Clinical Dementia Rating Sum Of Boxes Scores Research Articles

Sex-Specific Risk Factors and Clinical Dementia Outcomes for White Matter Hyperintensities in a large South Korean Cohort.

White matter hyperintensities (WMH) on brain MRI images are the most common feature of cerebral small vessel disease (CSVD). Studies have yielded divergent findings on the modifiable risk factors for WMH and WMH's impact on cognitive decline. Mounting evidence suggests sex differences in WMH burden and subsequent effects on cognition. Thus, we aimed to identify sex-specific modifiable risk factors for WMH. We then explored whether there were sex-specific associations of WMH to longitudinal clinical dementia outcomes. Participants aged 49-89 years were recruited at memory clinics and underwent a T2-weighted fluid-attenuated inversion recovery (FLAIR) 3T MRI scan to measure WMH volume. Participants were then recruited for two additional follow-up visits, 1-2 years apart, where clinical dementia rating sum of boxes (CDR-SB) scores were measured. We first explored which known modifiable risk factors for WMH were significant when tested for a sex-interaction effect. We additionally tested which risk factors were significant when stratified by sex. We then tested to see whether WMH is longitudinally associated with clinical dementia that is sex-specific. The study utilized data from 713 participants (241 males, 472 females) with a mean age of 72.3 years and 72.8 years for males and females, respectively. 57.3% and 59.5% of participants were diagnosed with mild cognitive impairment (MCI) for males and females, respectively. 40.7% and 39.4% were diagnosed with dementia for males and females, respectively. Of the 713 participants, 181 participants had CDR-SB scores available for three longitudinal time points. Compared to males, females showed stronger association of age to WMH volume. Type 2 Diabetes was associated with greater WMH burden in females but not males. Finally, baseline WMH burden was associated with worse clinical dementia outcomes longitudinally in females but not in males. Elderly females have an accelerated increase in cerebrovascular burden as they age, and subsequently are more vulnerable to clinical dementia decline due to CSVD. Additionally, females are more susceptible to the cerebrovascular consequences of diabetes. These findings emphasize the importance of considering sex when examining the consequences of CSVD. Future research should explore the underlying mechanisms driving these sex differences and personalized prevention and treatment strategies. The BICWALZS is registered in the Korean National Clinical Trial Registry (Clinical Research Information Service; identifier, KCT0003391). Registration Date 2018/12/14.

Clinical and Neuroimaging Predictors of Alzheimer's Dementia Conversion in Patients with Mild Cognitive Impairment Using Amyloid Positron Emission Tomography by Quantitative Analysis over 2 Years.

Patients with mild cognitive impairment (MCI) have a relatively high risk of developing Alzheimer's dementia (AD), so early identification of the risk for AD conversion can lessen the socioeconomic burden. In this study, 18F-Florapronol, newly developed in Korea, was used for qualitative and quantitative analyses to assess amyloid positivity. We also investigated the clinical predictors of the progression from MCI to dementia over 2 years. From December 2019 to December 2022, 50 patients with MCI were recruited at a single center, and 34 patients were included finally. Based on visual analysis, 13 (38.2%) of 34 participants were amyloid-positive, and 12 (35.3%) were positive by quantitative analysis. Moreover, 6 of 34 participants (17.6%) converted to dementia after a 2-year follow-up (p = 0.173). Among the 15 participants who were positive for amyloid in the posterior cingulate region, 5 (33.3%) patients developed dementia (p = 0.066). The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) at baseline was significantly associated with AD conversion in multivariate Cox regression analyses (p = 0.043). In conclusion, these results suggest that amyloid positivity in the posterior cingulate region and higher CDR-SOB scores at baseline can be useful predictors of AD conversion in patients with MCI.

Efficacy and safety of gantenerumab in the treatment of Alzheimer's disease: A meta-analysis of randomized controlled trials

IntroductionGantenerumab has garnered considerable attention for its potential to modify the natural course of Alzheimer's disease. However, recent studies have shown mixed results for the use of this medication for the treatment of Alzheimer's Disease. Therefore, this review compared the effects of Gantenerumab with placebo in patients with Alzheimer's disease. MethodsLiterature searches were conducted in PubMed, Embase and Cochrane database from inception to December 2023. Two independent authors (MS and LV) performed the study selection, data extraction and quality assessment. The outcomes of this review were: Clinical Dementia Rating - Sum of Boxes (CDR-SB), the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Mini-Mental State Evaluation (MMSE) and the incidence of Amyloid-Related Imaging Abnormalities with Edema (ARIA-E) or Amyloid-Related Imaging Abnormalities with Hemosiderosis (ARIA-H). Meta-analysis were performed using Review Manager 5.4 (Cochrane Collaboration). ResultsFour studies reporting data for 2,848 patients were included in this review. The lenght of follow-up assessments ranged from 50 to 104 weeks. When compared to placebo, Gantenerumab was significantly associated with a lower ADAS-Cog score (MD -1.05; 95 % CI: -1.85 to -0.25) and lower MMSE score (MD -0.31; 95 % CI: -0.55 to -0.07). There were no differences in the CDR-SB score. Gantenerumab group had a higher incidence of ARIA-E (RR 8.94; 95 % CI: 6.22 to 12.84). ConclusionGantenerumab showed negative effects on cognitive outcomes of people with Alzheimer's Disease. There was a higher incidence of ARIA-E and ARIA-H for gantenerumab. Additional high quality studies are needed to draw more robust conclusions about this treatment.

Psychosis in Alzheimer’s disease is associated with specific changes in brain MRI volume, cognition and neuropathology

Psychosis in Alzheimer’s Disease (AD) is prevalent and indicates poor prognosis. However, the neuropathological, cognitive and brain atrophy patterns underlying these symptoms have not been fully elucidated. In this study, we evaluated 178 patients with AD neuropathological change (ADNC) and ante-mortem volumetric brain magnetic resonance imaging (MRI). Presence of psychosis was determined using the Neuropsychiatric Inventory Questionnaire. Clinical Dementia Rating Sum-of-boxes (CDR-SB) was longitudinally compared between groups with a follow-up of 3000 days using mixed-effects multiple linear regression. Neuropsychological tests closest to the time of MRI and brain regional volumes were cross-sectionally compared. Psychosis was associated with lower age of death, higher longitudinal CDR-SB scores, multi-domain cognitive deficits, higher neuritic plaque severity, Braak stage, Lewy Body pathology (LB) and right temporal lobe regional atrophy. Division according to the presence of LB showed differential patterns of AD-typical pathology, cognitive deficits and regional atrophy. In conclusion, psychosis in ADNC with and without LB has clinical value and associates with subgroup patterns of neuropathology, cognition and regional atrophy.

Tau PET burden in Brodmann areas 35 and 36 is associated with individual differences in cognition in non-demented older adults.

The accumulation of neurofibrillary tau tangles, a neuropathological hallmark of Alzheimer's disease (AD), occurs in medial temporal lobe (MTL) regions early in the disease process, with some of the earliest deposits localized to subregions of the entorhinal cortex. Although functional specialization of entorhinal cortex subregions has been reported, few studies have considered functional associations with localized tau accumulation. In this study, stepwise linear regressions were used to examine the contributions of regional tau burden in specific MTL subregions, as measured by 18F-MK6240 PET, to individual variability in cognition. Dependent measures of interest included the Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini Mental State Examination (MMSE), and composite scores of delayed episodic memory and language. Other model variables included age, sex, education, APOE4 status, and global amyloid burden, indexed by 11C-PiB. Tau burden in right Brodmann area 35 (BA35), left and right Brodmann area 36 (BA36), and age each uniquely contributed to the proportion of explained variance in CDR-SB scores, while right BA36 and age were also significant predictors of MMSE scores, and right BA36 was significantly associated with delayed episodic memory performance. Tau burden in both left and right BA36, along with education, uniquely contributed to the proportion of explained variance in language composite scores. Importantly, the addition of more inclusive ROIs, encompassing less granular segmentation of the entorhinal cortex, did not significantly contribute to explained variance in cognition across any of the models. These findings suggest that the ability to quantify tau burden in more refined MTL subregions may better account for individual differences in cognition, which may improve the identification of non-demented older adults who are on a trajectory of decline due to AD.

Exploring the relationship between patient-relevant outcomes and Alzheimer's disease progression assessed using the clinical dementia rating scale: a systematic literature review.

People with Alzheimer's disease (AD) have difficulties in performing activities of daily living (ADLs) as the disease progresses, commonly experience neuropsychiatric symptoms (NPS), and often have comorbidities such as cardiovascular disease. These factors all contribute to a requirement for care and considerable healthcare costs in AD. The Clinical Dementia Rating (CDR) scale is a widely used measure of dementia staging, but the correlations between scores on this scale and patient-/care partner-relevant outcomes have not been characterized fully. We conducted a systematic literature review to address this evidence gap. Embase, MEDLINE, and the Cochrane Library were searched September 13, 2022, to identify published studies (no restriction by date or country) in populations with mild cognitive impairment due to AD or AD dementia. Studies of interest reported data on the relationships between CDR Global or CDR-Sum of Boxes (CDR-SB) scores and outcomes including NPS, comorbidities, ADLs, nursing home placement, healthcare costs, and resource use. Overall, 58 studies met the inclusion criteria (42 focusing on comorbidities, 14 on ADLs or dependence, five on nursing home placement, and six on economic outcomes). CDR/CDR-SB scores were correlated with the frequency of multiple NPS and with total scores on the Neuropsychiatric Inventory. For cardiovascular comorbidities, no single risk factor was consistently linked to AD progression. Increasing CDR/CDR-SB scores were correlated with decline in multiple different measures of ADLs and were also associated with nursing home placement and increasing costs of care. NPS, ADLs, and costs of care are clearly linked to AD progression, as measured using CDR Global or CDR-SB scores, from the earliest stages of disease. This indicates that scores derived from the CDR are a meaningful way to describe the severity and burden of AD for patients and care partners across disease stages.

Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer's Disease.

Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer's disease (AD). To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer's Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57). Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype.

Cognitive Function Remains Associated with Global Functional Impairment in Profound Dementia due to Alzheimer’s Disease and Dementia with Lewy Bodies (P6-6.011)

<h3>Objective:</h3> To determine if cognitive function is still related to overall functional impairment in profound dementia. <h3>Background:</h3> The Baylor Profound Mental Status Exam (BPMSE) was developed to assess cognitive function in profound dementia stage. The Clinical Dementia Rating (CDR) scale has been widely used in measuring functional performance in dementia. <h3>Design/Methods:</h3> We recruited 864 probable Alzheimer’s disease (AD) and 55 possible dementia with Lewy body (DLB) cases with profound dementia by MMSE or/and clinical global impression. We used BPMSE to measure cognitive function, and the CDR sum of boxes (CDR-SB) score to determine overall functional status. We used Spearman’s rank order correlation to examine the univariate association between CDR-SB and BPMSE in the two diagnostic groups separately, and multivariable regression analysis to investigate if BPMSE remained associated with functional decline after adjustment for age, sex, education, and APOE genotype. We expected to see an inverse correlation between BPMSE and CDR-SB scores based on the directionality of the rating scale scoring. <h3>Results:</h3> In both AD and DLB, total BPMSE score significantly correlated with CDR-SB score (AD: <i>r</i> = −0.453, <i>p &lt; 0.001;</i> DLB: <i>r</i> = −0.489, <i>p = 0.013</i>). Interestingly, in DLB, the “attention” domain of BPMSE had the strongest association with CDR-SB (r = −0.700, <i>p &lt; 0.001</i>) compared to other domains. The multivariable regression models showed that higher BPMSE scores (i.e., better cognitive function) were correlated with lower CDR-SB scores (i.e., better global function) in AD (CDR-SB: β = −0.340, <i>p &lt; 0.001</i>) but not as strongly in DLB (CDR-SB: β = −0.298, <i>p = 0.174</i>). <h3>Conclusions:</h3> In AD and DLB patients who enter the profound dementia stage, cognitive function is associated with the severity of functional impairment. The lack of significance for DLB in multivariable regression could be due to small sample size, as the correlation magnitude is similar to that in AD. <b>Disclosure:</b> Ms. Rampalli has nothing to disclose. Dr. Pavlik has nothing to disclose. An immediate family member of Dr. Yu has received personal compensation for serving as an employee of CVS/Aetna. The institution of Dr. Yu has received research support from Alzheimer’s Association. The institution of Dr. Yu has received research support from Biogen. The institution of Dr. Yu has received research support from Eisai. Dr. Yu has a non-compensated relationship as a Steering Board member with Epic Systems that is relevant to AAN interests or activities. Mr. BISHOP has nothing to disclose. Dr. Lin has a non-compensated relationship as a Secretary with Broadway for Ataxia Foundation (a 501 (c) (3) non-profit organization) that is relevant to AAN interests or activities.

FDA Approves Second Antibody Therapy for Alzheimer’s

FDA Approves Second Antibody Therapy for Alzheimer’s

Imaging features of small vessel disease in cerebral amyloid angiopathy among patients with Alzheimer’s disease

Background and purposeCerebral small vessel disease biomarkers including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (ePVS) are under investigation to identify those specific to cerebral amyloid angiopathy (CAA). In subjects with Alzheimer’s disease (AD), we assessed characteristic features and amounts of WMH, lacunes, and ePVS in four CAA categories (no, mild, moderate and severe CAA) and correlated these with Clinical Dementia Rating sum of boxes (CDRsb) score, ApoE genotype, and neuropathological changes at autopsy. MethodsThe study included patients with a clinical diagnosis of dementia due to AD and neuropathological confirmation of AD and CAA in the National Alzheimer’s Coordinating Center (NACC) database. The WMH, lacunes, and ePVS were evaluated using semi-quantitative scales. Statistical analyses compared the WMH, lacunes, and ePVS values in the four CAA groups with vascular risk factors and AD severity treated as covariates, and to correlate the imaging features with CDRsb score, ApoE genotype, and neuropathological findings. ResultsThe study consisted of 232 patients, of which 222 patients had FLAIR data available and 105 patients had T2-MRI. Occipital predominant WMH were significantly associated with the presence of CAA (p = 0.007). Among the CAA groups, occipital predominant WMH was associated with severe CAA (β = 1.22, p = 0.0001) compared with no CAA. Occipital predominant WMH were not associated with the CDRsb score performed at baseline (p = 0.68) or at follow-up 2–4 years after the MRI (p = 0.92). There was no significant difference in high grade ePVS in the basal ganglia (p = 0.63) and centrum semiovale (p = 0.95) among the four CAA groups. The WMH and ePVS on imaging did not correlate with the number of ApoE ε4 alleles but the WMH (periventricular and deep) correlated with the presence of infarcts, lacunes and microinfarcts on neuropathology. ConclusionAmong patients with AD, occipital predominant WMH is more likely to be found in patients with severe CAA than in those without CAA. The high-grade ePVS in centrum semiovale were common in all AD patients regardless of CAA severity.

Geo‐cultural influences on the relationship between the CDR and MMSE

AbstractBackgroundThe increasingly global scope of clinical trials in Alzheimer’s disease (AD) has led to the recruitment of subjects from various geo‐cultural regions. Recent studies suggest that commonly used objective measures of cognition such as the MMSE as well as subjective, clinician‐rated global measures such as the CDR might be impacted by cultural and/or linguistic differences. This raises the question regarding the impact of cultural differences on the convergent validity of the CDR and MMSE.In this analysis, we examined the extent to which the correspondence between the CDR and MMSE varied across seven geo‐cultural regions in multinational AD clinical trials.MethodThis study included electronic CDR (eCDR) and electronic MMSE (eMMSE) data from four multinational AD clinical trials of subjects with Prodromal to Mild AD. Data were collected at screening from seven geo‐cultural regions: East Asia (n = 1916), Eastern Europe (n = 1882), South America (n = 1601), Middle East/Africa (n = 188), North America (n = 9311), Oceania (n = 363), and Western Europe (n = 5174).ResultPearson correlations between eCDR Sum of Boxes (SOB) and eMMSE across the 7 geo‐cultural regions ranged from r = ‐.31 (East Asia, Western Europe) to r = ‐.48 (Mideast/Africa). A linear regression model with geo‐cultural regions entered as covariates further demonstrated that the relationship between eMMSE and eCDR SoB scores differed by region (Adjusted R2 = 0.14, p&lt;0.001).ConclusionFindings indicate the strength of the correlation between the CDR SOB and MMSE total score varied by geo‐cultural region. These results build on prior findings indicating that CDR SOB and MMSE scores vary across regions independent of each other. A growing body of literature suggests these differences might be due to cultural and/or linguistic factors.

Med Check: Lecanemab; ANEB-001; Azstarys; and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Lecanemab; ANEB-001; Azstarys; and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:27 Oct 2022https://doi.org/10.1176/appi.pn.2022.11.11.2Lecanemab May Slow Decline in Alzheimer’sLecanemab, an investigational anti-amyloid beta protofibril antibody, may slow cognitive decline in Alzheimer’s disease, Biogen Inc. and Esai Co. Ltd. announced in September. Lecanemab is being developed for the treatment of mild cognitive impairment from Alzheimer’s disease and mild or early Alzheimer’s disease with confirmed presence of amyloid pathology in the brain.In the phase 3 Clarity AD trial, 1,795 patients with early Alzheimer’s disease were randomized to receive either placebo or biweekly doses of 10 mg of lecanemab per kilogram of body weight. The primary endpoint was reduced clinical decline, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). At the end of 18 months, CDR-SB scores had declined by 27% less in patients who received lecanemab compared with those who received placebo. The CDR-SB scores were a mean 0.45 points lower for those who received lecanemab compared with those who received placebo.Last year the Food and Drug Administration (FDA) granted Breakthrough Therapy designation to lecanemab based on the results of a phase 2b clinical trial, which examined the impact of treatment with lecanemab on reducing amyloid beta and clinical decline, as measured by changes on the Alzheimer’s Disease Composite Score (ADCOMS). Breakthrough Therapy designation expedites the development and review of drugs for serious conditions.In the trial, 856 patients who had mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia were randomized to receive 2.5 mg/kg, 5 mg/kg, or 10 mg/kg of lecanemab once every two weeks; 5 mg/kg or 10 mg/kg of lecanemab once every four weeks; or placebo for 18 months. Patients who took 10 mg/kg biweekly lecanemab had a 76% probability of achieving 25% less decline on ADCOMS compared with those who took placebo. ANEB-001 May Reverse Cannabinoid IntoxicationA phase 2 trial of the investigational cannabinoid receptor agonist ANEB-001 suggests that the medication may reverse cannabinoid intoxication, Anebulo Pharmaceuticals Inc. announced in September.The trial involved approximately 60 participants, who were given 21 mg of delta-9-tetrahydrocannabinol (THC). They were then given 10 mg of ANEB-001, 30 mg of ANEB-001, or placebo.Those who received placebo reported a substantial increase in feeling high and body sway, decreased alertness, and a slightly increased heart rate from baseline. Participants who received either 10 mg or 30 mg of ANEB-001 experienced significant reductions in the visual analog scale (VAS) score for feeling high, improvement in the VAS alertness scale, and a reduction in THC-induced body sway compared with those who received placebo. Azstarys May Improve Sleep for Children with ADHDAzstarys (serdexmethylphenidate and dexmethylphenidate) may help improve sleep in children with attention-deficit/hyperactivity disorder (ADHD), Corium Inc. announced in September. Azstarys is approved for the treatment of ADHD in patients aged six years and older.In a one-year open-label study, 238 children with ADHD aged six to 12 years received Aztarys for one year. After one month of treatment with Azstarys, the children’s total average sleep disturbance score on the Children’s Sleep Habits Questionnaire (CSHQ) decreased significantly from a mean of 53.4 points to 50.5 points. Furthermore their total mean CSHQ scores remained between 48.9 to 50.1 points for up to 12 months, indicating that the improvements in their sleep were sustained.The results of the study were presented in a poster at the Psych Congress 2022 in New Orleans. FDA Reviews Two-Month Aripiprazole Injection for SchizophreniaIn September, Otsuka America Pharmaceutical Inc. and H. Lundbeck A/S announced that the FDA has accepted for review a New Drug Application (NDA) for aripiprazole two-month, long-acting injectable for the treatment of schizophrenia in adults and for maintenance monotherapy of bipolar I disorder in adults. The NDA is for a formulation designed to be administered via intramuscular injection in the gluteal muscle.The NDA is based on data from a clinical trial involving 266 patients who were randomized to receive either four 920 mg injections of aripiprazole two-month long-acting injectable or eight 400 mg injections of aripiprazole one-month depot. Plasma concentrations of aripiprazole were similar between both groups of patients, and the two-month injectable was well-tolerated and showed no safety concerns compared with the once-monthly injectable. ■ ISSUES NewArchived

Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease

Alzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression. To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD. Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively. Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks. The primary outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was -0.17 (95% CI, -0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point. Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD. ClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657.

Interactions Between Weight Loss and Plasma Neurodegenerative Markers for Determining Cognitive Decline Among Community-Dwelling Older Adults.

This study aimed to investigate the interaction between weight loss (WL) and plasma amyloid-β 42/40 (Aβ 42/40), neurofilament light chain (NfL), progranulin, and their association with cognitive decline over time among older adults. This 5-year observational approach included 470 participants from the Multidomain Alzheimer Preventive Trial, mean age 76.8 years (SD = 4.5), 59.4% women. WL was defined as ≥5% decrease over the first year. Biomarkers were measured at 12 months. Cognitive function was assessed yearly from 12 months onward by Mini-Mental State Examination (MMSE); Clinical Dementia Rating sum of boxes (CDR-SB); a composite score based on Category Naming Test; Digit Symbol Substitution Test; 10 MMSE orientation items (MMSEO) and free and total recall of the Free and Cued Selective Reminding test; and these tests individually. Twenty-seven participants (5.7%) presented WL. In adjusted analyses, combined WL + lower Aβ 42/40 (≤0.103, lowest quartile) was related with more pronounced 4-year cognitive decline according to CDR-SB (p < .0001) and MMSEO (p = .021), compared with non-WL + higher Aβ 42/40. WL + higher NfL (>94.55 pg/mL, highest quartile) or progranulin (>38.4 ng/mL, 3 higher quartiles) were related with higher cognitive decline according to CDR-SB, MMSE, MMSEO, and composite score (all p < .03), compared with non-WL + lower NfL or higher progranulin. Regrouping progranulin quartiles (Q1-Q3 vs Q4) revealed higher cognitive decline among the WL + lower progranulin group compared with non-WL + lower progranulin. In conclusion, 1-year WL was associated with subsequent higher 4-year cognitive decline among older adults presenting low Aβ 42/40 or high NfL. Future studies combining plasma biomarker assessments and body weight surveillance may be useful for identifying people at risk of cognitive impairment. Clinical trial number: NCT00672685.

Prediction and Modeling of Neuropsychological Scores in Alzheimer's Disease Using Multimodal Neuroimaging Data and Artificial Neural Networks.

Background: In recent years, predicting and modeling the progression of Alzheimer’s disease (AD) based on neuropsychological tests has become increasingly appealing in AD research.Objective: In this study, we aimed to predict the neuropsychological scores and investigate the non-linear progression trend of the cognitive declines based on multimodal neuroimaging data.Methods: We utilized unimodal/bimodal neuroimaging measures and a non-linear regression method (based on artificial neural networks) to predict the neuropsychological scores in a large number of subjects (n = 1143), including healthy controls (HC) and patients with mild cognitive impairment non-converter (MCI-NC), mild cognitive impairment converter (MCI-C), and AD. We predicted two neuropsychological scores, i.e., the clinical dementia rating sum of boxes (CDRSB) and Alzheimer’s disease assessment scale cognitive 13 (ADAS13), based on structural magnetic resonance imaging (sMRI) and positron emission tomography (PET) biomarkers.Results: Our results revealed that volumes of the entorhinal cortex and hippocampus and the average fluorodeoxyglucose (FDG)-PET of the angular gyrus, temporal gyrus, and posterior cingulate outperform other neuroimaging features in predicting ADAS13 and CDRSB scores. Compared to a unimodal approach, our results showed that a bimodal approach of integrating the top two neuroimaging features (i.e., the entorhinal volume and the average FDG of the angular gyrus, temporal gyrus, and posterior cingulate) increased the prediction performance of ADAS13 and CDRSB scores in the converting and stable stages of MCI and AD. Finally, a non-linear AD progression trend was modeled to describe the cognitive decline based on neuroimaging biomarkers in different stages of AD.Conclusion: Findings in this study show an association between neuropsychological scores and sMRI and FDG-PET biomarkers from normal aging to severe AD.

Coupling analysis between functional and structural brain networks in Alzheimer's disease.

The coupling between functional and structural brain networks is difficult to clarify due to the complicated alterations in gray matter and white matter for the development of Alzheimer's disease (AD). A cohort of 112 participants [normal control group (NC, 62 cases), mild cognitive impairment group (MCI, 31 cases) and AD group (19 cases)], was recruited in our study. The brain networks of rsfMRI functional connectivity (rsfMRI-FC) and diffusion tensor imaging structural connectivity (DTI-SC) across the three groups were constructed, and their correlations were evaluated by Pearson's correlation analyses and multiple comparison with Bonferroni correction. Furthermore, the correlations between rsfMRI-SC/DTI-FC coupling and four neuropsychological scores of mini-mental state examination (MMSE), clinical dementia rating-sum of boxes (CDR-SB), functional activities questionnaire (FAQ) and montreal cognitive assessment (MoCA) were inferred by partial correlation analyses, respectively. The results demonstrated that there existed significant correlation between rsfMRI-FC and DTI-SC (p < 0.05), and the coupling of rsfMRI-FC/DTI-SC showed negative correlation with MMSE score (p < 0.05), positive correlations with CDR-SB and FAQ scores (p < 0.05), and no correlation with MoCA score (p > 0.05). It was concluded that there existed FC/SC coupling and varied network characteristics for rsfMRI and DTI, and this would provide the clues to understand the underlying mechanisms of cognitive deficits of AD.

Efficacy and safety of Kami-guibi-tang for mild cognitive impairment: a pilot, randomized, double-blind, placebo-controlled trial

BackgroundMild cognitive impairment (MCI) is considered an intermediate phase between normal aging and dementia. As the majority of cases of amnestic MCI (aMCI) progress to Alzheimer’s disease (AD), it is considered the prodromal stage of AD, and a treatment target for prevention of further cognitive decline. However, no medications have been shown to have symptomatic or preventive benefits in MCI. Kami-guibi-tang (KGT) is a traditional herbal formula used in Korean medicine to treat amnesia, which is reported to increase acetylcholine levels via activation of choline acetyltransferase. The objective of this study was to evaluate the efficacy and safety of KGT in patients with aMCI.MethodsThis study was designed as a single-center, randomized, double-blind, placebo-controlled pilot study. Participants diagnosed with aMCI were randomized to receive either KGT or placebo granules for 24 weeks. The efficacy measure was a change in the Seoul Neuropsychological Screening Battery (SNSB) score. The safety measures included the occurrence of adverse events and abnormalities in vital signs and blood chemistry, electrocardiogram (ECG), and brain magnetic resonance imaging (MRI) findings.ResultsA total of 16 patients in the KGT group and 14 patients in the placebo group were investigated in the study. The mean score of Clinical Dementia Rating-Sum of Boxes (CDR-SB) significantly improved from 1.53 (0.64) points to 1.13 (0.62) points in the KGT group (p = 0.010), whereas it worsened from 1.61 (0.88) points to 1.75 (0.94) points in the placebo group. There was a significant difference in the CDR-SB scores between the two groups after the intervention (p = 0.045). The total SNSB-D scores and the scores in the memory domain after the treatment were significantly higher than the baseline values in the KGT group, but not in the placebo group. The frequency of adverse events was not significantly different between the two groups, and there were no abnormalities in vital signs or blood test, ECG, and brain MRI findings after the intervention.ConclusionsKGT may provide a safe and effective treatment option for patients with aMCI. Further studies with a larger sample size are needed to validate the findings.Trial registrationKorean Clinical Trial Registry, ID: KCT0002407; Registered on March 30, 2017, http://cris.nih.go.kr/

Association of the use of hearing aids with the conversion from mild cognitive impairment to dementia and progression of dementia: A longitudinal retrospective study.

IntroductionHearing aid usage has been linked to improvements in cognition, communication, and socialization, but the extent to which it can affect the incidence and progression of dementia is unknown. Such research is vital given the high prevalence of dementia and hearing impairment in older adults, and the fact that both conditions often coexist. In this study, we examined for the first time the effect of the use of hearing aids on the conversion from mild cognitive impairment (MCI) to dementia and progression of dementia.MethodsWe used a large referral‐based cohort of 2114 hearing‐impaired patients obtained from the National Alzheimer's Coordinating Center. Survival analyses using multivariable Cox proportional hazards regression model and weighted Cox regression model with censored data were performed to assess the effect of hearing aid use on the risk of conversion from MCI to dementia and risk of death in hearing‐impaired participants. Disease progression was assessed with Clinical Dementia Rating Sum of Boxes (CDR‐SB) scores. Three types of sensitivity analyses were performed to validate the robustness of the results.ResultsMCI participants that used hearing aids were at significantly lower risk of developing all‐cause dementia compared to those not using hearing aids (hazard ratio [HR] 0.73, 95% confidence interval [CI], 0.61 to 0.89; false discovery rate [FDR] P = 0.004). The mean annual rate of change (standard deviation) in CDR‐SB scores for hearing aid users with MCI was 1.3 (1.45) points and significantly lower than for individuals not wearing hearing aids with a 1.7 (1.95) point increase in CDR‐SB per year (P = 0.02). No association between hearing aid use and risk of death was observed. Our findings were robust subject to sensitivity analyses.DiscussionAmong hearing‐impaired adults, hearing aid use was independently associated with reduced dementia risk. The causality between hearing aid use and incident dementia should be further tested.

The Number Symbol Coding Task: A brief measure of executive function to detect dementia and cognitive impairment.

Alzheimer's disease and related dementias (ADRD) affect over 5.7 million Americans and over 35 million people worldwide. Detection of mild cognitive impairment (MCI) and early ADRD is a challenge to clinicians and researchers. Brief assessment tools frequently emphasize memory impairment, however executive dysfunction may be one of the earliest signs of impairment. To address the need for a brief, easy-to-score, open-access test of executive function for use in clinical practice and research, we created the Number Symbol Coding Task (NSCT). This study analyzed 320 consecutive patient-caregiver dyads who underwent a comprehensive evaluation including the Clinical Dementia Rating (CDR), patient and caregiver versions of the Quick Dementia Rating System (QDRS), caregiver ratings of behavior and function, and neuropsychological testing, with a subset undergoing volumetric magnetic resonance imaging (MRI). Estimates of cognitive reserve were calculated using education, combined indices of education and occupation, and verbal IQ. Psychometric properties of the NSCT including data quality, data distribution, floor and ceiling effects, construct and known-groups validity, discriminability, and clinical profiles were determined. The patients had a mean age of 75.3±9.2 years (range 38-98y) with a mean education of 15.7±2.8 years (range 6-26y) of education. The patients had a mean CDR-SB of 4.8±4.7 (range 0-18) and a mean MoCA score of 18.6±7.1 (range 1-30). The mean NSCT score was 30.1±13.8 and followed a normal distribution. All healthy controls and MCI cases were able to complete the NSCT. The NSCT showed moderate-to-strong correlations with clinical and neuropsychological measures with the strongest association (all p's < .001) for measures with executive components (e.g., Judgement and Problem Solving box of the CDR, Decision Making and Problem Solving domain of the QDRS, Trailmaking B, and Cognigram Attention and Executive Composite Scores). Women slightly outperformed men, and individuals with lower educational attainment and lower education-occupation indices had lower NSCT scores. Decreasing NSCT scores corresponded to older age, worse cognitive scores, higher CDR sum of boxes scores, worse caregiver ratings of function and behavior, worse patient and informant QDRS ratings, and smaller hippocampal volumes and hippocampal occupancy scores. The NSCT provided excellent discrimination (AUC: .866; 95% CI: .82-.91) with a cut-off score of 36 providing the best combination of sensitivity (0.880) and specificity (0.759). Combining the NSCT with patient QDRS and caregiver QDRS ratings improved discrimination (AUC: .908; 95% CI: .87-.94). The NSCT is a brief, 90-second executive task that incorporates attention, planning and set-switching that can be completed by individuals into the moderate-to-severe stages of dementia. The NSCT may be a useful tool for dementia screening, case-ascertainment in epidemiological or community-based ADRD studies, and in busy primary care settings where time is limited. Combining the NSCT with a brief structured interview tool such as the QDRS may provide excellent power to detect cognitive impairment. The NSCT performed well in comparison to standardized scales of a comprehensive cognitive neurology evaluation across a wide array of sociodemographic variables in a brief fashion that could facilitate its use in clinical care and research.

The Effect of Cognitive Training in a Day Care Center in Patients with Early Alzheimer's Disease Dementia: A Retrospective Study.

ObjectiveThis study aimed to evaluate the effect of cognitive training programs on the progression of dementia in patients with early stage Alzheimer’s disease dementia (ADD) at the day care center. MethodsFrom January 2015 to December 2018, a total of 119 patients with early ADD were evaluated. All subjects were classified into two groups according to participate in cognitive training program in addition to usual standard clinical care. Changes in scores for minimental status examination-dementia screening (MMSE-DS) and clinical dementia rating-sum of boxes (CDR-SOB) during the 12 months were compared between two groups. Multivariable logistic regression analyses were performed. ResultsAs compared to case-subjects (n=43), the MMSE-DS and CDR-SOB scores were significantly worse at 12 months in the control-subjects (n=76). A statistically significant difference between the two groups was observed due to changes in MMSE-DS (p=0.012) and CDR-SOB (p<0.001) scores. Multivariable logistic regression analysis showed that the cognitive training program (odds ratio and 95% confidence interval: 0.225, 0.070–0.725) was independently associated with less progression of ADD. ConclusionThe cognitive training program was associated with benefits in maintaining cognitive function for patients with early-stage ADD that were receiving medical treatment.