MMSE Change Research Articles

Effects of hippocampal atrophy and white matter lesions on cognitive function in Alzheimer’s disease

AbstractBackgroundWe investigated the effects of white matter lesions and hippocampal atrophy on head MRI on cognitive function in AD patients.MethodWe examined 47 patients who were diagnosed with Alzheimer’s disease according to the ATN classification at the geriatric department of Tokyo Medical University Hospital. We evaluated the severity of white matter damage by the sum of PVH and DWMH in the Fazekas classification on head MRI at the first visit, and hippocampal atrophy by VSRAD.ResultThere was a significant correlation between white matter impairment and cognitive changes (r = 0.292, p<0.05). And the correlation test for hippocampus atrophy and MMSE change was also performed with correlation coefficients r = 0.00926 and p = 0.951 (>0.05).ConclusionThe sum of PVH and DWMH and the amount of change in MMSE were positively correlated in AD patients. Therefore, it was concluded that the more severe the white matter disorder, the slower the progression of cognitive decline. These results suggest that advanced white matter disorders may inhibit the progression of AD in AD patients.

Reduction of Hippocampal Atrophy and Lateral Ventricle Enlargement Correlates with Clinical Benefit in APOE4 Carriers with Early AD: 1‐Year Results from a Phase 2 Biomarker Study with Oral Anti‐Amyloid Oligomer Inhibitor ALZ‐801

AbstractBackgroundALZ‐801 is an oral inhibitor of amyloid oligomer formation in development as a disease‐modifying Alzheimer’s treatment, including a Phase 3 trial in APOE4/4 homozygotes and a Phase 2 biomarker study in APOE4 carriers. We analyzed correlations between brain volume and cognitive effects of ALZ‐801 after 1 year in the Phase 2 study. We previously reported that at 1‐year timepoint, plasma p‐tau181 (primary outcome) was significantly reduced by 41% from baseline, and hippocampal volume (HV) showed ∼20% less atrophy compared to external matched controls.MethodThe study is conducted at 7 European sites and enrolled 84 APOE4 carriers (MMSE 22‐30) with positive amyloid/tau biomarkers who receive ALZ‐801 265 mg BID for 104 weeks. Primary outcome is plasma p‐tau181 at 104 weeks, and primary imaging outcome is hippocampal volume (HV) atrophy. Volumetric vMRI measures (baseline, 52 and 104 weeks) are performed by Clario, and MMSE conducted. A PK sub‐study was conducted at 65 weeks (n = 23) with bioanalysis at DDS (UK) and non‐compartmental PK analyzed by WinNonlin. Pearson correlations of MMSE changes to BSI changes of HV and lateral ventricle volume (LVV) were conducted, with two‐sided p‐values reported.ResultAt 52 and 65 weeks, changes of MMSE from baseline showed significant correlations to HV (r = 0.32 and 0.34; p<0.01, n = 66) and LVV changes (r = ‐0.42 and ‐0.44; p<0.001, n = 65). Correlations between DMMSE and DLVV were significant for both genders (range r = ‐0.54 to ‐0.42, p<0.02); correlations were observed for DHV in females (range r = 0.39‐0.47; p<0.05) and males (range r = 0.26‐0.23; p<0.18, ns). PK/PD analysis in 23 subjects showed trends (r = 0.21‐0.16, ns) between decreased HV atrophy/LVV expansion and plasma AUC24h of tramiprosate+3‐SPA (active and primary metabolite). ALZ‐801 exhibited favorable safety; main treatment‐related adverse event was mild nausea. No ARIA‐E was observed.ConclusionEarly AD subjects treated with ALZ‐801 for 65 weeks in the Phase 2 biomarker study showed strong correlations between MMSE stability, HV reduction, and decreased ventricular enlargement in overall group, and by genders. The significant correlations between cognitive and brain volume effects support the clinical benefits of ALZ‐801 in APOE4 carriers with early AD. Oral ALZ‐801 showed favorable safety and no brain edema/ARIA‐E.

Results of a low cost dance intervention for cognitive reablement in dementia

AbstractBackground, dance therapy may offer a solution to reduce morbidity, restore aspects of cognitive ability (even if only temporarily), and potentially reduce the total cost of care to individuals and the health care system. But more reliable data on the effectiveness of dance therapy within the dementia community is neededMethodFour female participants with severe major neurocognitive disorders and loss of Activities of Daily Living (ADL) function were included. Participants were selected by the facility’s life enrichment director based on their likelihood to consistently participate in the dance intervention. Loss of ADL function was confirmed by chart review in the facility’s electronic medical record monthly functional tracking summaries. The dance intervention was done for 30 minutes three days a week for four weeks. Though not by design, Participant 4 chose not to dance and served as a tacit “control” in our review. Popular music from the 1950s, country music, and/or Christmas music was played for the duration of each dance session. The participants were evaluated by an MMSE at the beginning of the month before starting the intervention and immediately following after the final dance session.ResultAverage Change in MMSE: 3.375 points. Participant 4 decreased in MMSE score, and participant 1,2, and 3 all improvedConclusionour intervention demonstrates the feasibility of dance therapy as a potentially effective, low‐cost cognitive reablement strategy that may improve function in those already suffering with dementia and loss of independence. Future studies should be prospectively designed, ideally contain a control group, and be statistically powered to explore the role of frequency, intensity, and duration on outcomes.

Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia.

There is a need to better understand the rate of cognitive and motor decline of Dementia with Lewy bodies (DLB) and Parkinson's disease Dementia (PDD). To compare the rate of cognitive and motor decline in patients with DLB and PDD from the E-DLB Consortium and the Parkinson's Incidence Cohorts Collaboration (PICC) Cohorts. The annual change in MMSE and MDS-UPDRS part III was estimated using linear mixed regression models in patients with at least one follow-up (DLB n = 837 and PDD n = 157). When adjusting for confounders, we found no difference in the annual change in MMSE between DLB and PDD (-1.8 [95% CI -2.3, -1.3] vs. -1.9 [95% CI -2.6, -1.2] [P = 0.74]). MDS-UPDRS part III showed nearly identical annual changes (DLB 4.8 [95% CI 2.1, 7.5]) (PDD 4.8 [95% CI 2.7, 6.9], [P = 0.98]). DLB and PDD showed similar rates of cognitive and motor decline. This is relevant for future clinical trial designs.

Trial Enrichment using Siamese Neural Networks and PET imaging

AbstractBackgroundBiomarker‐based patient selection is expected to increase success rates in AD clinical trials (e.g. identifying subjects that are at highest risk of cognitive decline). We present a computationally feasible modelling framework that provides a score for predicted decline based on a model trained through a Siamese Neural Network.MethodIn this proof‐of‐concept study, we use baseline data from the 1469 ADNI subjects (388 control, 798 MCI, 272 AD) with an FDG PET scan. 80% of the data was used to train a Siamese neural network after clustering subjects into ‘stable’ or ‘decline’ through the method of Bhagwat et al (2018), see Figure 1. 20% of the data was left out for testing.The model outputs points in a metric space, indicating likelihood of future decline (measured using 2‐year MMSE change from baseline). The first PCA component of the model metric space is used as a screening criterion (See Fig 2). Subjects below the threshold (screen failure rates of 30% and 50%) are not included in the trial simulation. Sample sizes are estimated assuming a 25% effect size, 95% alpha and 80% power (Fig 3). Enrichment performance of the model is compared with FDG SUVR and baseline MMSE score.ResultThe neural network provides a separable metric space of future declining and stable subjects. ‘Screening’ out 30% and 50% of subjects based on model‐predicted decline resulted in a sample size reduction of 45% and 64% respectively, a 5% and 10% improvement over the enriched FDG SUVR cohort. MMSE score yields marginal enrichment. Saliency analysis showed the model is sensitive to the precuneus, hippocampus, temporal lobe and cerebellum.ConclusionDeep learning models enable automated trial enrichment strategies, instead of handcrafted features and centralised processing. The saliency analysis shows that the nonlinear framework has identified the relevant regions for the pathology, providing additional support to their use. More work is needed to assess the ability of the developed method to capture multi‐modal biomarker (e.g. Amyloid, Tau, Neurodegeneration) data to obtain a more precise prediction of decline and to assess the trial operational and economic impact of the proposed screening process.

Potential Savings in Caregiver Time and Societal Costs Associated with Slowing Disease Progression over 36 months in Patients with Early Alzheimer’s Disease: Findings from GERAS‐US

AbstractBackgroundAlzheimer’s disease (AD) is associated with significant costs that increase with disease progression. These analyses describe the relationship between cognitive decline and measures of caregiver time and societal costs and estimate the impact of slowing disease progression over 36 months.MethodsAmyloid positive patients with mild cognitive impairment (MCI) and mild AD dementia (MILD) from the GERAS‐US study1 were included. Assessments included: Mini Mental State Examination (MMSE‐ cognition); Resource Utilization in Dementia (RUD‐ caregiver time, societal costs). The generalized linear model (GLM) with normal distribution was performed for caregiver time and with log link and gamma distribution for total societal cost. The associated outcome savings over 36 months were calculated based on least squares mean change (LSMC) in MMSE and coefficient of MMSE change from baseline to month 36.ResultsTable 1 shows baseline characteristics of 617 patients (300 MCI, 317 MILD, 47.3% male) with a mean (SD) age of 71.0 (7.8) years. MILD vs. MCI patients had greater cognitive impairment, higher caregiver time, and higher monthly societal cost. Over 36 months, MILD patients had significantly greater disease progression compared to MCI (MMSE LSMC 4.1 vs. 2.1). A 2.1‐point worsening in MMSE over 36 months for MCI was associated with an increase of 35.7 hours in total caregiver time and an increase of $8,084 per patient in total societal costs (Table 3). Delaying progression by 20% ‐30% could lead to a savings 7.2 to 10.7 hours for caregiver time and $1,675 to $2,502 in total societal costs. For MILD, a 4.1‐point worsening in MMSE was associated with an increase of 77.3 hours in total caregiver time and $12,807 per patient in total societal costs. Delaying progression by 20%‐30% could save 15.5 to 23.2 hours in caregiver time and $2,665 to $ 3,978 in total societal cost.ConclusionCaregiver time and total societal costs are higher in MILD than in MCI; caregiver time increases over 3 years for both MCI and Mild. Treatments that slow cognitive decline have the potential to keep patients in earlier disease stages longer with a resulting savings in caregiver time and societal cost. 1J Alzheimers Dis. 2019;72(1):279‐292

Characteristics of Cognitive Function Changes and Related Factors in Individuals with Cognitive Impairment during the Pandemic of COVID‐19

AbstractBackgroundThis study aimed to explore the characteristics and factors related to changes in cognitive function in vulnerable individuals with cognitive impairment affected by the coronavirus disease 2019 (COVID‐19) pandemic.MethodAmong patients who visited a local university hospital with subjective cognitive complaints, those who had been tested for cognitive function at least once after the onset of COVID‐19 and tested regularly at least three times within the last 5 years were included. Finally, 108 patients were included in this study. They were divided into groups according to whether the Clinical Dementia Rating (CDR) was maintained/improved and deteriorated. We investigated the characteristics of the changes in cognitive function and related factors during COVID‐19.ResultWhen comparing CDR changes before and after COVID‐19, there was no significant difference between the two groups (p = .317). Alternatively, the main effect of the time when the test was conducted was significant (p<.001). There was also a significant difference in the interaction between the groups and time. When the effect of the interaction was analyzed, the CDR score of the maintained/improved group significantly decreased before COVID‐19 (1st–2nd) (p = .045). After COVID‐19 (2nd–3rd), the CDR score of the deteriorated group was significantly higher than that of the maintained/improved group (p<.001). MMSE recall memory and changes in activity during COVID‐19 were significantly associated with CDR deterioration.ConclusionMemory dysfunction and decreased activity during the COVID‐19 pandemic are strongly related to the deterioration of cognitive impairment.

Influence of Baseline Diastolic Blood Pressure on the Effects of Systolic Blood Pressure Lowering on Cognitive Function in Type 2 Diabetes Mellitus.

Lowering of systolic blood pressure (SBP) in patients with low diastolic blood pressure (DBP), can further lower DBP. This can potentially decrease cerebral perfusion and cognition. We examined the influence of baseline DBP on the effect of lowering SBP on cognition. This is a post hoc analysis of the Memory in Diabetes (MIND) substudy (N = 1,430) of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (NCT00000620). Standard neuropsychological tests (Digit Symbol Substitution Test [DSST], Mini-Mental State Examination [MMSE], Rey Auditory Verbal Learning Test [RAVLT], and Stroop test) were performed at baseline and months 20 and 40. We compared the effects of intensive (goal SBP <120 mm Hg) vs. standard (goal SBP <140 mm Hg) SBP control on the changes in the 4 test scores from baseline to the averages of months 20 and 40 across the range of baseline DBP using cubic spline terms. Mean age was 63 ± 6 years, 55% were women and 66% White. Participates with lower baseline DBP were older, had more cardiovascular events and a longer duration of diabetes. There was no difference in the change in DSST (-0.22; 95% CI -0.97, 0.52), MMSE (-0.14; 95% CI -0.34, 0.06), RAVLT (-0.12; 95% CI -0.29, 0.06), and Stroop interference (-0.47; 95% CI -1.76, 0.82) in the intensive vs. standard SBP intervention. There was no interaction between baseline DBP and change in scores with the SBP intervention. Intensive SBP reduction does not adversely affect cognition, even in those with low baseline DBP.

Application of intraoperative electrocorticography in bypass surgery for adult moyamoya disease: a preliminary study.

Postoperative complications of surgical revascularization in moyamoya disease (MMD) are difficult to predict because of poor knowledge of the underlying pathophysiological process. Since the aim of surgery is to improve brain dynamics by increasing regional blood flow, we hypothesize that postoperative complications are closely related to aberrant electrophysiological changes. Thus, we evaluated the clinical significance of intraoperative electrocorticography (iECoG) in bypass surgery for adult MMD. Ninety-one adult patients operated on by the same neurosurgeon in our institute were involved (26 in the iECoG group, 65 in the traditional group). Two 1 × 6 subdural electrode grids were placed parallel to the middle frontal gyrus and superior temporal gyrus to record ECoG data continuously during the procedure in the iECoG group. Selected from several M4 candidate arteries, the recipient artery was determined to be closer to the cortex with lower power spectral density (PSD) in the beta band. The PSD parameter we used was the (delta+theta)/(alpha+beta) (DTAB) ratio (DTABR). Next, the pre- and post-bypass PSD values were evaluated, and correlations between post-/pre-bypass PSD parameter ratios and neurological/neuropsychological performance (in terms of changes in National Institutes of Health Stroke Scale [NIHSS] and Mini-Mental State Examination [MMSE] scores) were analyzed. Postoperative complications (transient neurological events) in the iECoG group were significantly lower than those in the traditional group (p = 0.046). In the iECoG group, the post-/pre-bypass DTABR ratio in the bypass area was significantly correlated with postoperative NIHSS (p = 0.002, r2 = 0.338) and MMSE changes (p = 0.007, r2 = 0.266). In the nonbypass area, neither postoperative NIHSS nor MMSE changes showed a significant correlation with the post-/pre-bypass DTABR ratio (p > 0.05). Additionally, patients with postoperative complications exhibited significantly higher DTABR (1.67 ± 0.33 vs. 0.95 ± 0.08, p = 0.003) and PSD of the theta band (1.54 ± 0.21 vs. 1.13 ± 0.08, p = 0.036). This study is the first to explain and guide surgical revascularization from the perspective of electrophysiology. Intraoperative ECoG is not only sensitive in reflecting and predicting postoperative neurological and cognitive performance but also usable as a reference for recipient artery selection.

Ability of tau‐PET, phospho‐tau217, NfL and cortical thickness to predict short‐term cognitive decline in early symptomatic Alzheimer’s disease

AbstractBackgroundBiomarkers for the prediction of cognitive decline in patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD dementia are needed for inclusion of suitable patients in clinical trials. We therefore assessed the ability of tau‐PET, blood and cerebrospinal fluid (CSF) phospho‐Tau217 (pTau217), CSF neurofilament light (NfL) and cortical thickness to predict cognitive decline early symptomatic AD.Method73 amyloid‐β positive (CSF Aβ42/Aβ40&lt;0.752) participants with MCI and mild AD dementia (MMSE ≥ 22) were assessed at baseline with cognitive testing, blood and cerebrospinal fluid (CSF)‐sampling, MRI and [18F]RO948 PET and were followed longitudinally with annual cognitive testing over 24 months. Slopes of change in MMSE and preclinical Alzheimer cognitive composite (PACC) were calculated over two years. We used linear regression models to assess the ability of biomarkers (plasma pTau217, CSF‐pTau217, temporal meta‐ROI [18F]RO948 PET standardized uptake value ratios (SUVR), CSF‐NfL and MRI “AD‐signature” cortical thickness) to predict cognitive decline both individually and in combination. The linear regression models were adjusted for age, sex, education, and baseline MMSE.ResultAll tested biomarkers individually showed significant associations with cognitive decline using both MMSE and PACC as outcome variables. For predicting longitudinal change in MMSE using individual biomarkers, [18F]RO948 SUVR showed the highest R2‐value (0.39, 95% CI [0.28‐0.67]) and best model fit (lowest Akaike Information Criterion score)(Table 1). Adding other biomarkers yielded a slightly higher R2‐value (0.44 [0.33‐0.63]), but did not improve the model fit. In a sensitivity analysis we performed a similar analysis in a subset of participants having undergone longitudinal testing with a modified PACC test battery (n=53). Results again showed the best performance for [18F]RO948 SUVRs, when tested alone, but with improved model fit and R2‐values with the addition of cortical thickness and CSF‐NfL data (Table 2).ConclusionTau‐PET imaging outperformed CSF, plasma and MRI measures when predicting cognitive decline in prodromal AD and mild AD dementia. Specifically, tau‐PET provided the best prediction alone for change in MMSE and in combination with NfL and cortical thickness for change in PACC, indicating that it would be a suitable biomarker for inclusion in clinical trials.

Impact of protocol design on between scale discrepancies in early AD clinical trials

AbstractBackgroundWe previously presented the impact of protocol design on the MMSE changes observed in the screening period. Protocols requiring inclusion criteria be met at Screening alone had significantly more large MMSE changes between Screening and Baseline than did protocols where the criteria needed to be met at both Screening and Baseline. [Kott,2020]. In the current analysis we explore the impact of protocol design on the presence of between scale change discrepancies at Baseline and 6 months after randomization.MethodData were pulled from multi‐national clinical trials in early Alzheimer's Disease (AD) where MMSE and ADAS‐Cog and/or CDR were collected at Screening, Baseline and 6 months after baseline. Subjects were categorized into 2 groups depending on whether inclusion criteria were required at Screening alone or at Screening and Baseline. We defined discordance as occurring when at least 2 of the 3 instruments showed a clinically meaningful change from the prior visit but the changes were in opposite directions. Chi‐square test was used to compare the distribution of discordances between the protocols at Baseline and at month 6.ResultOur dataset consisted of 4,237 subjects with data available from Screening, Baseline and month 6. At Baseline, we saw significantly more instances of discordance from Screening in studies requiring criteria be met at Screening alone (5%) vs 2% when the requirement needed to be met at both Screen and Baseline (chi2 = 12.5, P &lt; 0.001). At month 6, no difference between the protocol types was identified – (12.2% vs. 12.4%, chi2 = 0.01, p = 0.912).ConclusionOur analyses indicate a significant impact of protocol design on the presence of between scale change discrepancies. Protocols requiring criteria be met at Screening only had a significantly increased number of discordances at Baseline but this difference disappeared by month 6. Among the potential explanations for such between scale discordances, score manipulations to comply with inclusion criteria needs to be considered. These findings should be considered when designing protocol inclusion criteria. Further research is necessary to understand the impact of these discrepancies on drug‐placebo separation.

B vitamins and prevention of cognitive decline and incident dementia: A systematic review and meta‐analysis

AbstractBackgroundElevation of homocysteine levels is a well‐established risk factor for dementia, yet controversy exists regarding whether B‐vitamin‐mediated reduction of homocysteine levels can benefit cognitive function. We aimed to investigate whether B vitamins can reduce the risk of cognitive decline and incident dementia.MethodPubMed, EMBASE, Cochrane Library, and Web of Science were searched for articles published from the inception dates to March 1, 2020. Studies were eligible if the endpoints included MMSE changes and risk of cognitive decline and/or dementia. Random‐effect or fixed‐effect models, depending on the degree of heterogeneity, were performed to calculate mean differences (MDs), hazard ratios (HRs), and odds ratios (ORs).ResultA total of 95 studies with 46175 participants (25 RCTs, 20 cohorts, and 50 cross‐sectional studies) were included. B vitamins can benefit cognitive function as measured by MMSE changes (MD, 0.13, 95% CI 0.04‐0.23), and this result was also significant in studies where placebo groups developed cognitive decline, suggesting that B vitamins slow cognitive decline. For the &gt; 12 months interventional period stratum, B vitamins decreased cognitive decline (MD, 0.15, 95% CI 0.05‐0.25) compared to placebo; no such outcome was detected for the shorter interventional stratum. In the non‐dementia population, B vitamins slowed cognitive decline (MD, 0.15, 95% CI 0.04‐0.25) compared to placebo; this outcome was not found for the dementia population. Lower folate levels (but not B12 or B6) were associated with higher risk of dementia (OR, 1.76, 95% CI 1.24‐2.50) and cognitive decline (OR, 1.26, 95% CI 1.02‐1.55). Among the population without dementia aged 50 years and above, the risk of incident dementia was significantly decreased among individuals with higher intake of folate (HR, 0.61, 95% CI 0.47‐0.78) (but not B12 or B6).ConclusionOur meta‐analysis suggests that B vitamin supplementation is associated with slowing of cognitive decline, especially in populations who received early and long‐term intervention; higher intake of dietary folate is associated with a reduced risk of incident dementia in non‐dementia aged population.

Markers of Kidney Function and Longitudinal Cognitive Ability Among Older Community-Dwelling Adults: The Rancho Bernardo Study.

Reduced kidney function has been associated with cognitive decline. Most studies have examined a single marker of kidney function and have limited duration of follow-up. This study evaluated associations between markers of kidney function (urine albumin, estimated glomerular filtration rate [eGFR], and hyperuricemia) with cognitive performance over time. This is a longitudinal study of 1,634 community-dwelling adults (mean age = 71.7 years), with kidney function markers and cognitive ability measured at baseline (1992-1996) and at up to five additional time points with a maximum of 23.4 years (mean = 8.1 years) of follow-up. Associations between kidney function and cognitive performance were assessed using linear mixed effects models. Testing for interaction by sex was conducted. Albuminuria (urine albumin-to-creatinine ratio [ACR]≥30 mg/g) was associated with steeper annual declines in global cognitive function (MMSE, β= -0.12, p = 0.003), executive function (Trails B, β= 4.50, p < 0.0001) and episodic memory (Buschke total recall, β= -0.62, p = 0.02) scores in men. Results were similar when cognitive test scores were regressed on latent trajectory classes of ACR. In men, hyperuricemia (serum uric acid [SUA]≥6.8 mg/dl for men and SUA≥6.0 mg/dl for women) was associated with lower baseline MMSE (β= -0.70, p = 0.009) scores but not with MMSE change over time. No such associations were detected in women. There were no significant associations between eGFR and cognitive performance for either sex. In older men, albuminuria is an independent predictor of subsequent cognitive decline. More investigations are needed to explain the observed sex differences and the potential relationship between hyperuricemia and poorer global cognition.

The Impact of Adherence to Disease-Modifying Therapies on Functional Outcomes in Veterans with Multiple Sclerosis.

Background:Patients who adhere to their DMTs have lower rate of MS-related relapses and disability.Objective:We sought to determine the adherence rate to disease-modifying therapies (DMTs) and its impact on functional outcome(s) in veterans with multiple sclerosis (MS).Method:We reviewed the electronic records of 279 veterans with MS who were periodically followed in our MS clinic. We compared 3 groups of patients, defined according to their adherence to DMTs (non-adherent; poorly adherent; adherent) on their effect on disability progression and time to sustained EDSS score of 6.Results:There were 148 (53%) veterans with MS who were non-adherent to any DMT medication(s) while of the 131 (47%) veterans who were taking medications, 118 (42%) had a good- and 13 (5%) had poor-adherence. The mean age at MS onset was 36.6 (± 11.2) and mean duration of MS for the sample was 24 ± 13.5 years. The mean initial EDSS and TFIM scores were 4.09 ± 2.9 SD and 104 ± 25.7 for the study sample. The change in MMSE, TFIM scores, and time to sustained EDSS score of 6 significantly favored the good- compared to the non-adherence group (P < .01).Conclusion:This study suggests that veterans with MS who adhered to their DMTs had less decline in their MS-related cognition, disease severity and disability compared to non- and poorly-adherent groups even after adjusting for age, gender, MS duration, and type. Time to EDSS score of 6 was significantly prolonged in the good-adherence group.

The impact of protocol design on MMSE changes in the screening period

AbstractBackgroundAnecdotally, we have observed subgroups of subjects who in the screening period of clinical trials in early Alzheimer’s disease exhibit unexpectedly large changes in MMSE scores. Such changes could be explained by a number of reasons, such as learning effects, regression to the mean, measurement error, or intentional score manipulation. If the latter was the case, differences in MMSE changes between screening and baseline should be observed between protocols where MMSE inclusion criteria are required to be met at screening only and protocols requiring the criteria be met at screening and baseline. We hypothesized that MMSE changes would be larger in protocols with criteria required only at screening.MethodData were pooled from multi‐national dementia clinical trials in early AD where MMSE was collected at screening and baseline. Subjects were categorized into 2 groups depending on whether the inclusion criteria were applied to screening alone or to both the screen and baseline visits. T‐test was used to compare the change between screening and baseline between the two groups of subjects. Additionally we compared the distribution of subjects changing by a) 3 and b) 5 MMSE points in either direction between screening and baseline between the two protocol groups using a chi‐square test.ResultData were collected from 1,409 subjects. The MMSE change in subjects with criteria required at screening only was ‐1.2 points compared to ‐.05 points in subjects with criteria required at screening and baseline (t(1,407) = 5.99, p &lt; 0.001). MMSE changes of 3 or 5 points were seen significantly more often in studies where the requirement was applied at screen alone (chi2(1)=18.2, p &lt; 0.001 and chi2(1)=13.1, p &lt; 0.001, respectively).ConclusionOur analyses indicate that protocol design has a significant impact on the MMSE change observed in the screening period. Given the only difference between the two groups was the absence of inclusion criteria at baseline, we hypothesize that the MMSE score change observed differences can most likely be explained by score manipulation happening at either screening only or screening and baseline, depending on protocol type. We plan to replicate these results in larger datasets.

Ultrasensitive blood biomarkers to predict cognitive decline and diagnose Alzheimer’s disease in the absence of AT(N) classification as the reference standard

AbstractBackgroundIn recent years, blood biomarkers for Alzheimer’s disease (AD) have attracted much interest. Technological advances have allowed quantification of markers for neurodegeneration (NfL), neurofibrillary tangles (p‐tau181) and amyloid‐β pathology (Aβ42, Aβ42/Aβ40), which perform well in cohorts stratified by cerebrospinal fluid and positron emission tomography (PET) biomarkers. Here, we aimed to investigate i) the diagnostic performance of blood biomarkers in the absence of CSF/PET modalities; ii) how these markers change longitudinally and relate to cognitive decline.MethodsWe evaluated cross‐sectional data for 307 participants (100 cognitively unimpaired (CU, Clinical dementia rating (CDR) score = 0) elderly and 207 cognitively impaired (CI; 101 with mild cognitive impairment (MCI) (CDR=0.5) and 106 AD dementia (CDR&gt;0.5)) from the European multicentre AddNeuroMed cohort. 237 participants (76 CU, 161 CI) had longitudinal plasma biomarker and cognitive data (MMSE). Single molecule array (Simoa) assays were performed for NfL, t‐tau, Aβ42, Aβ40 and GFAp (all time‐points, single batch). P‐tau181 was measured using an in‐house Simoa assay. Cross‐sectional analyses were conducted using a generalized linear model for age‐adjustment, an ANOVA to compare biomarkers across groups, and correlation analysis to examine biomarker concentrations in relation to MMSE. Longitudinal analyses were performed using linear mixed models.ResultsAt baseline, neuronal and astrocytic biomarkers were increased (p‐tau181, NfL, t‐tau, GFAp; P&lt;0.001), whilst the amyloid marker (Aβ42/Aβ40 ratio) was decreased (P&lt;0.001) in AD compared with CU. Significant differences were also observed between AD and MCI for p‐tau181, Aβ42/Aβ40, GFAp (P&lt;0.001) and NfL (P&lt;0.05). P‐tau181 (P&lt;0.001) and NfL (P&lt;0.05) were increased in MCI compared with CU. ROC curves revealed high accuracy for p‐tau181 in separating AD from CU (AUC=0.921) and MCI (AUC=0.816), and in separating CU from CI (AUC=0.843). Linear mixed models showed increases in all five measures in both CU and CI subjects; when assessing change in MMSE, the strongest associations were seen for GFAp in CU (standardized‐β=‐0.27, P&lt;0.001) and for p‐tau181 in CI subjects (standardized‐β=‐0.34, P&lt;0.001).ConclusionThese results suggest that blood biomarkers have diagnostic potential for AD in the absence of AT(N) classification, and that longitudinally, levels of p‐tau181 have potential as a biomarker of cognitive decline.

Application of Intraoperative Electrocorticography in Precise Bypass Surgery of Adult Moyamoya Disease: A Preliminary Study

Abstract INTRODUCTION Postoperative complications of surgical revascularization are still difficult to predict because of poor knowledge of the underlying pathophysiological process. Since the aim of the surgery is to improve brain dynamics by increasing regional blood flow, we hypothesize that postoperative complications are determined by aberrant electrophysiological changes. Thus, we tried to evaluate the clinical significance of intraoperative electrocorticography (ECoG) in precise bypass surgery of adult moyamoya disease (MMD). METHODS Ninety-one adult patients operated by the same neurosurgeon in our institute was involved (26 in the precise group, 65 in the traditional group). Two 1 × 6 subdural electrode grids were placed parallelly on the middle frontal gyrus and superior temporal gyrus to record ECoG data continuously during the procedure in the precise group. For patients with several candidate recipient M4 arteries, we selected the one closer to the cortex with lower amplitude in the beta band and lower frequency. Postoperative complications, 1-mo follow-up NIHSS and MMSE scores were noted. The power spectral denstity (PSD) values, and its parameter of (delta + theta)/(alpha + beta) ratio (DTABR) were adopted as ECoG metrics. RESULTS No significant difference was noticed between the 2 groups in either postoperative NIHSS or MMSE, while postoperative complication of the precise group was significantly lower than that of the traditional group (P &lt; .05). In the precise group, the post/preop DTABR ratio in the bypass area was significantly correlated with postoperative NIHSS (P = .014 r2 = 0.289) and MMSE changes (P = .007 r2 = 0.266). While in the remote area, neither postoperative NIHSS nor MMSE changes showed significant correlation with post/pre-op DTABR ratio (P &gt; .05). Additionally, in the precise group, patients with postoperative complications exhibited significantly higher DTABR (1.67 ± 0.33 vs 0.95 ± 0.08, P = .003) and PSD of thata band than those without postoperative complications in only bypass area. CONCLUSION This study was the first to explain and guide surgical revascularization from the perspective of electrophysiology. Intraoperative ECoG was not only sensitive to reflect and predict postoperative neurological and cognitive performance, but also usable as a reference for recipient artery selection.

Cerebrovascular Hemodynamics on Transcranial Doppler Ultrasonography and Cognitive Decline in Mild Cognitive Impairment.

Vascular risk factors and neurovascular dysfunction may be closely related to cognitive impairment and dementia. In this study, we evaluated the association between hemodynamic markers and longitudinal cognitive changes in patients with mild cognitive impairment (MCI). Furthermore, we investigated whether hemodynamic markers could predict the risk of progression to Alzheimer's disease (AD) in patients with MCI. A total of 68 subjects with amnestic MCI were recruited. Using transcranial Doppler (TCD) ultrasonography, cerebrovascular reactivity was evaluated with a breath-holding test (breath holding index; BHI) in addition to the mean flow velocity (MFV) and pulsatility index (PI) of the middle cerebral artery. We followed subjects for 24 months and each subject underwent neuropsychological testing and TCD ultrasonography, annually. According to the follow-up neuropsychological studies and clinical interviews at 12 months, we divided the patients with MCI into two groups: patients with stable cognitive performance and patients who progressed to AD. Lower BHI and higher PI were observed in patients who progressed to AD. The changes of MMSE score over the first 12 months correlated with lower baseline MMSE score and changes of MFV and BHI. The changes of MMSE score over 24 months were closely related to higher baseline resistance index and PI values. Multivariate logistic regression showed that abnormal baseline BHI value could predict a conversion from MCI to AD. We confirmed there is a close association between hemodynamic changes represented by TCD markers and cognitive decline, supporting the clinical value of hemodynamic markers in predicting MCI patients who will progress toAD.

Rapidly Progressive Alzheimer's Disease inTwo Distinct Autopsy Cohorts.

A rapidly progressive phenotype of Alzheimer's disease (AD) has been described in some prion disease cohorts. Limited information regarding rapidly progressive AD (rpAD) is available from longitudinal national cohorts. To compare the clinical characteristics of rpAD in two different national cohorts. A retrospective analysis was performed on AD subjects with available neuropathology in the National Alzheimer's Coordinating Center (NACC) database and among neuropathologically characterized AD cases from the National Prion Disease Pathology Surveillance Center (NPDPSC) that were evaluated for suspected prion disease. In the NACC cohort, rpAD was delineated by the lower 10th percentile of follow up duration from pre-dementia to death duration among subjects meeting pathological diagnosis of AD. rpAD from the NPDPSC had a shorter mean symptom duration than the NACC identified rpAD cases (11.6 months versus 62.4 months) and were also younger at the time of their death (60.0 versus 81.8 years). NACC identified rpAD subjects, beginning from a predementia stage, had slower rate of MMSE change per year than NPDPSC cases (2.5 versus 6.0 points). rpAD constitute an important subset of AD subjects in whom a rapid course of symptomatic clinical decline is noted, as confirmed in both national cohorts. rpAD was best characterized by survival time (≤3 years), as there were clear differences between the rpAD cohorts in terms of symptom duration, age at death, and MMSE change per year, likely due to the strong selection biases. rpAD could shed light on the biology of rate of progression in AD.

Effect of Vitamins in Prevention of Alzheimer’s Development: A Meta-Analysis of Randomized Controlled Trials

Vitamins have demonstrated anti-Alzheimer’s efficacy in clinical investigations however, results are inconclusive therefore, we conducted this meta-analysis. Systematic literature searches were conducted on electronic databases using different combinations of key words for vitamins and Alzheimer’s disease. Randomized controlled trials of vitamins reporting ADAS CoG and MMSE scores were included. Effect size and 95% confidence interval (CI) were pooled separately for both endpoints The search yielded 40 studies, 6 of them met inclusion criteria. Three studies were pooled for ADAS-cog change from baseline. The combined results showed that there was no significant difference between the placebo and the vitamin group (mean difference: -0.19, 95% CI: -1.38 to 1.00, P= 0.76). The I2 value (82%), and P value for distribution (P= 0.004) showed that data were heterogeneous. The sensitivity analysis showed that the mean difference between the two treatment arms varied from -0.72 to 0.37. Six studies were pooled for MMSE change from baseline. The combined results showed that there was no significant difference between the placebo and vitamin group (mean difference: 0.28, 95% CI:-0.08 to 0.63, P= 0.12). The I2 values was 0%, showing a homogeneous distribution. The sensitivity analysis showed that the mean difference between the two treatment arms varied from 0.06 to 0.37. Overall, the treatment effect of vitamins was comparable to the effect of placebo. There was no significant difference between two therapies in prevention of Alzheimer’s disease.