A Remotely Coached Multimodal Lifestyle Intervention for Alzheimer's Disease Ameliorates Functional and Cognitive Outcomes.

BACKGROUND: Comprehensive treatment of Alzheimer's disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. Personalized, multimodal therapies are needed to best prevent and treat Alzheimer's disease (AD). OBJECTIVE: The Coaching for Cognition in Alzheimer's (COCOA) trial was a prospective randomized controlled trial to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage AD. METHODS: Participants with early-stage AD were randomized into two arms. Arm 1 (N = 24) received standard of care. Arm 2 (N = 31) additionally received telephonic personalized coaching for multiple lifestyle interventions. The primary outcome was a test of the hypothesis that the Memory Performance Index (MPI) change over time would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test was assessed for a secondary outcome. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints (dynamic dense data) across two years for each participant. RESULTS: The intervention arm ameliorated 2.1 [1.0] MPI points (mean [SD], p = 0.016) compared to the control over the two-year intervention. No important adverse events or side effects were observed. CONCLUSION: Multimodal lifestyle interventions are effective for ameliorating cognitive decline and have a larger effect size than pharmacological interventions. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.

The Coaching for Cognition in Alzheimer's (COCOA) trial: Study design.

Comprehensive treatment of Alzheimer's disease (AD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. We present the design and methodology for the Coaching for Cognition in Alzheimer's (COCOA) trial. AD and other dementias result from the interplay of multiple interacting dysfunctional biological systems. Monotherapies have had limited success. More interventional studies are needed to test the effectiveness of multimodal multi-domain therapies for dementia prevention and treatment. Multimodal therapies use multiple interventions to address multiple systemic causes and potentiators of cognitive decline and functional loss; they can be personalized, as different sets of etiologies and systems responsive to therapy may be present in different individuals. COCOA is designed to test the hypothesis that coached multimodal interventions beneficially alter the trajectory of cognitive decline for individuals on the spectrum of AD and related dementias (ADRD). COCOA is a two-arm prospective randomized controlled trial (RCT). COCOA collects psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints across 2 years for each participant. These data enable systems biology analyses. One arm receives standard of care and generic healthy aging recommendations. The other arm receives standard of care and personalized data-driven remote coaching. The primary outcome measure is the Memory Performance Index (MPI), a measure of cognition. The MPI is a summary statistic of the MCI Screen (MCIS). Secondary outcome measures include the Functional Assessment Staging Test (FAST), a measure of function. COCOA began enrollment in January 2018. We hypothesize that multimodal interventions will ameliorate cognitive decline and that data-driven health coaching will increase compliance, assist in personalizing multimodal interventions, and improve outcomes for patients, particularly for those in the early stages of the AD spectrum. Highlights: The Coaching for Cognition in Alzheimer's (COCOA) trial tests personalized multimodal lifestyle interventions for Alzheimer's disease and related dementias.Dense longitudinal molecular data will be useful for future studies.Increased use of Hill's criteria in analyses may advance knowledge generation.Remote coaching may be an effective intervention.Because lifestyle interventions are inexpensive, they may be particularly valuable in reducing global socioeconomic disparities in dementia care.

Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F 18.

Alzheimer disease (AD) is characterized by ß-amyloid (Aß) plaques and tau neurofibrillary tangles. There are several PET imaging biomarkers for Aß including 11C-PiB and 18F-florbetapir. Recently, PET tracers for tau neurofibrillary tangles have become available and have shown utility in detection and monitoring of neurofibrillary pathology over time. Flortaucipir F 18 is one such tracer. Initial clinical studies indicated greater tau binding in AD and mild cognitive impairment patients than in controls in a pattern consistent with tau pathology observed at autopsy. However, little is known about the reproducibility of such findings. To our knowledge, this study reports the first data regarding test-retest reproducibility of flortaucipir F 18 PET. Methods: Twenty-one subjects who completed the study (5 healthy controls, 6 mild cognitive impairment, and 10 AD) received 370 MBq of flortaucipir F 18 and were imaged for 20 min beginning 80 min after injection and again at 110 min after injection. Follow-up (retest) imaging occurred between 48 h and 4 wk after initial imaging. Images were spatially normalized to Montreal Neurological Institute template space. SUVRs were calculated using AAL (Automated Anatomical Labeling atlas) volumes of interest (VOIs) for parietal, temporal, occipital, anterior, and posterior hippocampal, parahippocampal, and fusiform regions, as well as a posterior neocortical VOI composed of average values from parietal, temporal, and occipital areas. Further, a VOI derived by discriminant analysis that maximally separated diagnostic groups (multiblock barycentric discriminant analysis [MUBADA]) was used. All VOIs were referenced to a subsection of cerebellar gray matter (cere-crus) as well as a parametrically derived white matter-based reference region (parametric estimate of reference signal intensity [PERSI]). t test, correlation analyses, and intraclass correlation coefficient were used to explore test-retest performance. Results: Test-retest analyses demonstrated low variability in flortaucipir F 18 SUVR. The SD of mean percentage change between test and retest using the PERSI reference region was 2.22% for a large posterior neocortical VOI, 1.84% for MUBADA, 1.46% for frontal, 1.98% for temporal, 2.28% for parietal, and 3.27% for occipital VOIs. Further, significant correlations (R2 > 0.85; P < 0.001) were observed for all regions, and intraclass correlation coefficient values (test-retest consistency) were greater than 0.92 for all regions. Conclusion: Significant test-retest reproducibility for flortaucipir F 18 was found across neocortical and mesial temporal lobe structures. These preliminary data suggest that flortaucipir F 18 tau imaging could be used to examine changes in tau burden over time.

CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer's Disease and Cerebrovascular Disease.

We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [µ ±  σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [µ ±  σ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [µ ±  σ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.

Kinetics of the Tau PET Tracer 18F-AV-1451 (T807) in Subjects with Normal Cognitive Function, Mild Cognitive Impairment, and Alzheimer Disease.

We report kinetic modeling results of dynamic acquisition data from 0 to 100 min after injection with the tau PET tracer 18F-AV-1451 in 19 subjects. METHODS: Subjects were clinically diagnosed as 4 young cognitively normal, 5 old cognitively normal, 5 mild cognitive impairment, and 5 Alzheimer disease (AD). Kinetic modeling was performed using Logan graphical analysis with the cerebellum crus as a reference region. Voxelwise binding potential ([Formula: see text]) and SUV ratio ([Formula: see text]) images were compared. RESULTS: In AD subjects, slower and spatially nonuniform clearance from cortical regions was observed as compared with the controls, which led to focal uptake and elevated retention in the imaging data from 80 to 100 min after injection. BP from the dynamic data from 0 to 100 min correlated strongly (R2 > 0.86) with corresponding regional [Formula: see text] values. In the putamen, the observed kinetics (positive [Formula: see text] at the tracer delivery stage and plateauing time-SUVR curves for all diagnostic categories) may suggest either additional off-target binding or a second binding site with different kinetics. CONCLUSION: The kinetics of the 18F-AV-1451 tracer in cortical areas, as examined in this small group of subjects, differed by diagnostic stage. A delayed 80- to 100-min scan provided a reasonable substitute for a dynamic 0- to 100-min acquisition for cortical regions although other windows (e.g., 75-105 min) may be useful to evaluate.

New methods, measures, and models for analyzing memory impairment using triadic comparisons.

We study the effect of memory impairment on triadic comparisons of animal names in a large clinical data set. We define eight groups of subjects in terms of their delayed free recall performance, and present standard analyses of the triadic comparison and free recall data that provide little insight into the effect of memory impairment on semantic structure. We then develop and apply two new methods for analyzing the data, based on cognitive models and using Bayesian statistical inference. The first new method focuses on modeling changes in semantic representation, by inferring multidimensional scaling (MDS) representations for each group based on their triadic comparisons. These representations reveal a successive decrease in semantic cluster structure and increase in uncertainty with increasing impairment. We propose a measure of spatial organization as a means of quantifying the visually evident changes in semantic organization, and demonstrate its usefulness. The second new method focuses on modeling changes in memory access with impairment, inferring the extent to which each individual makes triadic comparisons consistent with a common semantic representation. Although these inferences are based on just 12 comparisons per subject, we show that they vary systematically with memory impairment group. We conclude by discussing the potential for clinical application of our new models, measures, and methods.

Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808.

Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have recently reported early clinical results of a novel PHF-tau targeting PET imaging agent, [F18]-T807. Since then, we have investigated a second novel PHF-tau targeting PET imaging agent, [F18]-T808, with different pharmacokinetic characteristics, which may be favorable for imaging Alzheimer's disease and other tauopathies. Here, we describe the first human brain images with [F18]-T808.

Capillary electrophoresis-mass spectrometry-based metabolome analysis of serum and saliva from neurodegenerative dementia patients.

Despite increasing global prevalence, the precise pathogenesis and terms for objective diagnosis of neurodegenerative dementias remain controversial, and comprehensive understanding of the disease remains lacking. Here, we conducted metabolomic analysis of serum and saliva obtained from patients with neurodegenerative dementias (n = 10), including Alzheimer's disease, frontotemporal lobe dementia, and Lewy body disease, as well as from age-matched healthy controls (n = 9). Using CE-TOF-MS, six metabolites in serum (ß-alanine, creatinine, hydroxyproline, glutamine, iso-citrate, and cytidine) and two in saliva (arginine and tyrosine) were significantly different between dementias and controls. Using multivariate analysis, serum was confirmed as a more efficient biological fluid for diagnosis compared to saliva; additionally, 45 metabolites in total were identified as candidate markers that could discriminate at least one pair of diagnostic groups from the healthy control group. These metabolites possibly provide an objective method for diagnosing dementia-type by multiphase screening. Moreover, diagnostic-type-dependent differences were observed in several tricarboxylic acid cycle compounds detected in serum, indicating that some pathways in glucose metabolism may be altered in dementia patients. This pilot study revealed novel alterations in metabolomic profiles between various neurodegenerative dementias, which would contribute to etiological investigations.

Relating memory to functional performance in normal aging to dementia using hierarchical Bayesian cognitive processing models.

Determining how cognition affects functional abilities is important in Alzheimer disease and related disorders. A total of 280 patients (normal or Alzheimer disease and related disorders) received a total of 1514 assessments using the functional assessment staging test (FAST) procedure and the MCI Screen. A hierarchical Bayesian cognitive processing model was created by embedding a signal detection theory model of the MCI Screen-delayed recognition memory task into a hierarchical Bayesian framework. The signal detection theory model used latent parameters of discriminability (memory process) and response bias (executive function) to predict, simultaneously, recognition memory performance for each patient and each FAST severity group. The observed recognition memory data did not distinguish the 6 FAST severity stages, but the latent parameters completely separated them. The latent parameters were also used successfully to transform the ordinal FAST measure into a continuous measure reflecting the underlying continuum of functional severity. Hierarchical Bayesian cognitive processing models applied to recognition memory data from clinical practice settings accurately translated a latent measure of cognition into a continuous measure of functional severity for both individuals and FAST groups. Such a translation links 2 levels of brain information processing and may enable more accurate correlations with other levels, such as those characterized by biomarkers.

Hierarchical Bayesian cognitive processing models to analyze clinical trial data.

Identifying disease-modifying treatment effects in earlier stages of Alzheimer's disease (AD)-when changes are subtle-will require improved trial design and more sensitive analytical methods. We applied hierarchical Bayesian analysis with cognitive processing (HBCP) models to the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and MCI (mild cognitive impairment) Screen word list memory task data from 14 Alzheimer's disease AD patients of the Myriad Pharmaceuticals' phase III clinical trial of Flurizan (a γ-secretase modulator) versus placebo. The original analysis of 1649 patients found no treatment group differences. HBCP analysis and the original ADAS-Cog analysis were performed on the small sample. HBCP analysis detected impaired memory storage during delayed recall, whereas the original ADAS-Cog analytical method did not. The HBCP model identified a harmful treatment effect in a small sample, which has been independently confirmed from the results of other γ-secretase inhibitor. The original analytical method applied to the ADAS-Cog data did not detect this harmful treatment effect on either the full or the small sample. These findings suggest that HBCP models can detect treatment effects more sensitively than currently used analytical methods required by the Food and Drug Administration, and they do so using small patient samples.

Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807.

Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have developed a novel PHF-tau targeting positron emission tomography imaging agent, [F-18]-T807, which may be useful for imaging Alzheimer's disease and other tauopathies. Here in, we describe the first human brain images with [F-18]-T807.

Optimizing the Hachinski Ischemic Scale.

BACKGROUND: Vascular causes and factors remain the most significant preventable component of cognitive disorders of elderly individuals. The Hachinski Ischemic Score (HIS) is the questionnaire most commonly used for diagnosis of vascular dementia. OBJECTIVE: To consolidate and further validate the HIS. DESIGN: The Canadian Study for Health and Aging was used for this study. It was a cohort study conducted in 3 waves in 1991, 1996-1997, and 2001-2002. The HIS containing 13 items was subjected to correspondence analysis to identify its optimal scaling of item scores and minimal set of items while maximizing the explainable variance. SETTING: A community-based cohort study. PATIENTS: For this analysis, we used 2968 of 3054 well-characterized and well-diagnosed cases with complete HIS data (86 cases had ≥1 item missing) from Canadian Study for Health and Aging phases 2 (1996-1997; n = 2431) and 3 (2001-2002; n = 623). RESULTS: Two optimized HIS versions were identified that classify patients with vascular dementia vs those with nonvascular dementia as well as or more accurately than the original HIS instrument. Assuming the HIS instrument measures only a single dimension, correspondence analysis identified the 7 most discriminative HIS items. Binary scoring (0, 1) of these items led to a 7-item HIS model that classified as well as the original 13-item HIS instrument. By merging highly similar HIS items and applying correspondence analysis, a 5-item composite HIS model was created that measures 2 meaningful dimensions of information and classified vascular vs nonvascular dementia better than the original HIS instrument. Each HIS version developed has specific advantages and disadvantages in terms of simplicity, scoring, generalizability, and accuracy. CONCLUSION: Depending on the specific setting, 2 reduced HIS versions consisting of 5 composite-question items or 7 single-question items classify as well as or better than the original HIS instrument.

Developing a national strategy to prevent dementia: Leon Thal Symposium 2009.

Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27-28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.

Development and validation of the Memory Performance Index: reducing measurement error in recall tests.

BACKGROUND: The Memory Performance Index (MPI) quantifies the pattern of recalled and nonrecalled words of the Consortium to Establish a Registry for Alzheimer's Disease Wordlist (CWL) onto a 0 to 100 scale and distinguishes normal from mild cognitive impairment with 96% to 97% accuracy. METHODS: In group A, 121,481 independently living individuals, 18 to 106 years old, were assessed with the CWL and classified as cognitively impaired (N = 5,971) or normal (N = 115,510). The MPI and CWL immediate free recall (IFR), delayed free recall (DFR), and total free recall (TFR) scores (the outcome measures) were each regressed against predictors of age, gender, race, education, test administration method (in-person or telephone), and wordlist used. Predictor effect sizes (Cohen's f(2)) were computed for each outcome. In addition, CWL plus Functional Assessment Staging Tests (FAST) were administered to 441 normal to moderately severely demented (FAST stages 1 to 6) patients (group B). Median MPI scores were tested for significant differences across FAST stage. RESULTS: For group A, the variance explained by all predictors combined was MPI = 55.0%, IFR = 24.9%, DFR = 23.4%, and TFR = 26.9%. The age effect size on MPI score was large, but it was small on IFR, DFR, and TFR. The other predictors all had negligible (<0.02) or small effect sizes (0.02 to 0.15). For group B, median MPI scores progressively declined across all FAST stages (P < .0002). CONCLUSIONS: MPI score progressively declines with increasing dementia severity. Also, MPI score explains 2 to 3 times more variance than total scores, which improves ability to detect treatment effects.

Omental therapy for primary progressive aphasia with tau negative histopathology: 3 year study.

OBJECTIVE: Omentum transposition surgery (OT) applied to various neurodegenerative disorders has produced clinically significant improvement, which may be due to omentally-derived factors. To evaluate the clinical effect of left hemisphere OT in a primary progressive aphasia (PPA) patient, 3 year follow-up data were analysed. METHODS: Left hemisphere OT was performed on a 68-year-old male with PPA, characterized by moderate dementia and severe expressive aphasia with relatively preserved comprehension, object recognition and visual-spatial abilities. He was longitudinally assessed with cognitive, functional, behavioral and brain HMPAO SPECT measures pre-OT, at baseline and every 3-6 months for 34 months. RESULTS: All measures improved above baseline for >20 months and persisted at or above baseline for 34 months. Cortical activity increased by a maximum of 21% underneath transposed omentum and in synaptically connected areas, and persisted in >50% of the cortex for at least 12 months. Subjectively, family members observed improved verbal and non-verbal communication. CONCLUSION: OT produced a sustained, beneficial treatment effect in PPA and warrants further clinical and basic research to identify explanatory factors.

Omentum transposition surgery for patients with Alzheimer's disease: a case series.

OBJECTIVE: To examine effect of omentum transposition surgery (OT) in Alzheimer's disease (AD). METHODS: Within-subjects design, also known as repeated-measures design, was used. OT was performed on six biopsy-confirmed AD patients (three to the left and right hemispheres each). Follow-up was conducted over 16-50 months. Outcome measures included the sum of the sub-scores of the clinical dementia rating scale (CDRSS), dementia severity rating scale (DSRS), mini-mental status exam (MMSE) and neuropsychiatric inventory (NPI), all normalized to 0-1.0. Outcomes were compared to baseline values and to expected decline with and without cholinesterase inhibitors therapy (ChEI). RESULTS: Compared to baseline and to expected decline with ChEI, CDRSS scores were 22 and 39% less impaired at means of 14 and 25 months post-OT, and DSRS scores were 12 and 22% less impaired at means of 14 and 19 months post-OT (p<0.0001). Compared to baseline and expected course with and without ChEI, the MMSE scores of the left hemisphere OT patients were not significantly different for 11, 17 and 22 months respectively (p>0.49), while those of the right hemisphere OT patients more rapidly declined. The two patients with significant pre-operative behavioral problems markedly improved; NPI severity scores decreased by 23 (16%) and 78 (54%) points and were sustained for 22 and 42 months. DISCUSSION: OT yielded cognitive, functional or behavioral improvement for up to 3.5 years in these AD patients. Compared to randomized ChEI clinical trials, OT was 34 times more likely to produce clinically significant improvement. Basic research to identify the mechanisms underlying the therapeutic effect of omentum is warranted.

Detecting cognitive impairment in primary care: performance assessment of three screening instruments.

Early detection of Alzheimer's disease and related disorders (ADRD) is important, especially in primary care settings. We compared performances of two common screening tests, the Mini-Mental State Exam (MMSE) and Clock Drawing Test (CDT), with that of the MCI Screen ({MCIS}) in 254 patients over 65. None had previous diagnosis of ADRD, and 81% were asymptomatic by Functional Assessment Staging Test ({FAST}) (FAST=1). 215 patients completed all screening tests - 141 had >or= 1 abnormal result, 121/141 completed standardized diagnostic assessment, and the remaining 74/215 (34%) screened entirely normally and weren't further evaluated. Potential bias due to unevaluated cases was statistically adjusted. Among diagnosed cases: AD=43%, cerebrovascular disease=36%, other causes=21%. Bias-adjusted MCI prevalence for FAST stages 1 and 1-3 were 13.9-20.3% and 23.0-28.3%. Bias-adjusted results for the CDT, MMSE and MCIS were: clinical diagnosis validity (kappa statistic)={-0.02 (p=0.61), 0.06 (p=0.23), 0.92 (p< 0.0001)}; sensitivity={59%, 71%, 94%}; specificity={39%, 36%, 97%}; overall accuracy={54%, 62%, 96%}; positive predictive value={16%, 17%, 86%}; and negative predictive value={83%, 87%, 96%}. The MMSE and CDT were not valid for early detection, while the MCIS had high validity and accuracy in the primary care cohort.