 who fulfilled criteria for treatment resistance were included, with 19 participants being nonresponders to electroconvulsive therapy during the current depressive episode. Fifty-two participants completed the study period. Scores on the Hamilton Depression Scale 17-items version (HAM-D17) decreased significantly from baseline (mean = 20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N = 58). At endpoint, utilizing a Last Observation Carried Forward analysis, 49 and 28% of those participants with, respectively, a nonchronic current episode (≤2 years; N = 33) and a chronic current episode (>2 years; N = 25) were responders, that is, achieved a reduction of 50% or more on the HAM-D17 scale. At endpoint, respectively, 30 and 16% obtained remission, defined as HAM-D17 ≤ 7. On the Hamilton Scale 6-item version (HAM-D6), respectively, 51 and 16% obtained remission, defined as HAM-D6 ≤ 4. CONCLUSIONS: The findings indicate a potential beneficial role of T-PEMF therapy as an augmentation treatment to ongoing pharmacotherapy in treatment-resistant depression.

Analgesics use and withdrawal in people with dementia - a register-based Danish study and a systematic review.

INTRODUCTION: Pain assessment in people with dementia is difficult, and withdrawal of analgesics may allow for assessment of treatment efficacy whilst decreasing pill burden, adverse events and interactions. We aimed to describe the use of analgesics among elderly in Denmark and to compile the evidence for withdrawal of analgesics among people with dementia. METHODS: With respect to analgesics use, we employed data from national registries on the analgesic prescription use (opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen) in 2017 among elderly people with and without dementia. Trial evidence was produced by performing a systematic search in MEDLINE, Embase and Cinahl for trials evaluating withdrawal of analgesics in people with dementia. RESULTS: Opioids were prescribed more frequently (p = 0.026) and NSAIDs less frequently (p = 0.026) to people with dementia. With respect to trial evidence, we identified two studies: An observational cross-over study (n = 3) reporting acetaminophen withdrawal leading to increases in pain frequency and duration, and a cluster-randomised clinical trial (n = 352) reporting changes in mobilization-observation-behaviour-intensity-dementia-2 (MOBID-2) pain score during a four-week withdrawal period (acetaminophen, opioids and/or pregabaline) from a mean ± standard deviation of 2.3 ± 2.1 to 2.9 ± 2.6 compared with 3.5 ± 2.6 to 3.5 ± 2.5 in the control group. CONCLUSIONS: In Denmark, use of opioids is higher in elderly with dementia compared to elderly without dementia. The evidence suggests that withdrawal of analgesics may aggravate pain but increases in pain scores may be of little clinical relevance in most people. Clinical trials investigating analgesics withdrawal are warranted.

Effects of Antipsychotics on Secular Mortality Trends in Patients With Alzheimer's Disease.

OBJECTIVE: To investigate secular changes in mortality rates between patients with Alzheimer's disease (AD) and the general population as well as changes in antipsychotic drug treatment and the association between drug treatment and mortality in patients with AD in Denmark during a 12-year study period. METHODS: This nationwide, retrospective cohort study identified all-cause mortality in all Danish patients with incident ICD-10-defined AD from 2000 through 2011. The cumulative antipsychotic dosages from dementia diagnosis until end of study for each participant were calculated and categorized in 1 of 5 groups per the World Health Organization Defined Daily Doses (DDDs). Data were obtained from relevant Danish national registers. RESULTS: The study included 32,001 patients (11,194 male and 20,807 female). During the study period, an increasing trend was found in median survival time, but no decline was seen in standardized mortality ratios, which spanned from 1.19 (95% CI, 0.98-1.46) in 2001 to 1.52 (95% CI, 1.38-1.68) in 2011. The findings showed a decline in proportion of patients with incident AD exposed to antipsychotic drugs as well as decline in mean annual cumulative DDDs. Adjusted Cox regression analyses revealed that current exposure to antipsychotic drugs was associated with increased mortality, although hazard ratios declined during the study period from 2.24 (95% CI, 2.07-2.43) in 2000-2002 to 1.24 (95% CI, 1.09-1.41) in 2009-2011, with P values < .001. CONCLUSIONS: These findings appear to underscore the current guideline recommendations for using antipsychotic drugs at only the lowest effective dose and only in patients for whom all non-pharmacologic options have been exhausted. Furthermore, these results seem to indicate that the reduced use of antipsychotic drugs has no impact on relative mortality, suggesting that the AD population has gained less from improvements in care of other diseases that impact mortality rates in patients with AD as well as in the general population.

Effect of aerobic exercise on physical performance in patients with Alzheimer's disease.

INTRODUCTION: Knowledge about the feasibility and effects of exercise programs to persons with Alzheimer's disease is lacking. This study investigated the effect of aerobic exercise on physical performance in community-dwelling persons with mild Alzheimer's disease. METHODS: The single blinded multi-center RCT (ADEX) included 200 patients, median age 71 yrs (50-89). The intervention group received supervised moderate-to-high intensity aerobic exercise 1 hour × 3/week for 16 weeks. Assessments included cardiorespiratory fitness, single-task physical performance, dual-task performance and exercise self-efficacy. RESULTS: Significant between-group differences in change from baseline (mean [95%CI]) favored the intervention group for cardiorespiratory fitness (4.0 [2.3-5.8] ml/kg/min, P <0.0001) and exercise self-efficacy (1.7 [0.5-2.8] points, P =0.004). Furthermore, an exercise attendance of ≥66.6% resulted in significant positive effects on single-task physical performance and dual-task performance. DISCUSSION: Aerobic exercise has the potential to improve cardiorespiratory fitness, single-task physical performance, dual-task performance and exercise self-efficacy in community-dwelling patients with mild Alzheimer's disease.

Associations between physical function, dual-task performance and cognition in patients with mild Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) causes a gradual decline in cognition, limitations of dual-tasking and physical function leading to total dependence. Hence, information about the interaction between physical function, dual-task performance and cognition may lead to new treatment strategies with the purpose of preserving function and quality of life. The objective of this study was to investigate the associations between physical function, dual-task performance and cognition in community-dwelling patients with mild AD. METHODS: Baseline results from 185 participants (50-90 years old) in the single blinded multicenter RCT 'ADEX' (Alzheimer's disease: the effect of physical exercise) were used. Assessments included tests of physical function: 400-m walk test, 10-m walk test, Timed Up and Go test and 30-s chair stand test; dual-task performance, i.e., 10-m walk while counting backwards from 50 or naming the months backwards; and cognition, i.e., Mini Mental State Examination, Symbol Digit Modalities Test, the Stroop Color and Word Test, and Lexical verbal fluency test. RESULTS: Results in the 30-s chair stand test correlated significantly with all tests of cognition (r = .208-.242) while the other physical function tests only randomly correlated with tests of cognition. Results in the dual-task counting backwards correlated significantly with results in all tests of cognition (r = .259-.388), which accounted for 7%-15% of the variation indicating that a faster time to complete dual-task performance was associated with better cognitive performance. CONCLUSION: The evidence of the associations between physical function, dual-task performance and cognition is important when creating new rehabilitation interventions to patients with mild AD.

Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease: A Randomized Controlled Trial.

BACKGROUND: Studies of physical exercise in patients with Alzheimer's disease (AD) are few and results have been inconsistent. OBJECTIVE: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. METHODS: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. RESULTS: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition. CONCLUSIONS: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.

[Prevalence of depression and dementia among nursing home residents]. / Forekomst af depression og demens blandt plejehjemsbeboere

The population of older adults will increase in the coming years and the number of elderly in nursing homes is expected to rise considerably. The most frequent psychiatric diseases among nursing home residents are depression and dementia. We examined the prevalence of depression and dementia in nursing home populations reported in literature reviews. The included studies were published from 1986 to 2014. At least one out of ten persons living in a nursing home seems to have depression and more have depressive symptoms. Three out of four residents in nursing homes suffer from dementia.

[Withdrawal versus continuation of antipsychotic drugs in people with dementia]. / Seponering versus fortsat behandling med antipsykotika af demente patienter--en gennemgang af et Cochranereview.

Antipsychotics are often prescribed for treatment of psychiatric symptoms. The efficacy is very limited and must be weighed against the risk of adverse effects. A Cochrane review included randomized, placebo-controlled trials comparing an antipsychotic withdrawal with continuing treatment. Nine studies (606 patients) were included. Only in two studies with patients who had responded to antipsychotic treatment, withdrawal resulted in an increased risk of relapse. Withdrawal of antipsychotics should be incorporated in daily practice in primary care.

Preserving cognition, quality of life, physical health and functional ability in Alzheimer's disease: the effect of physical exercise (ADEX trial): rationale and design.

BACKGROUND: Exercise is hypothesized to improve cognition, physical performance, functional ability and quality of life, but evidence is scarce. Previous studies were of short duration, often underpowered and involving home-based light exercise programs in patients with undefined dementia. The aim of the ADEX ('Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: the Effect of Physical Exercise') trial is to establish whether aerobic exercise is effective in improving cognition as well as in reducing the prevalence of psychiatric symptoms among patients with Alzheimer's disease (AD). METHODS: The ADEX study is a multicenter, single-blind, randomized trial with two arms: an intervention group attending 16 weeks of continuously supervised moderate-to-high intensity aerobic exercise and a control group receiving usual care. We plan to recruit 192 patients with mild AD. The primary outcome measure is change from baseline in cognitive performance at 16 weeks (as measured by the Symbol Digit Modalities test). CONCLUSIONS: To our knowledge this is the first large-scale controlled study to investigate the effects of supervised moderate aerobic exercise on cognition in patients with AD. Recruitment began in January 2012 and results are expected to be available in 2014. We summarize the methodological challenges we and other studies have faced in this type of complex multicenter intervention with unique challenges to study design.

Simple scoring of the Clock-Drawing test for dementia screening.

INTRODUCTION: This study assessed five scoring methods of the Clock-Drawing test (CDT). MATERIAL AND METHODS: A total of 72 out-patients and 29 healthy controls were assessed three times. At Visit 1, diagnostic procedure and assessments were performed with the Clinical Global Impressions (CGI) and Global Deterioration Scale (GDS), and the CDT and the Mini Mental State Examination (MMSE) were done blinded by a nurse. At Visit 2, CDT and MMSE were repeated, and at Visit 3 the CDT, CGI and the GDS were repeated. The CDTs were then rated by physicians and nurses using five different methods of scoring. Receiver-operating characteristics curve analyses were used to assess the CDT's suitability as a screening tool. Correlations between the five CDTs, other scales and predictive values were calculated. The extent to which three-word recall could improve the predictive values was analysed. RESULTS: Correlations between the CDTs and the other scales were good. The predictive values were almost identical (positive values: 93-97%; negative values: 70-74%). Three-word recall improved the values. Rates of dementia in general practice and corresponding predictive values were estimated which resulted in markedly lower positive values around 60% for a rate of dementia of 20%, and 40% for a rate of dementia of 10%. CONCLUSION: As predictive values were nearly identical, the shortest scoring manual (0 to 1) seems preferable. FUNDING: The study was partly funded by Novartis Pharma A/S. TRIAL REGISTRATION: Scientific Ethical Committee, 2003-2-17.

Very mild to severe dementia and mortality: A 14-year follow-up - The Odense study.

BACKGROUND/AIMS: To examine the mortality of very mildly to severely demented persons compared to nondemented persons. METHODS: Participants in a randomly drawn population-based cohort study on dementia were followed for 14 years from 1992 to 2006. Participants were examined at baseline (3,065 nondemented and 234 prevalent demented), after 2 years (2,286 nondemented and 145 incident demented) and again after 5 years (1,669 nondemented and 124 new cases of dementia). Causes of death were ascertained in 884 nondemented and 286 demented participants. Survival for demented compared to nondemented persons was analyzed with the Cox proportional hazards model with time-dependent covariates adjusted for gender and age. RESULTS: The hazard ratio of death (95% confidence interval) increased from 1.82 (1.55-2.14) for the very mildly demented to 9.52 (6.60-13.74) for the severely demented subjects. The demented participants died significantly more often of neurological causes other than dementia and of pneumonia than the nondemented participants. No other significant differences in causes of death were found. CONCLUSION: Dementia increased the risk of death. Even in the very early stages of dementia the risk of death was increased.

The Neuropsychiatric Inventory--NPI. Validation of the Danish version.

Assessment of neuropsychiatric symptoms in dementia has great clinical importance. The aim of the study was validation of the Danish version of the NPI, using assessments of 72 demented and 29 non-demented of age 65+ years and their caregivers at three visits. The NPI was administered by the same psychiatric nurse interviewing the same caregiver. At visits 1 and 3, a psychogeriatrician assessed the participant using the ICD-10, the Geriatric Deterioration Scale (GDS) and the Clinical Global Impression (CGI) as well as the NPI in a visual analogue scale (VAS) version. These scores were blindly converted into scores equalling the frequency and severity of the NPI by one of the investigators. Data analysis comprised inter-rater reliabilities (intra-class coefficients, ICC); NPI scores and corresponding VAS scores were compared using Spearman's correlation coefficients. NPI scores at visits 1 and 2 were used to assess the test-retest reliabilities. The scalability of the NPI was assessed with Mokken and Loevinger coefficients. The ICC for all the NPI domains and the GDS (>0.80) were perfect, the ICC for the NPI-VAS (0.68-0.95) and the CGI (0.69) was satisfactory to perfect. Correlations between NPI and NPI-VAS were high; only two domains had coefficients below 0.60: depression and agitation/aggression. NPI-total scores increase with increasing severity of dementia. The NPI did not fulfil the scalability assessed by the Mokken and Loevinger coefficients. The NPI Danish version is valid and reliable in assessing neuropsychiatric symptoms in dementia but not fully scalable. The use of single item scores and not total sum score is recommended.

[Mini mental state examination. Validation of new Danish version]. / Mini mental state examination. Validering af en ny dansk udgave.

INTRODUCTION: The Mini Mental State Examination (MMSE) is widely used in Denmark, but often in non-validated versions. In 2000 a cross-sectional workgroup decided on a new common version of the MMSE with a corresponding manual, which is validated for the first time in the present study. MATERIALS AND METHODS: The study was performed from April 2003 until August 2005 in four psycho-geriatric departments. The participants (65+ years) were assessed on three consecutive occasions (week 0, 1 and 26) with the MMSE (nurse), and global scales as well as diagnostically with ICD-10 (psycho-geriatrician). RESULTS: 101 persons were included, 29 were healthy, non-demented; 82 participants were assessed at visit two, 90 at visit three, but only 88 ratings were useable. The best cut-off value for the MMSE was > or = 26. Inter-rater and test-retest (r=0.91) correlations of the MMSE were high as were the correlations to the global scales. However, there were considerable variations in mean score (+/-SD) as well as median score and range in relation to CGI and GDS values. The MMSE score is independent of sex and educational level. CONCLUSION: The MMSE also proved to be a robust scale in the present Danish version. It achieved excellent inter-rater and test-retest reliability. A cut-off value of = 26 proved better than 24 which was preferred hitherto. However, the ranges of the MMSE scores are so dispersed within the same global degree of severity that the MMSE should not generally be used to describe the severity of dementia disorders.

[Depression in old age]. / Depression hos aeldre.

Affecting 3% of the old-age population and 10-20% of elderly patients with chronic medical illness or dementia, depression is an important health problem in late life. Depression with first onset in late life differs from early-onset depression clinically as well as by more organic cerebral involvement. If untreated, depression in the elderly leads to severe disability and to excess mortality by suicide and by adverse outcome of medical illness. The response to antidepressant drugs in old age is on the same level as in younger age-groups, and as less than 1 in 5 elderly people with depression is diagnosed and treated, there is substantial room for improving the prognosis of old-age depression.

[Depression and the risk of Alzheimer's disease]. / Depression og risikoen for Alzheimers sygdom--sekundaerpublikation.

A population based cohort study consisting of 3346 participants aged 65-84 years was examined at baseline (1992-94) and after two and five years. The purpose was to examine whether a history of depression increased the risk of Alzheimer's disease (AD). History of depression was based on self-report and AD was diagnosed according to NINCDS-ADRDA. Logistic regression was used to calculate the odds ratio (OR (95% confidence interval)). Subjects with a history of depression had an increased risk of AD: Baseline (OR = 1,7 (1,0-2,7)); after two years (1,9 (1,0-3,3)); after five years (1,6 (0,9-2,7)).