Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia: Design of the ADvance Randomized Controlled Trial

Background: There are currently few available treatments and no cure for Alzheimer disease (AD), a growing public health burden. Animal models and an open-label human trial have indicated that deep brain stimulation (DBS) of memory circuits may improve symptoms and possibly slow disease progression. The ADvance trial was designed to examine DBS of the fornix as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebo-controlled, delayed-start, multicenter clinical trial conducted at six sites in the US and one site in Canada. Eighty-five subjects initially consented to be screened for the trial. Of these, 42 subjects who met inclusion and exclusion criteria were implanted with DBS leads anterior to the columns of the fornix bilaterally. They were randomized 1:1 to DBS off or DBS on groups for the initial 12 months of follow-up. After 1 year, all subjects will have their devices turned on for the remainder of the study. Postimplantation, subjects will return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months), and safety monitoring. The primary outcome measures include Alzheimer\u27s Disease Assessment Scale -- cognitive component (ADAS-cog-13), Clinical Dementia Rating sum of boxes (CDR-SB), and cerebral glucose metabolism measured with positron emission tomography. This report details the study methods, baseline subject characteristics of screened and implanted participants, and screen-to-baseline test€“retest reliability of the cognitive outcomes. Results: Implanted subjects had a mean age of 68.2 years, were mostly male (55%), and had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD, 5.2) and 3.9 (SD, 1.6), respectively. There were no significant differences between screened and implanted or nonimplanted subjects on most demographic or clinical assessments. Implanted subjects had significantly lower (better) ADAS-cog-11 (17.5 vs 21.1) scores, but did not differ on CDR-SB. Scores on the major outcome measures for the trial were consistent at screening and baseline. Conclusion: ADvance was successful in enrolling a substantial group of patients for this novel application of DBS, and the study design is strengthened by rigorous subject selection from seven sites, a double-blind placebo-controlled design, and extensive open-label follow-up

Neuronal-Derived EV Biomarkers Track Cognitive Decline in Alzheimer’s Disease

The hallmarks of Alzheimer’s disease (AD) pathology are senile plaques containing amyloid-beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. Additional pathologies often co-exist, whereas multiple pathogenic mechanisms are involved in AD, especially synaptic degeneration, which necessitate the need for synaptic integrity-related biomarkers alongside Aβ- and tau-related biomarkers. Plasma neuron-derived Extracellular Vesicles EVs (NDEVs) provide biomarkers related to Aβ and tau and synaptic degeneration. Here, to further establish the latter as a “liquid biopsy” for AD, we examined their relationship with ante-mortem cognition in pathologically-confirmed AD cases. We immunoprecipitated NDEVs by targeting neuronal marker L1CAM from ante-mortem plasma samples from 61 autopsy-confirmed cases of pure AD or AD with additional pathologies and measured Aβ42, p181-Tau, total Tau, synaptophysin, synaptopodin and three canonical EV markers, CD63, CD81 and CD9. Higher NDEV Aβ42 levels were consistently associated with better cognitive status, memory, fluency, working memory and executive function. Higher levels of NDEV synaptic integrity-related biomarkers were associated with better performance on executive function tasks. Our findings motivate the hypothesis that releasing Aβ42-laden NDEVs may be an adaptive mechanism in AD

Alzheimer's disease biomarkers as predictors of trajectories of depression and apathy in cognitively normal individuals, mild cognitive impairment,and Alzheimer's disease dementia

Objectives To examine trajectories of depression and apathy over a 5-year follow-up period in (prodromal) Alzheimer's disease (AD), and to relate these trajectories to AD biomarkers. Methods The trajectories of depression and apathy (measured with the Neuropsychiatric Inventory or its questionnaire) were separately modeled using growth mixture models for two cohorts (National Alzheimer's Coordinating Center, NACC, n = 22 760 and Alzheimer's Disease Neuroimaging Initiative, ADNI, n = 1 733). The trajectories in ADNI were associated with baseline CSF AD biomarkers (A beta(42,)t-tau, and p-tau) using bias-corrected multinomial logistic regression. Results Multiple classes were identified, with the largest classes having no symptoms over time. Lower A beta(42)and higher tau (ie, more AD pathology) was associated with increased probability of depression and apathy over time, compared to classes without symptoms. Lower A beta(42)(but not tau) was associated with a steep increase of apathy, whereas higher tau (but not A beta(42)) was associated with a steep decrease of apathy. Discussion The trajectories of depression and apathy in individuals on the AD spectrum are associated with AD biomarkers

Oral glucose tolerance testing to modulate plasma amyloid levels: A novel biomarker.

IntroductionPlasma levels of amyloid-beta (Aβ) do not correlate well with different stages of Alzheimer's disease (AD) in cross-sectional studies. Measuring the changes in Aβ plasma levels with an acute intervention may be more sensitive to distinguishing individuals in earlier stages of AD (mild cognitive impairment; MCI) from normal controls.Methods57 participants (18 with AD/MCI and 39 cognitively normal controls) underwent oral glucose tolerance testing (OGTT). Blood samples were obtained over a 2 hour time period. Changes in plasma Aβ40 and42 levels were measured from either baseline or 5 minutes to the 10 minute time point.ResultsCompared to normal controls, subjects with AD/MCI had significantly less change (Δ) in plasma levels for both Aβ40(-3.13(40.93)pg/ml vs. 41.34(57.16)pg/ml;p=0.002) and Aβ42(-0.15(3.77)pg/ml vs. 5.64(10.65)pg/ml; p=0.004).DiscussionOGTT combined with measures of plasma Aβ40 and 42 is potentially useful in distinguishing aging individuals who are in different stages of AD

Oral glucose tolerance testing to modulate plasma amyloid levels: A novel biomarker.

IntroductionPlasma levels of amyloid-beta (Aβ) do not correlate well with different stages of Alzheimer's disease (AD) in cross-sectional studies. Measuring the changes in Aβ plasma levels with an acute intervention may be more sensitive to distinguishing individuals in earlier stages of AD (mild cognitive impairment; MCI) from normal controls.Methods57 participants (18 with AD/MCI and 39 cognitively normal controls) underwent oral glucose tolerance testing (OGTT). Blood samples were obtained over a 2 hour time period. Changes in plasma Aβ40 and42 levels were measured from either baseline or 5 minutes to the 10 minute time point.ResultsCompared to normal controls, subjects with AD/MCI had significantly less change (Δ) in plasma levels for both Aβ40(-3.13(40.93)pg/ml vs. 41.34(57.16)pg/ml;p=0.002) and Aβ42(-0.15(3.77)pg/ml vs. 5.64(10.65)pg/ml; p=0.004).DiscussionOGTT combined with measures of plasma Aβ40 and 42 is potentially useful in distinguishing aging individuals who are in different stages of AD

Comorbidity and progression of late onset Alzheimer's disease: A systematic review

Alzheimer's disease is a neurodegenerative syndrome characterized by multiple dimensions including cognitive decline, decreased daily functioning and psychiatric symptoms. This systematic review aims to investigate the relation between somatic comorbidity burden and progression in late-onset Alzheimer's disease (LOAD).We searched four databases for observational studies that examined cross-sectional or longitudinal associations of cognitive or functional or neuropsychiatric outcomes with comorbidity in individuals with LOAD. From the 7966 articles identified originally, 11 studies were included in this review. The Newcastle-Ottawa quality assessment was used. The large variation in progression measures, comorbidity indexes and study designs hampered the ability to perform a meta-analysis. This review was registered with PROSPERO under DIO: 10.15124/CRD42015027046.Nine studies indicated that comorbidity burden was associated with deterioration in at least one of the three dimensions of LOAD examined. Seven out of ten studies investigating cognition found comorbidities to be related to decreased cognitive performance. Five out of the seven studies investigating daily functioning showed an association between comorbidity burden and decreased daily functioning. Neuropsychiatric symptoms (NPS) increased with increasing comorbidity burden in two out of three studies investigating NPS. Associations were predominantly found in studies analyzing the association cross-sectionally, in a time-varying manner or across short follow-up (≤2 years). Rarely baseline comorbidity burden appeared to be associated with outcomes in studies analyzing progression over longer follow-up periods (>2 years).This review provides evidence of an association between somatic comorbidities and multifaceted LOAD progression. Given that time-varying comorbidity burden, but much less so baseline comorbidity burden, was associated with the three dimensions prospectively, this relationship cannot be reduced to a simple cause-effect relation and is more likely to be dynamic. Therefore, both future studies and clinical practice may benefit from regarding comorbidity as a modifiable factor with a possibly fluctuating influence on LOAD