Cerebrospinal Fluid Biomarker Levels as Markers for Nursing Home Placement and Survival Time in Alzheimer's Disease.

BACKGROUND: Cerebrospinal Fluid (CSF) biomarkers are associated with conversion from mild cognitive impairment to Alzheimer's Disease (AD), but their predictive value for later end-points has been less evaluated with inconsistent results. OBJECTIVE: We investigated potential relationships between CSF amyloid-ß1-42 (Aß42), Phosphorylated tau (P-tau), and Total tau (T-tau) with time to Nursing Home Placement (NHP) and life expectancy after diagnosis. METHODS: This prospective observational study included 129 outpatients clinically diagnosed with mild-to-moderate AD who underwent a lumbar puncture. The CSF biomarkers were analysed with xMAP technology. Dates of institutionalisation and death were recorded. RESULTS: After 20 years of follow-up, 123 patients (95%) were deceased. The participants with abnormal P-tau and T-tau (A+ T+ (N)+) died earlier than those with normal P-tau/abnormal T-tau (A+ T- (N)+) (mean, 80.5 vs. 85.4 years). Linear associations were demonstrated between lower Aß42 and shorter time to NHP (p = 0.017), and higher P-tau and younger age at death (p = 0.016). No correlations were detected between survival after AD diagnosis and CSF biomarkers. In sexand- age-adjusted Cox regression models, higher P-tau and T-tau were independent predictors of shorter lifespan after diagnosis. In multivariate Cox models, older age and lower baseline cognitive status, but not elevated tau, significantly precipitated both institutionalisation and death. CONCLUSION: These findings suggest that CSF biomarker levels plateau in the dementia phase of AD, which may limit their possible relationships with clinical end-points, such as NHP and survival time. However, the biomarkers reflect the central pathophysiologies of AD. In particular, pathologic tau is associated with more advanced disease, younger age at onset, and earlier death.

Differences in Dementia Care Between Swedish-Born and Foreign-Born from Countries with Different Country Level Socioeconomic Position: A Nationwide Register-Based Study.

BACKGROUND: With a growing elderly population worldwide, the prevalence of dementia is rapidly increasing. Studies from high income countries have shown that belonging to a minority ethnic group increases the risk of health disadvantages. OBJECTIVE: The aim of the present registry-based study was to identify potential differences in diagnostics, treatment, and care of individuals with dementia focusing on foreign-born in Sweden and the impact of country level socioeconomic position (SEP). METHODS: The study was based on a large dataset from the Swedish Dementia Registry (SveDem) and the Swedish Tax Agency's population registry. Data on demographic variables, cognitive tests, clinical assessments, medication, diagnosis, and interventions initiated at diagnosis were collected. Country level SEP was determined by country of birth as classified by World Bank Country and Lending groups. RESULTS: Of 57,982 patients with dementia registered in SveDem, 7,171 (12.4%) were foreign-born. The foreign-born were significantly younger at diagnosis (p < 0.001), had a lower MMSE score (p < 0.001), lower odds of receiving a specific dementia diagnosis (p < 0.001), lower use of acetylcholinesterase inhibitors (p < 0.001), and overall a higher use of neuroleptics compared with the Swedish-born group. The lower SEP, the greater differences to Swedish-born were seen in many of the examined variables. CONCLUSION: There were significant differences in dementia diagnostics, treatment, and care between foreign-born and Swedish-born, a lower SEP indicating greater differences. Further research should focus on various socioeconomic aspects and health care outcomes for a more profound analysis of equity in dementia care.

Cerebro-spinal fluid biomarker levels: phosphorylated tau (T) and total tau (N) as markers for rate of progression in Alzheimer's disease.

BACKGROUND: We investigated the potential associations between cerebro-spinal fluid (CSF) levels of phosphorylated tau (P-tau) and total tau (T-tau) with short-term response to cholinesterase inhibitor (ChEI) treatment, longitudinal outcome and progression rates in Alzheimer's disease (AD). METHODS: This prospective, observational study included 129 participants clinically diagnosed with mild-to-moderate AD, who underwent a lumbar puncture. The CSF biomarkers amyloid-ß1-42 (Aß42), P-tau and T-tau were analysed with xMAP technology. Cognitive, global, instrumental and basic activities of daily living (ADL) capacities at the start of ChEI therapy and semi-annually over 3 years were evaluated. RESULTS: All patients had abnormal Aß42 (A+). Fifty-eight individuals (45%) exhibited normal P-tau and T-tau (A+ T- (N)-), 12 (9%) abnormal P-tau/normal T-tau (A+ T+ (N)-), 17 (13%) normal P-tau/abnormal T-tau (A+ T- (N)+) and 42 (33%) abnormal P-tau and T-tau (A+ T+ (N)+). The participants with A+ T+ (N)+ were younger than A+ T- (N)+ at the estimated onset of AD and the initiation of ChEIs. The proportion of 6-month responders to ChEI and deterioration/year after start of treatment did not differ between the AT(N) profiles in any scales. A higher percentage of globally improved/unchanged patients was exhibited in the A+ T- (N)- group after 12, 30 and 36 months of ChEI therapy but not at other assessments. In apolipoprotein E (APOE) ε4-carriers, linear relationships were found between greater cognitive decline/year and higher tau; Mini-Mental State Examination score - T-tau (rs = - 0.257, p = 0.014) and Alzheimer's Disease Assessment Scale-cognitive subscale - P-tau (rs = - 0.242, p = 0.022). A correlation between faster progression in instrumental ADL (IADL) and higher T-tau was also detected (rs = - 0.232, p = 0.028). These associations were not demonstrated in non-ε4-carriers. CONCLUSIONS: Younger age and faster global deterioration were observed in AD patients with pathologic tau and neurodegeneration, whereas more rapid cognitive and IADL decline were related to higher P-tau or T-tau in APOE ε4-carriers only. The results might indicate an association between more pronounced tau pathology/neuronal injury and the APOE ε4-allele leading to a worse prognosis. Our findings showed that the AT(N) biomarker profiles have limited utility to predict AD progression rates and, thus, measure change and interpreting outcomes from clinical trials of future therapies.

Survival among the older adults with clinical signs of Lewy body dementia in 40 Swedish nursing homes: a 6-year follow-up study.

OBJECTIVES: To investigate survival among elderly residents of Swedish nursing homes (NHs), with specific focus on those with two or more signs of Lewy body dementia (LBD). DESIGN: Prospective observational study. SETTING: NHs in Malmö, the third largest city in Sweden. PARTICIPANTS: The study population was older adults (aged ≥65 years) living in the 40 NHs in Malmö. Clinical data were collected with a customised questionnaire assessing core clinical LBD signs. Patients were categorised based on 0-1 or 2-4 LBD signs. The head nurse at each NH collected the study data: LBD questionnaires, electronic medication lists and electronic medical records from 2012 to 2013. MAIN OUTCOME MEASURES: 80-month mortality. RESULTS: Five hundred and fifty-eight (96%) of the residents were deceased at follow-up; among these, mean (95% CI) overall survival time was 29 (28-31) months. Mean survival differed between the LBD groups; those with 0-1 LBD signs lived 8 months longer than those with 2-4 LBD signs. Mortality risk for residents in the LBD 2-4 group was also significantly higher. HR adjusted for age and sex was HR (95% CI) 1.60 (1.30 to 1.97). Mortality risk was also significantly higher in residents with signs of fluctuating cognition 1.36 (1.15 to 1.62), rapid eye movement sleep behaviour disorder 1.49 (1.11 to 1.98), balance problems 1.36 (1.14 to 1.61) or rigidity 1.41 (1.18 to 1.68). CONCLUSIONS: This large, longitudinal study shows the important survival effects of identifying and diagnosing older adults NH residents who have two or more LBD signs.

Short-Term Response to Cholinesterase Inhibitors in Alzheimer's Disease Delays Time to Nursing Home Placement.

BACKGROUND: A varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer's disease (AD). Whether the individual-specific response directly affects time to nursing home placement (NHP) was not investigated. OBJECTIVE: We examined the relationship between the 6-month response to ChEI and institutionalization. METHODS: In a prospective, observational, multicenter study, 881 outpatients with a clinical AD diagnosis and a Mini-Mental State Examination score of 10-26 at the start of ChEI therapy (baseline) were included. The participants were evaluated using cognitive, global, and activities of daily living (ADL) scales at baseline and semiannually over 3 years. The date of NHP was recorded. RESULTS: During the study, 213 patients (24%) were admitted to nursing homes. The mean ± standard deviation time from baseline (AD diagnosis) to NHP was 20.8 ± 9.3 months. After 6 months of ChEI treatment, the improved/unchanged individuals had longer time to NHP than those who worsened. The prolonged time to NHP was 3 months for cognitive response (P=0.022), 4 months for global response (P=0.004), 6 months for basic ADL response (P<0.001), and 8 months for response in all three scales (P<0.001). No differences were detected between the improved and unchanged groups in any scales. CONCLUSION: Patients who exhibit a positive short-term response to ChEI can expect to stay in their own home for 3-8 months longer. These findings underline the importance of a comprehensive clinical examination including various assessment scales to evaluate treatment response and provide a more accurate prognosis.

Psychotropic and anti-dementia treatment in elderly persons with clinical signs of dementia with Lewy bodies: a cross-sectional study in 40 nursing homes in Sweden.

BACKGROUND: Elderly persons with a dementia diagnosis often suffer from different neuropsychiatric symptoms (NPS) such as delusions, hallucinations, depression, anxiety, irritability and agitation. Currently, the medical treatment for NPS consists mostly of psychotropic medication such as hypnotics/sedatives, anxiolytics and antipsychotics. In elderly persons with dementia, usage of antipsychotics is less appropriate because of the risk of side effects such as parkinsonism, rapid cognitive decline, cerebrovascular events and finally mortality. Furthermore, elderly persons with dementia with Lewy bodies (DLB) are often hypersensitive to antipsychotics with numerous serious adverse events such as somnolence, sedation, extra-pyramidal symptoms, delirium and increased mortality. The aim of this study was to investigate the usage of psychotropics with a focus on antipsychotics and anti-dementia medication (according to the Anatomical Therapeutic Chemical Classification System) in elderly persons with clinical signs of DLB living in dementia nursing homes (NHs) in Sweden. METHODS: Between 2012 and 2013, we applied a specially designed questionnaire that covered the clinical DLB features according to the consensus criteria of DLB. We also collected computerized medical lists from the Swedish National Medication Dispensing System from the same period. All dementia NHs (n = 40) in Malmö, the third largest city in Sweden, were covered. Of 650 eligible residents, 610 (94%) were included with 576 medical lists. The mean age was 86 years and 76% were women. RESULTS: Treatment with antipsychotics was seen in 22% of residents, hypnotics/sedatives in 41%, antidepressants in 50% and anxiolytics in 58%. We also found an increasing usage of antipsychotics from 25% to 43% in residents with the increasing number of DLB features. Anti-dementia medications were found in 45% of the elderly with a dementia diagnosis. However, residents with two or more DLB features had less anti-dementia medication (37%) than the rest of the dementia-diagnosed NH residents (62-69%). CONCLUSIONS: Residents with 2-4 DLB clinical features in Swedish NHs receive an unfavourable medical treatment with high antipsychotic usage and insufficient anti-dementia medication. These findings show the importance of identifying elderly persons with DLB features more effectively and improving the collaboration with nursing care to provide better medical prescription.

Early- versus late-onset Alzheimer's disease in clinical practice: cognitive and global outcomes over 3 years.

BACKGROUND: Whether age at onset influences Alzheimer's disease (AD) progression and the effectiveness of cholinesterase inhibitor (ChEI) therapy is not clear. We aimed to compare longitudinal cognitive and global outcomes in ChEI-treated patients with early-onset Alzheimer's disease (EOAD) versus late-onset Alzheimer's disease (LOAD) in clinical practice. METHODS: This 3-year, prospective, observational, multicentre study included 1017 participants with mild to moderate AD; 143 had EOAD (age at onset < 65 years) and 874 had LOAD (age at onset ≥ 65 years). At baseline and semi-annually, patients were assessed using cognitive, global and activities of daily living (ADL) scales, and the dose of ChEI was recorded. Potential predictors of decline were analysed using mixed-effects models. RESULTS: Six-month response to ChEI therapy and long-term prognosis in cognitive and global performance were similar between the age-at-onset groups. However, deterioration was significantly faster when using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) over 3 years in participants with EOAD than in those with LOAD; hence, prediction models for the mean ADAS-Cog trajectories are presented. The younger cohort had a larger proportion of homozygote apolipoprotein E (APOE) ε4 allele carriers than the older cohort; however, APOE genotype was not a significant predictor of cognitive impairment in the multivariate models. A slower rate of cognitive progression was related to initiation of ChEIs at an earlier stage of AD, higher ChEI dose and fewer years of education in both groups. In LOAD, male sex, better instrumental ADL ability and no antipsychotic drug use were additional protective characteristics. The older patients received a lower ChEI dose than the younger individuals during most of the study period. CONCLUSIONS: Although the participants with EOAD showed a faster decline in ADAS-Cog, had a longer duration of AD before diagnosis, and had a higher frequency of two APOE ε4 alleles than those with LOAD, the cognitive and global responses to ChEI treatment and the longitudinal outcomes after 3 years were similar between the age-at-onset groups. A higher mean dose of ChEI and better cognitive status at the start of therapy were independent protective factors in both groups, stressing the importance of early treatment in adequate doses for all patients with AD.

Early-versus Late-Onset Alzheimer Disease: Long-Term Functional Outcomes, Nursing Home Placement, and Risk Factors for Rate of Progression.

BACKGROUND/AIMS: Whether age at onset influences functional deterioration in Alzheimer disease (AD) is unclear. We, therefore, investigated risk factors for progression in activities of daily living (ADL) and nursing home placement (NHP) in cholinesterase inhibitor (ChEI)-treated patients with early-onset AD (EOAD) versus late-onset AD (LOAD). METHODS: This 3-year, prospective, observational, multicenter study included 1,017 participants with mild-to-moderate AD; 143 had EOAD (onset <65 years) and 874 LOAD (onset ≥65 years). Possible sociodemographic and clinical factors that could affect functional outcome and NHP were analyzed using mixed-effects models and logistic regression, respectively. RESULTS: Younger individuals exhibited longer illness duration before AD diagnosis, whereas 6-month functional response to ChEI therapy, 3-year changes in ADL capacities, time from diagnosis to NHP, and survival time in nursing homes were similar between the groups. In LOAD, a higher ChEI dose, no antidepressant use, and lower education level were protective factors for slower instrumental ADL (IADL) decline. In EOAD, antihypertensives/cardiac therapy implied faster IADL progression but lower risk of NHP. CONCLUSION: This study highlights the clinical importance of an earlier diagnosis and treatment initiation and the need for functional evaluations in EOAD. Despite the age differences between EOAD and LOAD, a similar need for nursing homes was observed.

Cholinesterase inhibitors do not alter the length of stay in nursing homes among patients with Alzheimer's disease: a prospective, observational study of factors affecting survival time from admission to death.

BACKGROUND: The survival time in nursing homes (NHs) in Alzheimer's disease (AD) might be affected by sociodemographic/clinical characteristics, rate of disease progression, and use of specific medications and community-based services. Whether different aspects of cholinesterase inhibitor (ChEI) therapy modify time spent in NHs is unclear. Therefore, we examined the relationship between these potential predictors and survival time in NHs. METHODS: This prospective, multicenter study of ChEI treatment in clinical practice included 220 deceased patients clinically diagnosed with mild-to-moderate AD who were admitted to NHs during the study. Cognitive and activities of daily living (ADL) performance, ChEI dose, and amount of services used/week were evaluated every 6 months over 3 years. Dates of nursing-home placement (NHP) and death were recorded. Variables that determined survival time in NHs were analyzed using general linear models. RESULTS: The mean survival time in NHs was 4.06 years (men, 2.78 years; women, 4.53 years; P < 0.001). The multivariate model showed that a shorter stay in NHs was associated with the interaction term male living with a family member, use of antihypertensive/cardiac therapy or anxiolytics/sedatives/hypnotics, and worse basic ADL at NHP, but not with age or cognitive and instrumental ADL capacities. CONCLUSIONS: Increased community-based care did not reduce the survival time in NHs among individuals with AD. Men living with family spent significantly less time in NHs compared with the corresponding women, which suggests that the situation of female spouses of AD patients may need attention and possibly support. There was no indication that different aspects of ChEI therapy, e.g., drug type, dose, or duration, alter survival time in NHs.

Prevalence of Dementia With Lewy Body Symptoms: A Cross-Sectional Study in 40 Swedish Nursing Homes.

OBJECTIVES: To investigate and establish the prevalence of dementia with Lewy body (DLB) symptoms in all nursing home (NH) residents in Malmö, the third largest city in Sweden. DLB is a neurocognitive disorder with core features, such as parkinsonism, visual hallucinations, and fluctuating cognition/excessive daytime sleepiness, and supportive features, such as rapid eye movement sleep behavior disorder. DLB is often misdiagnosed and unrecognized in elderly individuals. DESIGN: A questionnaire, designed to cover the main DLB symptoms, according to consensus criteria from the third report of the DLB Consortium from 2005, was distributed in 40 NHs. The questionnaires were completed by the nursing staff after receiving specifically designed teaching. Medication lists were collected from the Swedish national medication dispensing system. SETTING: Nursing homes. PARTICIPANTS: Of 650 eligible residents, 620 (96%) were included. The mean age was 86.0 ± 7.5 years; 467 (75%) were women. RESULTS: We found a prevalence of 16% of 2 or more main symptoms of DLB in the NH residents. However, when a wider more inclusive parkinsonism variable was used, the prevalence of DLB symptoms increased to 20%. CONCLUSION: We conclude that elderly with 2 or more DLB symptoms may constitute between 16% and 20% of all residents in NHs. This emphasizes the importance of identification of DLB and guides clinicians to deliver appropriate treatment for this fragile patient group.

Mild versus moderate stages of Alzheimer's disease: three-year outcomes in a routine clinical setting of cholinesterase inhibitor therapy.

BACKGROUND: There is an increasing interest in cognitive and functional outcomes in the respective stages of Alzheimer's disease (AD) and in novel therapies particularly for the milder phases of AD. Our aim was to describe and compare various aspects of disease progression in patients with mild versus moderate AD in routine clinical practice of cholinesterase inhibitor (ChEI) therapy. METHODS: This 3-year, prospective, observational, multicentre study included 1021 participants. Of these, 734 had mild AD (Mini-Mental State Examination (MMSE) score, 20-26) and 287 had moderate AD (MMSE score, 10-19) at the start of ChEI treatment. At baseline and every 6 months, patients were assessed using cognitive, global, instrumental and basic activities of daily living (ADL) scales. Potential predictors of deterioration in moderate AD were analysed using mixed-effects models. RESULTS: The change from baseline between participants with mild and moderate stages of AD after 3 years of ChEI therapy differed significantly on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and basic ADL, but not using the MMSE and instrumental ADL scales. Protective independent factors for better cognitive long-term outcome in the group with moderate AD were older age, higher instrumental ADL ability, no antipsychotics, usage of non-steroidal anti-inflammatory drugs/acetylsalicylic acid, living with family member, lower education and a higher mean dose of ChEI. Apolipoprotein E genotype did not influence the rates of disease progression or the longitudinal outcomes. Prediction models were provided for moderate AD. CONCLUSIONS: More sensitive cognitive measures, such as the ADAS-cog scale, are required to detect a possibly faster deterioration among the participants with moderate AD. This study highlighted the clinical importance of instrumental ADL evaluations in patients at a mild stage of AD, and the importance of optimizing the ChEI dose even for individuals with moderate AD. Solitary living was a risk factor for faster cognitive decline, and probably expanded the need for formal care in the group with moderate AD. The patients with more advanced AD and presumably more pronounced neuroinflammation might have additional cognitive benefits from longer-term treatment with anti-inflammatory drugs.

Longitudinal Associations between Survival in Alzheimer's Disease and Cholinesterase Inhibitor Use, Progression, and Community-Based Services.

BACKGROUND/AIMS: Factors including rate of disease progression, different aspects of cholinesterase inhibitor (ChEI) treatment, and use of community-based services might affect the longitudinal outcome of Alzheimer's disease (AD). Whether these factors alter life expectancy in AD is unclear. We therefore examined the association between long-term ChEI therapy and survival. METHODS: The present study included 1,021 patients with a clinical diagnosis of AD and a Mini-Mental State Examination score of 10-26 at baseline from a 3-year, prospective, multicenter study of ChEI therapy in clinical practice. The relationship of potential predictors with mortality was analyzed using Cox regression models. RESULTS: After up to 16 years of follow-up, 841 (82%) of the participants had died. In the Alzheimer's Disease Assessment Scale-cognitive subscale, a mean decline of ≥ 4 points/year or ≥ 2 points/year on the Physical Self-Maintenance Scale was a risk factor for an earlier death. In the multivariate models, longer survival was associated with higher ChEI dose and longer duration of treatment. Users of community-based services at baseline exhibited a 1-year shorter mean life expectancy than nonusers. CONCLUSION: A longer survival time can be anticipated for AD patients with slower deterioration who receive and tolerate higher ChEI doses and a longer duration of treatment.

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review.

INTRODUCTION: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. METHODS: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. RESULTS: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer's disease and healthy controls. CONCLUSION: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

Cerebral inflammation is an underlying mechanism of early death in Alzheimer's disease: a 13-year cause-specific multivariate mortality study.

INTRODUCTION: Although Alzheimer's disease (AD) is associated with early death, its life expectancy differs greatly between patients. A better understanding of this heterogeneity may reveal important disease mechanisms underlying the malignancy of AD. The aim of this study was to examine the relation between AD pathologies and early death in AD caused by dementia. METHODS: At a memory clinic, 247 referred consecutive patients with AD were monitored during 12.6 ± 1.6 years. Multivariate Cox regression analyses were performed with baseline measures of amyloid beta (Aß) pathology (APOE genotype, cerebrospinal fluid (CSF) Aß42) tau pathology (CSF phosphorylated tau and total tau), cerebrovascular pathology (white-matter lesions and CSF/serum albumin ratio), neuroinflammatory pathology (CSF soluble vascular cell adhesion molecule-1, sVCAM-1), frontal, temporal, and central brain atrophies, global cognition, sex, and age. Comorbidities and medications also were analyzed. All continuous variables were transformed to z scores to compare hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: At follow-up, 89% of the patients had died. The mean survival time was 6.4 ± 3.0 years. The AD pathology that independently predicted an early death caused by dementia was cerebral inflammation (sVCAM-1; HR, 1.32; 95% CI, 1.07-1.64). Other independent predictors were lower global cognition (HR, 0.51; 95% CI, 0.43-0.61), frontal atrophy (HR, 1.38; 95% CI, 1.12-1.70), and medial temporal atrophy (HR, 1.23; 95% CI, 1.02-1.49). When examining death caused by dementia and related causes (vascular diseases and infections), age (HR, 1.23; 95% CI, 1.04-1.46) and cerebrovascular pathology (white-matter lesions: HR, 1.17; 95% CI, 1.01-1.36; and CSF/serum albumin ratio: HR, 1.16; 95% CI, 1.001-1.34) were also significant risk factors in addition to the previous variables. No comorbidity or medication was significant in the specific-cause models. CONCLUSIONS: This is the first study to link neuroinflammation independently to early death in AD and, hence, a rapidly progressing disease. Frontal and medial temporal atrophies and low cognition were also significant predictors. These are probably downstream biomarkers that reflect neuronal degeneration and late-stage disease. Our results suggest that inflammation, and not amyloid or tau pathology, is an independent underlying mechanism in the malignancy of AD.

Solitary living in Alzheimer's disease over 3 years: association between cognitive and functional impairment and community-based services.

INTRODUCTION: Many individuals with Alzheimer's disease (AD) live alone, and this figure is expected to increase. This study aimed to describe the cognitive and functional abilities of solitary-living AD patients, and the potential predictors of their usage of community-based services. METHODS: This 3-year, prospective, multicenter study included 1,021 participants with mild-to-moderate AD (Mini-Mental State Examination score, 10-26) treated with a cholinesterase inhibitor in a routine clinical setting. At baseline and every 6 months, patients were assessed using cognitive, instrumental, and basic activities of daily living (ADL) scales, and service utilization was recorded. Logistic regression models were used to predict the usage of community-based services. RESULTS: At the start of cholinesterase inhibitor therapy (time of AD diagnosis), 355 individuals (35%) were living alone. They were mainly female, older, had more impaired basic ADL capacity, and had a larger number of concomitant medications when compared with those living with family. Regarding the solitary-living patients, lower instrumental ADL (IADL) ability and more medications were independent predictors of usage of home-help services, whereas more impaired IADL at baseline and faster IADL deterioration were predictors of nursing home admission. For those living with family, older age, lower basic ADL, and a greater number of medications predicted home-help services, whereas a larger amount of home help predicted nursing home placement. In addition, female sex was a risk factor for both the utilization of home-help services and nursing home placement. Cognitive ability was not significantly associated with the usage of community-based services. CONCLUSION: A large number of AD patients, predominantly females, live alone with severe cognitive and functional impairment. The amount of home-help services used did not reflect cognitive severity, suggesting that home help did not meet the needs related to cognitive deterioration. Increased knowledge of how community-based services can better accommodate the care needs of solitary-living individuals with AD is essential.

Response to cholinesterase inhibitors affects lifespan in Alzheimer's disease.

BACKGROUND: A varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer's disease (AD). Whether the individual-specific response, specific ChEI agent or dose affects mortality is unclear. We aimed to examine the relationship between the 6-month response to ChEI and lifespan. METHODS: Six hundred and eighty-one deceased patients with a clinical AD diagnosis and a Mini-Mental State Examination (MMSE) score of 10-26 at the start of ChEI therapy (baseline) were included in a prospective, observational, multicentre study in clinical practice. At baseline and after 6 months of treatment, the participants were assessed using the MMSE, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician's Interview-Based Impression of Change (CIBIC), the Instrumental Activities of Daily Living (IADL) scale, and the Physical Self-Maintenance Scale (PSMS). The individuals' socio-demographic characteristics, ChEI dose, and date of death were recorded. Responses to ChEI and the association of possible risk factors with survival were analysed using general linear models. RESULTS: A longer lifespan (mean of 0.5 years) was observed among the improved/unchanged patients, as measured by MMSE or CIBIC score, but not by ADAS-cog score, after 6 months of ChEI therapy. In the multivariate models, increased survival time was independently related to a better 6-month response in MMSE, CIBIC, IADL, and PSMS scores, female sex, no antihypertensive/cardiac or antidiabetic therapy, younger age, lower education, milder disease stage at baseline, and higher ChEI dose. Apolipoprotein E genotype did not affect mortality significantly. The patients who received a higher ChEI dose during the first 6 months had a mean lifespan after baseline that was 15 months longer than that of those who received a lower dose. CONCLUSIONS: A better short-term response to ChEI might prolong survival in naturalistic AD patients. In individuals who received and tolerated higher ChEI doses, a longer lifespan can be expected.

Risk factors that affect life expectancy in Alzheimer's disease: a 15-year follow-up.

BACKGROUNDS/AIMS: Future disease-modifying therapies might affect the expected life span in Alzheimer's disease (AD). Our aim was to identify factors that influence life expectancy in cholinesterase inhibitor (ChEI)-treated patients. METHODS: This study included 791 deceased individuals with a clinical diagnosis of AD and a Mini-Mental State Examination score of 10-26 at baseline who were recruited from a 3-year, prospective, multicenter study of ChEI therapy in clinical practice. The participants' date of death was recorded and their survival was compared with the gender- and age-matched general population. RESULTS: The mean survival time after the start of ChEI therapy (time of AD diagnosis) was 5.10 years for men and 6.12 years for women. Better cognitive ability, less impaired basic functional capacity, and fewer medications, but not education level or apolipoprotein E (APOE) genotype, were independent prognostic factors of longer survival after diagnosis, after controlling for gender and age. CONCLUSION: AD shortens life expectancy in ChEI-treated patients diagnosed before the age of 85 years, similar to that reported previously for untreated individuals. A longer life span was observed in the eldest patients (≥85 years) compared with untreated cohorts, which did not differ from that observed in the general population. Higher education or carrying two APOE ε4 alleles were risk factors for earlier death.

Progression of mild Alzheimer's disease: knowledge and prediction models required for future treatment strategies.

INTRODUCTION: Knowledge of longitudinal progression in mild Alzheimer's disease (AD) is required for the evaluation of disease-modifying therapies. Our aim was to observe the effects of long-term cholinesterase inhibitor (ChEI) therapy in mild AD patients in a routine clinical setting. METHODS: This was a prospective, open-label, non-randomized, multicenter study of ChEI treatment (donepezil, rivastigmine or galantamine) conducted during clinical practice. The 734 mild AD patients (Mini-Mental State Examination (MMSE) score 20 to 26) were assessed at baseline and then semi-annually over three years. Outcome measures included the MMSE, Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change (CIBIC) and Instrumental Activities of Daily Living (IADL) scale. RESULTS: After three years of ChEI therapy, 31% (MMSE) and 33% (ADAS-cog) of the patients showed improved/unchanged cognitive ability, 33% showed improved/unchanged global performance and 14% showed improved/unchanged IADL capacity. Higher mean dose of ChEI and lower educational level were both predictors of more positive longitudinal cognitive and functional outcomes. Older participants and those with a better IADL score at baseline exhibited a slower rate of cognitive decline, whereas younger participants and those with higher cognitive status showed more preserved IADL ability over time. Gender and apolipoprotein E (APOE) genotype showed inconsistent results. Prediction models using the abovementioned scales are presented. CONCLUSIONS: In naturalistic mild AD patients, a marked deterioration in IADL compared with cognitive and global long-term outcomes was observed, indicating the importance of functional assessments during the early stages of the disease. The participants' time on ChEI treatment before inclusion in studies of new therapies might affect their rate of decline and thus the comparisons of changes in scores between various studies. An increased understanding of expected disease progression in different domains and potential predictors of disease progression is essential for assessment of future therapies in AD.

A longitudinal study of risk factors for community-based home help services in Alzheimer's disease: the influence of cholinesterase inhibitor therapy.

BACKGROUND: To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer's disease (AD). METHODS: This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL), and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used. RESULTS: During the study, 332 patients (38%) used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS. CONCLUSIONS: Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.