Clinical Dementia Rating Scale Sum Of Boxes Research Articles

MOTOR SYMPTOMS IN FAMILIAL ALZHEIMER’S DISEASE: FREQUENCY, SEVERITY AND PREDICTIVE VALUE

To evaluate motor dysfunction as a potential symptom of autosomal dominant Alzheimer's disease (ADAD). We utilized data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study to assess motor dysfunction as determined by the Unified Parkinson Disease Rating Scale part-three (UPDRS-III). We analyzed UPDRS-III scores (0 (best) to 108 (worst)) at baseline for all 433 participants at data freeze 10. We compared the frequency (UPDRS-III 0 vs. >0) and severity (UPDRS-III scores) of motor symptoms between mutation carriers (MC) and non-carriers (NC). In MC, correlations of UPDRS-III scores with estimated years to symptom onset (EYO) and Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) were analyzed. Fisher's exact test, Mann-Whitney U test, Spearman correlation and Holm-Bonferroni correction were used. MC exhibited a higher frequency (28.4% vs. 12.8%; p=0.0001) and severity (mean UPDRS-III scores 2.0 vs. 0.4; p=0.00007) of motor symptoms compared to NC. 13 out of 27 symptoms assessed in UPDRS-III were statistically more frequent in MC, with 7 symptoms surviving Holm-Bonferroni correction: finger taps right hand (6.9% vs. 0%; p=0.001), hand movements right hand (5.7% vs. 0%; p=0.0076) and left hand (6.1% vs. 0.6%; p=0.039), rapid alternating movements right hand (7.7% vs. 0%; p=0.0008) and left hand (9.6% vs. 0.6%; p=0.0005), leg agility right leg (4.6% vs. 0%; p=0.026), and gait (4.2% vs. 0%; p=0.039). In cognitively asymptomatic MC (CDR Global=0) rapid alternating movements right hand (3.8% vs. 0%; p=0.02) and left hand (4.4% vs. 0.6%; p=0.03) were more frequently impaired compared to NC after Holm-Bonferroni correction. The positive predictive value to predict MC status in cognitively asymptomatic persons with 50% a priori risk was 100% for right hand and 87.5% for left hand rapid alternating movements. In MC, highly significant positive correlations between UPDRS-III scores and EYO (rs=0.409; p=6.7597E-12) (increasing scores with disease duration) and CDR-SOB (rs=0.420; p=1.3918E-12) were found. In ADAD, motor symptoms occur more frequently and to a larger extend. Furthermore, their degree increases with disease progression and cognitive decline. Impairment in rapid alternating hand movements is a very strong predictor of mutation carrier status in cognitively asymptomatic ADAD family members.

DESIGN AND EXECUTION OF THE NILVAD STUDY

NILVAD is an investigator driven phase III clinical trial of nilvadipine in mild to moderate Alzheimer's disease. Nilvadipine, a dihyropyridine calcium channel blocker, is a licensed antihypertensive and is being repurposed for AD based on clinical and basic science evidence for its potential as a disease-modifying agent in AD. 511 subjects with mild to moderate AD were recruited across 23 sites in 9 different European countries. Subjects received 8 mg over encapsulated nilvadipine or matching placebo over a period of 18 months. The sponsor of the trial was St. James's Hospital, Dublin. Academic trial units were used to monitor the trial in each country. The primary outcome measures were Alzheimer's disease Assessment Scale Cognitive (ADAS-Cog) and Clinical Dementia Rating Scale sum of boxes (CDR-sb). There were a number of challenges to overcome in successfully completing this trial including: recruitment and exclusion of patients on multiple antihypertensive agents, in particular other calcium channel blockers and beta blockers; IMP manufacture: sourcing and over capsulation of study drug and matching placebo and independently establishing blindedness and stability testing of the over encapsulated repurposed agent; safety monitoring and pharmacovigilance. NILVAD is an example of an investigator driven repurposing program for an antihypertensive in AD. The NILVAD trial provides multiple learnings that can be captured and help inform future efforts in this challenging area of drug discovery.

THE ASSOCIATION BETWEEN NEUROPSYCHIATRIC SYMPTOMS, APOE ε4 AND PROGRESSION OF ALZHEIMER'S DISEASE

The progression of Alzheimer disease is very difficult to predict. Whether neuropsychiatric symptoms, APOE ε4 may play a role is still unknown. From 2012 to 2015, we prospectively followed 492 patients with probable AD from the memory clinic of Taipei Veterans General Hospital for median of 3 years. All patients underwent standard assessments, including brain magnetic resonance imaging or computed tomography, neuropsychological tests, neuropsychiatry inventory (NPI-Q) and related blood tests. A logistic regression analysis was performed to investigate the relationship between change of clinical dementia rating scale-sum of boxes (CDR-SOB) and age, gender, education, APOE ε4 allele and various neuropsychiatric symptoms. Of all the participants, 306 (62.1%) completed the initial examinations and 2 times of follow-up. Among 306 patients, 222 (73%) showed CDR-SOB decline. We observed initial neuropsychiatric symptom of agitation (OR = 1.24; 95% CI = 1.03–1.419, p = 0.021) and APOE ε4 (OR = 1.83; 95% CI = 1.10–3.04, p = 0.019) both related to CDR-SOB decline. Baseline agitation and APOE ε4 significantly associated with clinical progression of Alzheimer disease.

THE COALITION AGAINST MAJOR DISEASES: TOWARD U.S. FDA QUALIFICATION OF HIPPOCAMPAL VOLUME AS A BIOMARKER FOR ENRICHMENT IN CLINICAL TRIALS FOR PRE-DEMENTIA STAGES OF ALZHEIMER'S DISEASE

The development of therapeutic agents for pre-dementia stages of Alzheimer's disease (AD) poses the challenge of selecting homogeneous cohorts of individuals for clinical trials. Trial enrichment via prognostic biomarkers provides one means of doing so. In pre-dementia patients, hippocampal atrophy is associated with progression to dementia. CAMD is pursuing regulatory qualification of baseline intracranial volume-adjusted hippocampal volume (ICV-HV) as an enrichment biomarker in pre-dementia trials, supported by a model-based analysis, through the development of a quantitative description of disease progression. To assess the utility of ICV-HV as a prognostic biomarker for clinical trial enrichment, patient-level data from three sources – the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2 observational studies, and the Investigation Into Delay to Diagnosis of Alzheimer's Disease With Exelon (InDDEx) clinical trial – have been standardized to the Clinical Data Interchange Standards Consortium (CDISC) therapeutic-area standards for AD. Briefing documents and face-to-face meetings have been held with the US FDA to finalize the proposed Context of Use Statement for the biomarker, as well as the intended statistical analysis plan. The analysis dataset, consisting of pre-dementia patient-level data from ADNI-1 (n≈305), late pre-dementia from ADNI-2 (n≈122) and InDDEx (n≈394), has been standardized and curated. Imaging data have been re-processed, and ICV-HV was determined by two image analysis algorithms, namely LEAP™ and FreeSurfer™. As per guidance from FDA, temporal changes in Clinical Dementia Rating Scale Sum-of-Boxes (CDR-SB) will be described by a non-linear mixed-effects model. Along with ICV-HV, sex, baseline age and disease severity, and apolipoprotein E genotype will be included as covariates. Clinical trial simulations using the Monte Carlo technique will be performed to compare the statistical power by sample size in trials with and trials without ICV-HV enrichment. The full qualification document will be submitted to the FDA by 3Q 2017. This ongoing biomarker qualification effort with the FDA highlights the importance of understanding disease progression quantitatively to support the qualification of ICV-HV for prognostic purposes. If ICV-HV demonstrates utility in clinical trial enrichment, qualification of this biomarker can streamline drug development programs in AD by insuring the right patients are enrolled into our trials.

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.

Macular Ganglion Cell -Inner Plexiform Layer Thickness Is Associated with Clinical Progression in Mild Cognitive Impairment and Alzheimers Disease.

PurposeWe investigated the association of the macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thicknesses with disease progression in mild cognitive impairment (MCI) and Alzheimer’s disease (AD).MethodsWe recruited 42 patients with AD, 26 with MCI, and 66 normal elderly controls. The thicknesses of the RNFL and GCIPL were measured via spectral-domain optic coherent tomography in all participants at baseline. The patients with MCI or AD underwent clinical and neuropsychological tests at baseline and once every year thereafter for 2 years.ResultsThe Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score exhibited significant negative relationships with the average GCIPL thickness (β = -0.15, p < 0.05) and the GCIPL thickness in the superotemporal, superonasal, and inferonasal sectors. The composite memory score exhibited significant positive associations with the average GCIPL thickness and the GCIPL thickness in the superotemporal, inferonasal, and inferotemporal sectors. The temporal RNFL thickness, the average and minimum GCIPL thicknesses, and the GCIPL thickness in the inferonasal, inferior, and inferotemporal sectors at baseline were significantly reduced in MCI patients who were converted to AD compared to stable MCI patients. The change of CDR-SB from baseline to 2 years exhibited significant negative associations with the average (β = -0.150, p = 0.006) and minimum GCIPL thicknesses as well as GCIPL thickness in the superotemporal, superior, superonasal, and inferonasal sectors at baseline.ConclusionsOur data suggest that macular GCIPL thickness represents a promising biomarker for monitoring the progression of MCI and AD.

Alzheimer's Symptomatic Drug Set to Test as Donepezil Combo

BARCELONA — RVT-101, a novel small molecule that increases acetylcholine release, is poised for what its developers say could be its pivotal trial for U.S. approval. The MINDSET study will examine the effect of the 5-HT6 receptor antagonist RVT-101, which will be given in conjunction with donepezil. As an acetylcholine booster, RVT-101 would not be a disease-modifying therapy. And like other symptomatic drugs, it would not alter the trajectory of Alzheimer's disease. Launched last month, MINDSET will be conducted in North America, South America, Europe, and Asia. The study investigators want to enroll least 1,000 patients with mild to moderate Alzheimer's disease who are on stable doses of donepezil, Lawrence Friedhoff, MD, PhD, said at the Clinical Trials on Alzheimer's Disease conference. Axovant Sciences' RVT-101, formerly developed as SB742457 by GlaxoSmithKline, has been investigated in 13 studies of both monotherapy and adjunctive therapy in more than 2,000 patients with Alzheimer's, said Dr. Friedhoff, chief development officer at Axovant Sciences. As monotherapy, it was ineffective, conferring no significant benefits on either cognition or function. The earlier study upon which MINDSET is modeled was a modestly successful phase IIb dose-ranging trial that comprised 684 patients. At 48 weeks, the combination of 35 mg SB742457 (RVT-101) and donepezil conferred about a 2-point benefit on the Alzheimer's Disease Assessment Scale–Cognitive (ADAS-cog) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) over donepezil alone. Neither the 35-mg dose nor the 15-mg dose, which was also tested, conferred any benefit on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) test. “Regulators have told us that if our results are similar, then this study will be suitable for submission for approval,” Dr. Friedhoff said. “We have a reasonably high level of confidence that it will also be effective in this trial.” The 24-week MINDSET will randomize patients to their donepezil dosage plus either placebo or 35 mg RVT-101 daily. Coprimary endpoints are the ADAS-cog and the ADCS-ADL. The CDR-SB is not an endpoint in MINDSET, which Dr. Friedhoff noted was designed to maximize the chance of success. A 12-month open-label extension study focusing on long-term safety will follow the randomized trial. GSK ceased development of RVT-101 in 2010 without public explanation. However, a recent review of several of the GSK studies suggests that it simply didn't meet the studies' success criteria. Axovant was formed in 2014 to give RVT-101 a new shot as an add-on treatment. The combination makes sense, Dr. Friedhoff said. “It increases acetylcholine in the brain. We already know this is an effective way to treat Alzheimer's because our acetylcholinesterase inhibitors achieve this in a different way, by inhibiting the breakdown of acetylcholine,” Dr. Friedhoff explained. “It makes sense that they should work well together. It doesn't help much to increase the release if it's broken down quickly.” RVT-101 has an attractive safety profile, Dr. Friedhoff said. It had a low rate of gastrointestinal side effects (nausea, 2%; diarrhea, 5%) and was associated with very few falls in prior studies (about 3%). That relatively benign side effect profile is probably reflected in the study's large completer rate, Dr. Friedhoff said. The placebo and 35-mg dose had virtually identical completer rates of 88% and 89%, respectively. The dropout rates were low and similar in both groups. Axovant also aims to investigate RVT-101 in patients with Lewy body dementia, he added. The company expects to launch a phase IIb clinical study early next year. Dr. Friedhoff is an employee of Axovant Sciences. Michele G. Sullivan is with the Mid-Atlantic bureau of Frontline Medical News.

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.

Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer's disease clinical trials.

IntroductionMost Alzheimer’s disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region.MethodsWe used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan.ResultsNorth America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan.ConclusionsThese findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.

Non-Steroidal Anti-Inflammatory Drugs as a Treatment for Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Treatment Effect

Alzheimer's disease (AD) is the cause of more than two-thirds of all dementia cases. Although there is no effective treatment against this disorder, its association with neuroinflammation suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might represent a potential therapeutic option. The objective of this study was to evaluate the efficacy of NSAIDs in the treatment of AD using a meta-analysis approach. MEDLINE, Web of Science, Science Direct, and the Cochrane Library were used to search all the randomized controlled trials that have evaluated the efficacy of NSAIDs as a treatment for AD (up to 1 October 2014). The overall effect of NSAIDs versus placebo was determined using a random effects model meta-analysis where we compared changes (i.e., mean differences pre- vs. post-treatment) between the two conditions in test scores indicative of cognition, disease severity, and related outcomes. Seven studies were finally included in the meta-analysis. Diclofenac/misoprostol, nimesulide, naproxen, rofecoxib, ibuprofen, indomethacin, tarenflurbil, and celecoxib were the NSAIDs used in these reports. The results of the AD Assessment Scale-cognitive subscale (ADAS-cog), the Clinical Dementia Rating Scale sum-of-boxes (CDR-SOB), and the Mini-Mental State Examination (MMSE) showed no statistical or clinical significance of NSAIDs treatment compared with placebo, i.e., mean differences of -0.24 (95% Confidence Interval (CI) -1.04 to 0.57; P = 0.52), -0.07 (95% CI -0.7 to 0.56; P = 0.82), and 0.35 (95% CI -0.34 to 1.04; P = 0.32), respectively. Current preliminary evidence suggests no beneficial effect of NSAIDs on cognition or overall AD severity. Thus, although more research is needed in the field, the evidence available does not support the use of NSAIDs for AD treatment.

The Progression of Alzheimer's Disease Can Be Assessed with a Short Version of the CERAD Neuropsychological Battery: The Kuopio ALSOVA Study

Background/Aims: Measuring and predicting Alzheimer's disease (AD) progression is important in order to adjust treatment and allocate care resources. We aimed to identify a combination of subtests from the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) that best correlated with AD progression in follow-up as well as to predict AD progression. Method: A total of 236 participants with very mild [Clinical Dementia Rating (CDR) = 0.5] or mild AD (CDR = 1.0) at baseline were followed up for 3 years. The CERAD-NB and Mini-Mental State Examination (MMSE) were used to assess cognition, and the CDR scale sum of boxes (CDR-sb) was employed to evaluate AD progression. Generalized estimating equations were used to develop models to predict and follow up disease progression. Results: Performance declined on all CERAD-NB subtests. The ability of the separate subtests to distinguish between groups (baseline CDR = 0.5 or 1.0) diminished during follow-up. The best combination of subtests that explained 62% of CDR-sb variance in follow-up included verbal fluency, constructional praxis, the clock drawing test, and the MMSE. Baseline values of the same combination predicted 37% of the CDR-sb change. Conclusion: A short version of the CERAD-NB subtests provides a promising and time-efficient alternative for measuring cognitive deterioration during AD follow-up. Although the initial signs of AD include memory difficulties, it may be useful to assess non-memory tasks in follow-up.

NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease

IntroductionThis study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a...

Striatal and extrastriatal dopamine transporter levels relate to cognition in Lewy body diseases: an (11)C altropane positron emission tomography study.

IntroductionThe biological basis of cognitive impairment in parkinsonian diseases is believed to be multifactorial. We investigated the contribution of dopamine deficiency to cognition in Parkinson disease (PD) and dementia with Lewy bodies (DLB) with dopamine transporter (DAT) imaging.MethodsWe acquired 11C altropane PET, magnetic resonance imaging and cognitive testing in 19 nondemented subjects with PD, 10 DLB and 17 healthy control subjects (HCS). We analyzed DAT concentration in putamen, caudate, anterior cingulate (AC), orbitofrontal and prefrontal regions, using the Standardized Uptake Volume Ratio with partial volume correction, and we related DAT concentration and global cortical thickness to neuropsychological performance.ResultsDAT concentration in putamen and in caudate were similar in PD and DLB groups and significantly lower than in HCS. Reduced caudate DAT concentration was associated with worse Clinical Dementia Rating Scale–sum of boxes (CDR-SB) scores and visuospatial skills in DLB but not in PD or HCS groups. Adjusting for putamen DAT concentration, as a measure of severity of motor disease, caudate DAT concentration was lower in DLB than in PD. Higher AC DAT concentration was associated with lower putamen DAT concentration in DLB and with higher putamen DAT concentration in PD. Higher AC DAT concentration in DLB correlated with greater impairment in semantic memory and language.ConclusionsCaudate and AC dopamine dysfunction contribute in opposing directions to cognitive impairment in DLB.

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.

Telephone Screening for Mild Cognitive Impairment in Hispanics Using the Alzheimer’s Questionnaire

Background/Study Context: There is a need for a simple and reliable screening test to detect individuals with mild cognitive impairment (MCI). The authors analyzed the relationship between performance of the Alzheimer’s Questionnaire (AQ), an informant-rated measure of dementia-related behaviors, relative to the Telephone Interview for Cognitive Status—modified (TICS-m), Memory Impairment Scale—telephone version (MIS-t), and the Telephone Executive Assessment (TEXAS) as predictors of MCI.Methods: Comparative cross-sectional design, with data collected from participants in the Texas Alzheimer’s Research and Care Consortium’s (TARCC) San Antonio site. One-hundred percent of our sample was Hispanic. The San Antonio subset of TARCC sample is highly enriched with Mexican Americans (MAs). Fifty-five percent of the interviews were conducted in Spanish. Of the 184 persons enrolled, 124 were normal controls (NCs), and 60 participants had MCI. MCI status and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) were determined through clinical consensus and performed blind to telephone assessments. Controlling for age, gender, education, and language of interview, the association between telephone measures and CDR-SOB was evaluated by multivariate regression.Results: AQ scores were not affected by education, gender, and language of interview, but subject’s age did show a positive correlation with informant AQ ratings. The AQ predicted CDR-SOB independently of the cognitive measures, adding variance above and beyond demographics. The TICS-m and the TEXAS appear to have additive value in improving the detection of cognitively impaired patients. The MIS-t failed to contribute significantly to CDR-SOB, independent of the other measures.Conclusion: The AQ may have utility as a culture-fair telephone screening for MCI. The AQ was able to modestly distinguish MCI from NCs. The TEXAS adds variance to a model of dementia severity independent of the AQ, suggesting that the latter may weakly assess that cognitive domain (executive control function). On the other hand, the AQ attenuates the MIS-t effect. This suggests a prominent AQ bias in favor of detecting memory impairment. Additional studies are required to determine if the AQ can distinguish between amnestic and dysexecutive MCI subtypes, or between MCI and Alzheimer’s disease in Hispanics.

Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration

Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders, including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD. CSF NfL, amyloid-β1-42 (Aβ42), tau, and phosphorylated tau concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene carriers (NC2) of FTD-causing mutations, and 79 FTD (45 behavioral variant frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16 semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer disease, 6 Parkinson disease, and 17 corticobasal syndrome patients. Correlations between CSF analyte levels were performed with neuropsychological measures and the Clinical Dementia Rating scale sum of boxes (CDRsb). Voxel-based morphometry of structural magnetic resonance images determined the relationship between brain volume and CSF NfL. Mean CSF NfL concentrations were higher in bvFTD, SD, and PNFA than other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures, correlated with CDRsb and neuropsychological measures in FTD, but not in other diagnostic groups. Analyses in 2 independent FTD cohorts and a group of autopsy-verified or biomarker-enriched cases confirmed the larger group analysis. In FTD, gray and white matter volume negatively correlated with CSF NfL concentration, such that individuals with the highest NfL levels exhibited the most atrophy. CSF NfL is elevated in symptomatic FTD and correlates with disease severity. This measurement may be a useful surrogate endpoint of disease severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are warranted.

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.

Whole Brain Atrophy and Sample Size Estimate via Iterative Principal Component Analysis for Twelve-month Alzheimer's Disease Trials

In this study, we used Iterative Principal Components Analysis (IPCA) to characterize twelve-month wholebrain atrophy rates in 125 Alzheimer’s disease (AD) patients, 288 subjects with amnestic mild cognitive impairment (MCI), and 167 elderly healthy controls (HCs). We compared IPCA to the widely used Brain Boundary Shift Integral (BBSI) and clinical measures of change from the same subjects. Both IPCA and BBSI techniques correlated with changes in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Mini Mental State Exam (MMSE). Both IPCA and BBSI–based whole brain atrophy differed among AD, MCI and NC groups and had comparable statistical power. For AD, we estimate the need for 70 patients per group using IPCA and 80 using BBSI to detect a 25% atrophy-slowing effect over twelve months with p=0.05 and 80% power, compared to 514, 636 and 843 using CDR-SB, ADAS-Cog and MMSE. For MCI, we estimate the need for 128 patients per group using IPCA and 136 using BBSI compared to 798, 5392 and 3531 using CDR-SB, ADAS-Cog and MMSE. As an alternative for characterizing whole brain atrophy, the fully automatic IPCA procedure offers sample size precision comparable to that of BBSI. Keywords: Alzheimer's disease, iterative principal component analysis (IPCA), sample size, statistical power, structural MRI, whole brain atrophy.