Clinical Dementia Rating Scale Sum Of Boxes Scores Research Articles

Effect of altered gene expression in lipid metabolism on cognitive improvement in patients with Alzheimer's dementia following fecal microbiota transplantation: a preliminary study.

The brain-gut axis has emerged as a potential target in neurodegenerative diseases, including dementia, as individuals with dementia exhibit distinct gut microbiota compositions. Fecal microbiota transplantation (FMT), the transfer of fecal solution from a healthy donor to a patient, has shown promise in restoring homeostasis and cognitive enhancement. This study aimed to explore the effects of FMT on specific cognitive performance measures in Alzheimer's dementia (AD) patients and investigate the relationship between cognition and the gut microbiota by evaluating changes in gene expression following FMT. Five AD patients underwent FMT, and their cognitive function [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)] was assessed before and after FMT. The patients' fecal samples were analyzed with 16S rRNA to compare the composition of their gut microbiota. We also assessed modifications in the serum mRNA expression of patients' genes related to lipid metabolism using serum RNA sequencing and quantitative real-time polymerase chain reaction. Significant improvements in cognitive function, as measured by the MMSE (pre- and post-FMT was 13.00 and 18.00) and MoCA were seen. The MoCA scores at 3 months post-FMT (21.0) were the highest (12.0). The CDR-SOB scores at pre- and post-FMT were 10.00 and 5.50, respectively. Analysis of the gut microbiome composition revealed changes via 16S rRNA sequencing with an increase in Bacteroidaceae and a decrease in Enterococcaceae. Gene expression analysis identified alterations in lipid metabolism-related genes after FMT. These findings suggest a link between alterations in the gut microbiome, gene expression related to lipid metabolism, and cognitive function. The study highlights the importance of gut microbiota in cognitive function and provides insights into potential biomarkers for cognitive decline progression. FMT could complement existing therapies and show potential as a therapeutic intervention to mitigate cognitive decline in AD.

MACHINE-LEARNING-BASED INTERPRETABLE PREDICTION FOR MILD COGNITIVE IMPAIRMENT: FROM ADNI DATABASE

Abstract Objective An accurate prediction model was still lacking for mild cognitive impairment (MCI). Therefore, this study aimed to predict the 3- and 5-year MCI risk utilizing interpretable machine learning, and to identify possible biomarkers for intervention. Methods A total of 444 participants were obtained from the ADNI database. Sociodemographic, neuropsychological, ApoE gene, and structural MRI imaging information was used as predictors. Data was randomly divided into training (70%) and test sets (30%). Six machine learning methods were constructed to predict the risk of MCI. Model performance was assessed by area under the ROC curve (AUC). SHapley Additive exPlanations (SHAP) was used to select important predictors. We also constructed a simplified MCI prediction model for clinical practice. Results The mean age (standard deviation) of study population was 73.7 (6.1) years old. A total of 40, and 60 participants progressed into MCI within 3, and 5 years, respectively. Logistic regression (AUC: 0.97) and support vector machine (AUC: 0.93) are the optimal model for 3- and 5-year prediction. The simplified models based on top three neuropsychological test scores also showed high prediction accuracy (AUC > 0.90). APOE gene, intracranial volume, and Clinical Dementia Rating Scale Sum of Boxes (CDRSB) score were top three predictors for 3-year prediction, while CDRSB score, modified Preclinical Alzheimer’s Cognitive Composite Test with Follow-up Test scale (mPACCtrailsB) score, and Functional Activity Questionnaire (FAQ) score were top three predictors for 5-year prediction. Conclusion Interpretable machine learning showed promise in early identification of MCI, and would be valuable for targeted prevention.

TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer’s disease

In Alzheimer’s disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO (NCT03352557), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab—a monoclonal antibody to N-terminal tau—in patients with early Alzheimer’s disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

The Effectiveness of Community Aging Care Centers on Global Function for People Living with Dementia.

The global population with dementia is growing rapidly. Dementia patients have been included in the services of the long-term care Act 2.0, supported by Taiwan's government since 2017. Community aging care centers are extensively established, which are places providing social connections and group physical and cognitive training programs for elderly people. To elucidate the efficacy of community aging care centers on cognitive function in people with dementia. A total of 1,277 patients with dementia diagnosed at the Changhua Christian Hospital outpatient departments were enrolled. A total of 113 patients who used community aging care centers and 452 subjects matched for age, education, and initial score of clinical dementia rating scale sum of boxes (CDR-SOB) control group were analyzed. The primary outcome was the change in CDR-SOB scores before and after utilization of community aging care centers. The mean annual change of CDR-SOB scores were 1.72±2.97, 1.08±2.36, and 1.04±3.64 in control, Community Service Centers for Dementia, and community elderly stations, respectively, after about 1.5 years follow-up. Patients with dementia using community aging care centers had significantly less progression in CDR-SOB scores than those in the control group (-0.65; 95% CI: -1.27, -0.03; p = 0.041). Using one more day of community aging care centers per week significantly promotes 0.16 points of CDR-SOB decline (-0.16, 95% CI: -0.31; -0.00; p = 0.045). Community aging care centers, based on the long-term care Act 2.0 in Taiwan, were effective in delaying the decline in global function in people living with dementia.

Development and validation of the Ascertain Dementia 8 (AD8) Thai version.

The Ascertain Dementia 8 (AD8) is a brief informant-based questionnaire which reliably distinguishes patients with neurocognitive disorder (NCD) and normal cognition. Our objective was to translate the AD8 into Thai and test its validity as a potentially useful measure to detect patients with the mild stage of major NCD due to Alzheimer disease (major NCD-AD). Evaluations of 144 informant-patient dyads were made. Participants were patients who attended the memory clinic at Ramathibodi Hospital and non-patient volunteers. The AD8-Thai version was administered separately from doctor's interviews and neuropsychological assessments. Diagnostic workups included a complete medical history, physical and neurological examinations, neuropsychological testing, the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB), Montreal Cognitive Assessment (MoCA), blood tests and brain imaging, preferably with magnetic resonance imaging. All researchers were blinded to the AD8 results. An AD8 score ≥3 had a sensitivity of 95.5%, a specificity of 89.5%, a positive predictive value of 84%, and a negative predictive value of 97.1% for screening major NCD-AD and those with normal cognition. A subgroup analysis with participants aged ≥65 years and with ≥12 years of education revealed comparable ability to the whole group. AD8 scores had a moderate negative relationship with MoCA scores (r= -0.470) and a strong positive relationship with CDR-SOB scores (r= 0.547). The performance of AD8 scores in differentiating mild NCD from normal cognition was not as good as for major NCD-AD. AD8-Thai version is an acceptable screening tool for major NCD-AD. For patients aged 65 years or older, with at least 12 years of education, and with cognitive complaints in memory clinic, an AD8-Thai score of 3 or more would be sufficient to work on major NCD diagnosis. The performance of the AD8-Thai in mild NCD needs further investigation.

Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease.

Cerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors. The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3, Consortium to Establish a Registry for Alzheimer's Disease score ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes. Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (β = -0.93, 95% CI -1.35, -0.51, Bayes factor [BF] 130.75), working memory (β = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (β = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (β = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (β = -0.08, 95% CI -0.12, -0.05, BF 18.11). Effects ranged from weak (BFs <3.0) to strong (BFs <150). We also found worse performance in the AD+/CBVD+ group across time on naming (β = -1.04, 95% CI -1.83, -0.25, BF 2.52) and verbal fluency (β = -0.73, 95% CI -1.30, -0.15, BF 1.34) and more impaired CDR-SB scores (β = 0.45, 95% CI 0.01, 0.89, BF 0.33). In brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.

Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease.

Removal of the extracellular Aβ plaques in the brain is one of the mechanisms to treat Alzheimer's disease (AD). Separate clinical trials for several therapeutic compounds that target amyloid plaque reduction have shown noteworthy correlations among plaque removal, the Amyloid-Related Imaging Abnormalities (ARIA) rate, and clinical efficacy of the treatment. The relationships among therapeutic dose levels, the rate of amyloid removal, and the clinical efficacy deserve further investigation across therapeutic agents, particularly for clinical trials to provide insights for strategies to develop amyloid therapies in Alzheimer's disease. Published data summaries from clinical trials with amyloid therapies of aducanumab, donanemab, lecanemab, and gantenerumab are evaluated with meta-analyses. Linear mixed models for repeated measurements for visits and random study effects are applied to analyze amyloid centiloid value reduction from baseline and clinical cognition change from baseline for treatment groups according to doses and compounds for the clinical trials. Logistic regression analysis is applied to evaluate the relationship between the amyloid removal rate and the ARIA-Edema (ARIA-E) rate across different dose groups and clinical trials. The extent of amyloid removal varies among therapeutic agents and their dose levels. Across treatment groups and clinical trials, amyloid centiloid value reductions at Weeks 26 and 52 are strongly correlated with both ARIA-E rate over 78weeks and the clinical efficacy response in the Clinical Dementia-Rating Scale Sum of Boxes (CDR-SB) score change from baseline at Week 78; and the Spearman rank correlations for amyloid reduction at Week 52 are stronger as - 0.79 with the ARIA-E rate over 78weeks and 0.73 with the Week 78 CDR-SB score change from baseline. Aβ plaques removal in the brain due to amyloid therapy is strongly correlated with a better clinical response in patients with early Alzheimer's disease and a higher ARIA-E rate for the treatment groups and clinical trials in this meta-analysis. These relationships suggest that the balance between the clinical efficacy response and safety in ARIA-E rate is relevant for the choice of doses for amyloid therapies in confirmatory clinical trials.

Psychotropic Medication and Cognitive, Functional, and Neuropsychiatric Outcomes in Alzheimer's Disease (AD).

There are growing concerns about the safety and efficacy of psychotropic medications in Alzheimer's disease (AD). We sought to examine associations between psychotropic medication exposure and longitudinal change in cognitive, functional, and neuropsychiatric outcomes in a large clinical AD cohort. Longitudinal observational study. National Alzheimer's Disease Coordinating Center combining data from 39 Alzheimer's disease centers. 8,034 participants with AD dementia. Mini-Mental State Exam (MMSE), Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), and Neuropsychiatric Inventory Questionnaire (NPI-Q) Total. Probability of exposure to medication (the propensity score, PS) calculated via logistic regression. Medication classes included all antipsychotics (atypical vs conventional), antidepressants (Selective Serotonin Reuptake Inhibitor [SSRI] vs non-SSRI), and benzodiazepines. Participants treated with a medication class were matched with participants not treated with that class with the closest-matched PS. The effect of medication treatment was assessed using linear mixed-effects models. Participants had a mean (SD) age of 75.5 (9.8) years, and mean (SD) scores of MMSE 21.3 (5.7), CDR-SB 5.5 (3.4), and NPI-Q Total 4.5 (4.4). Mean duration of follow-up was 2.9-3.3 years depending on medication class. Non-SSRI antidepressant use was associated with better CDR-SB (2-year difference in change-DIC: -0.38 [-0.61, -0.15], P = .001). Atypical antipsychotic use was associated with greater decline on MMSE (DIC: -0.91 [-1.54, -0.28] P = .005) and CDR-SB scores (DIC: 0.50 [0.14, 0.86], P = .006). Notably, no drug class was associated with better NPI-Q scores. Use of atypical antipsychotics was associated with poorer cognition and function, and no drug class was associated with improvement in neuropsychiatric symptoms.

Psychometric Properties of the Clinical Dementia Rating Scale Sum of Boxes in Parkinson's Disease.

Background:A composite measure that assesses both cognitive and functional abilities in Parkinson’s disease (PD) would be useful for diagnosing mild cognitive impairment (MCI) and PD dementia (PDD) and as an outcome measure in randomized controlled trials. The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) was designed to assess both cognition and basic-instrumental activities of daily living in Alzheimer’s disease but has not yet been validated in PD.Objective:To validate the CDR-SOB as a composite cognitive-functional measure for PD patients, as well as to assess its sensitivity to change.Methods:The CDR-SOB and a comprehensive cognitive and functional battery was administered to 101 PD patients at baseline (39 normal cognition [NC], 41 MCI and 21 PDD by expert consensus panel), and re-administered to 64 patients after 1-2 years follow-up (32 NC and 32 cognitive impairment [CI] at baseline).Results:Cross-sectionally, CDR-SOB and domain scores were correlated with corresponding neuropsychological or functional measures and were significantly different between cognitive subgroups both at baseline and at follow-up. In addition, CDR-SOB ROC curves distinguished between normal cognition and dementia with high sensitivity, but did not distinguish well between NC and MCI. Longitudinal changes in the CDR-SOB and domain scores were not significant and were inconsistent in predicting change in commonly-used cognitive and functional tests.Conclusion:The CDR-SOB detects dementia-level cognitive impairment in PD but may not be appropriate for predicting longitudinal combined cognitive-functional changes in patients without significant cognitive impairment at baseline.

The Association Between Circulating Inflammatory Markers and the Progression of Alzheimer Disease in Norwegian Memory Clinic Patients With Mild Cognitive Impairment or Dementia.

Neuroinflammation may play an important role in the pathogenesis and progression of Alzheimer disease (AD). The aim of the present study was to detect whether increased inflammatory activity at baseline could predict cognitive and functional decline in patients with amnestic mild cognitive impairment (aMCI) or AD dementia after 2 years. Serum samples from 242 memory clinic patients with an aMCI (n=88) or AD dementia (n=154) were analyzed for C-reactive protein and for 14 other inflammatory markers [interleukin (IL)-1β, interleukin-1 receptor antagonist, IL-6, IL-10, IL-12p40, IL-17a, IL-18, IL-22, IL-33, tumor necrosis factor, cluster of differentiation 40 ligand, interferon-γ, chemokine ligand (CCL) 2, and CCL4] by bead-based multiplex immunoassay. Disease progression was measured by the annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and annual decrease in the score on the Mini-Mental State Examination (MMSE). No association between increased levels of the inflammatory markers and change on the CDR-SB or MMSE score was found, but there was a significant difference in baseline IL-6 and interleukin-1 receptor antagonist levels between aMCI and AD dementia groups. Increased levels of inflammatory markers were not associated with faster progression as measured by the annual change on the CDR-SB or MMSE score.

The efficacy of a "cocktail therapy" on Parkinson's disease with dementia.

Objective: To explore the efficacy and safety of “cocktail therapy” in Parkinson’s disease with dementia (PDD).Patients and methods: Sixty patients with PDD were randomly assigned to the test group (n=30) and a control group (n=30). The control group received 10 mg of donepezil hydrochloride tablets orally, once a day. The test group was treated with a “cocktail therapy”, which consisted of 10 mg of donepezil hydrochloride tablets taken orally, once a day; 200 mg of dl-3n-butylphthalide soft capsules taken orally, 15 mins before each meal, three times daily; 800 mg of oxiracetam capsules taken orally, three times daily; and 80 mg of Ginkgo biloba extract tablets taken orally, three times daily. Treatment was administered for six months. The Montreal cognitive assessment scale (MoCA), Blessed-Roth dementia scale, and Clinical Dementia Rating Scale sum of boxes (CDR-SB) were used before treatment and on the third and sixth month after treatment. Adverse events were also monitored.Results: There were no statistical differences in MoCA, CDR-SB, or Blessed-Roth dementia scale scores between the two groups before treatment. MoCA scores of the test group at six months were significantly higher than those before the treatment and at three months, while both the Blessed-Roth and CDR-SB scores were significantly lower than those before treatment and at three months (p<0.05). Compared with the control group, MoCA scores of the test group were significantly higher, while both the Blessed-Roth and CDR-SB scores were significantly lower (p<0.05), at six months after treatment. There was no statistical difference (p>0.05) between the test group (16.67%) and the control group (13.33%) in the rate of abnormal liver function after treatment.Conclusion: Treatment with “cocktail therapy” was safe and improved the conditions of patients with PDD, as well as the quality of life of the patients.

Progression of Alzheimer's Disease: A Longitudinal Study in Norwegian Memory Clinics.

The course of Alzheimer's disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression. The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0-18), the cognitive test Mini-Mental State Examination (MMSE, 0-30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1). The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics. In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores. Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate.

Factors affecting therapeutic response to Rivastigmine in Alzheimer's disease patients in Taiwan

Rivastigmine has been widely used in mild-to-moderate Alzheimer's disease (AD), but the therapeutic response rate varies from 20 to 60%. A dose-dependent effect has been suggested, but the plasma concentration of rivastigmine and its metabolite, NAP 226-90, were not measured in previous studies. The influencing factors of therapeutic response are complicated and discordant in various studies among different ethnic groups. Hence, we analyzed the therapeutic responses of rivastigmine, measured by neuropsychological assessments, among 63 clinically diagnosed AD patients taking a daily dosage of 6–9 mg in relation to their plasma concentration of rivastigmine and NAP 226-90, apolipoprotein E (APOE) genotype and demographic characteristics. Our reports revealed that 41.3% of recruited AD patients had improvement in cognition, measured by Mini-Mental Status Examination (MMSE), and 63.5% in global status, by Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. In cognition, the clinically improving group had a significantly higher rivastigmine concentration [p = 0.049, odds ratio (OR) = 1.029, 95%CI = 1.000–1.058], lower initial MMSE score (p = 0.010, OR = 0.708, 95%CI = 0.546–0.920), and lower initial CDR-SB score (p = 0.003, OR = 0.552, 95%CI = 0.372–0.817). The patients with APOE ε4 allele had worsening cognition (p = 0.037, OR = 3.870, 95%CI = 1.082–13.840). In global status, only higher education (p = 0.043, OR = 1.222, 95%CI = 1.007–1.484) was significantly associated with clinical improvement. In conclusion, high concentrations of rivastigmine may benefit cognitive function of AD patients, especially in APOE ε4 (−) carriers.

Alzheimer’s Candidate Drug Aducanumab Moves to Phase III

Alzheimer’s Candidate Drug Aducanumab Moves to Phase III

Effect of Vascular Risk Factors on the Progression of Mild Alzheimer's Disease and Lewy Body Dementia.

Vascular risk factors (VRF) are associated with an increased risk of neurodegenerative disease. To examine the association between VRF and cognitive decline in patients with Alzheimer's disease (AD) and Lewy body dementia (LBD). We included consecutive referrals with mild AD or LBD to dementia clinics in western Norway from 2005 to 2013. The Mini-Mental Status Exam (MMSE) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) were administered at baseline and then annually for up to five years. The VRF include diabetes mellitus, hypertension, hypercholesterolemia, overweight and smoking. Generalized Estimating Equations (GEE) were used to examine the potential association between VRF scores and the change in MMSE and CDR-SB scores, adjusting for age, sex, and the apolipoprotein ɛ4 allele (APOE4). A total of 200 patients were included (113 AD, 87 LBD) (mean age 76 years, mean baseline MMSE 24.0, mean follow-up time 3.5 years). Smoking was the only VRF significantly associated with a more rapid cognitive decline, however only in the AD group. Being overweight at baseline was associated with a slower cognitive decline. Moreover, hypertension at baseline predicted a slower decline in MMSE scores. In the LBD group diabetes mellitus was found to be associated with a slower increase in CDR-SB scores. With the exception of smoking, VRF at time of dementia diagnosis were not associated with a more rapid cognitive decline.

Self-Rated and Caregiver-Rated Quality of Life in Alzheimer Disease with a Focus on Evolving Patient Ability to Respond to Questionnaires: 5-Year Prospective ALSOVA Cohort Study

To examine and compare self-rated and caregiver-rated measures of quality of life (QoL) in relation to disease progression in patients with very mild or mild Alzheimer disease (AD) and at what disease stage patient's ability to respond to QoL questionnaires with or without assistance begins to diminish. 236 patients with very mild or mild AD and their family caregivers from three Finnish hospital districts participated in this prospective, longitudinal study with 5 years of follow-up. Three patient-reported instruments were used to assess QoL (the generic 15D, the Quality of Life in Alzheimer Disease [QoL-AD] questionnaire, and a visual analogue scale) as well as one caregiver-rated assessment of patient QoL (QoL-AD). AD severity was evaluated with the Clinical Dementia Rating Scale- Sum of Boxes (CDR-SOB). All self- and caregiver-rated QoL estimates correlated with AD severity. The self- and caregiver-rated QoL scores began to diverge even with very mild cognitive impairment after CDR-SOB reached 4, the value that corresponds with a Mini-Mental State Examination (MMSE) score of 25-30. Patients also began to need assistance in responding to questionnaires at very early stages of AD (CDR-SOB score: 4-6). Furthermore, their ability to respond to QoL questionnaires with or without assistance declined after CDR-SOB reached 11 points, a value that correlates with an early moderate stage of AD and MMSE score of 11-20. AD patients' self-rated QoL ratings are much more insensitive to disease progression than caregiver ratings.

PATTERNS OF HIPPOCAMPAL SHAPE CHANGES IN PATIENTS WITH FRONTOTEMPORAL DEMENTIA

one and two-year hippocampal atrophy and cortical atrophy in CN and MCI subjects in the Alzheimer ’s disease Neuroimaging Initiative (ADNI) using a registration-based cube propagation method. Among 504 subjects with 234 MCI, and 169 CN, we defined apriori a group with predominant hippocampal atrophy at year one (>1 standard deviation of the hippocampal atrophy of the population and<1 standard deviation of the cortical atrophy). We tested two hypotheses 1) Subjects meeting criteria at year one are consistent in their atrophy pattern at year two. 2) Subjects with stable hippocampal predominant atrophy have slower functional decline on (Clinical Dementia Rating Scale: Sum of Boxes (CDR-SB). Results: 110 subjects met criteria for hippocampal predominant atrophy. Among these 52% (57 subjects) meeting criteria at year one remain in the same group at year two i.e., with persistent hippocampal predominant atrophy. At baseline, persistent hippocampal atrophy group had a lower CDR SB mean than the non-persistent hippocampal atrophy group (1.1 vs. 1.9, p<0.001). In a linear regression with CDR-SB scores as outcome and controlling for age, sex, education and APOE, persistent hippocampal atrophy group had a slower decline in the CDR SB scores over a year than the non-persistent group (F (1,80) 1⁄4 28.6, p < .0001). Among the unstable ones (in hippocampal predominant atrophy group at year one and not in the same group at year two), 32% go on to develop both hippocampal and cortical atrophy. Conclusions: Identifying the groups with persisting hippocampal predominant atrophy patterns in the predementia stages could help delineate the future clinical trajectories of clinical phenotypes very early in the disease course. This could have direct implications for diagnosis, patient counseling, management and design of clinical trials in AD.

Modeling Alzheimer's Disease Progression Using Disease Onset Time and Disease Trajectory Concepts Applied to CDR‐SOB Scores From ADNI

Disease-onset time (DOT) and disease trajectory concepts were applied to derive an Alzheimer's disease (AD) progression population model using the clinical dementia rating scale—sum of boxes (CDR-SOB) from the AD neuroimaging initiative (ADNI) database. The model enabled the estimation of a DOT and a disease trajectory for each patient. The model also allowed distinguishing fast and slow-progressing subpopulations according to the functional assessment questionnaire, normalized hippocampal volume, and CDR-SOB score at study entry. On the basis of these prognostic factors, 81% of the mild cognitive impairment (MCI) subjects could correctly be assigned to slow or fast progressers, and 77% of MCI to AD conversions could be predicted whereas the model described correctly 84% of the conversions. Finally, synchronization of the biomarker-time profiles on estimated individual DOT virtually expanded the population observation period from 3 to 8 years. DOT-disease trajectory model is a powerful approach that could be applied to many progressive diseases.

Validation of the New Interpretive Guidelines for the Clinical Dementia Rating Scale Sum of Boxes Score in the National Alzheimer's Coordinating Center Database

It was recently demonstrated that the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) score can be used to accurately stage severity of Alzheimer dementia and mild cognitive impairment (MCI). However, to our knowledge, the utility of those interpretive guidelines has not been cross-validated or applied to a heterogeneous sample of dementia cases. To cross-validate the staging guidelines proposed in a previous study using the National Alzheimer's Coordinating Center (NACC) database. The previously published cut scores were applied to the NACC sample and diagnostic accuracy estimates obtained. Next, analyses were restricted to NACC participants with a CDR global score (CDR-GS) of 0.5 and receiver operating characteristic curves generated to determine optimal CDR-SB cut scores for distinguishing MCI from very early dementia. The 2008 NACC uniform data set. There were 12 462 participants (5115 controls; 2551 patients with MCI; 4796 patients with dementia, all etiologies) in the NACC data set used for the current analysis. Main Outcome Measure Accurate prediction of diagnoses (MCI or dementia) using the CDR-SB score. The previously proposed CDR-SB ranges successfully classified the vast majority of patients across all impairment ranges with a kappa of 0.91 and 94% overall correct classification rate. Additionally, the CDR-SB score discriminated between patients diagnosed with MCI and dementia when CDR-GS was restricted to 0.5 (overall area under the curve = 0.83). These findings cross-validate the previously published CDR-SB interpretative guidelines for staging dementia severity and extend those findings to a large heterogeneous sample of patients with dementia. Additionally, the CDR-SB scores distinguished MCI from dementia in patients with reasonable accuracy when CDR-GS was restricted to 0.5.

Staging Dementia Using Clinical Dementia Rating Scale Sum of Boxes Scores

The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score is commonly used, although the utility regarding this score in staging dementia severity is not well established. To investigate the effectiveness of CDR-SOB scores in staging dementia severity compared with the global CDR score. Retrospective study. Texas Alzheimer's Research Consortium minimum data set cohort. A total of 1577 participants (110 controls, 202 patients with mild cognitive impairment, and 1265 patients with probable Alzheimer disease) were available for analysis. Receiver operating characteristic curves were generated from a derivation sample to determine optimal cutoff scores and ranges, which were then applied to the validation sample. Optimal ranges of CDR-SOB scores corresponding to the global CDR scores were 0.5 to 4.0 for a global score of 0.5, 4.5 to 9.0 for a global score of 1.0, 9.5 to 15.5 for a global score of 2.0, and 16.0 to 18.0 for a global score of 3.0. When applied to the validation sample, kappa scores ranged from 0.86 to 0.94 (P < .001 for all), with 93.0% of the participants falling within the new staging categories. The CDR-SOB score compares well with the global CDR score for dementia staging. Owing to the increased range of values, the CDR-SOB score offers several advantages over the global score, including increased utility in tracking changes within and between stages of dementia severity. Interpretive guidelines for CDR-SOB scores are provided.