Probable AD Research Articles

A Two-Year Observational Study to Evaluate Conversion Rates from High- and Low-Risk Patients with Amnestic Mild Cognitive Impairment to Probable Alzheimer's Disease in a Real-World Setting.

Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI. To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram. This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion rate to probable AD and brain structure changes between the two groups. In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001). The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making.Trial Registration: ClinicalTrials.gov (NCT03448445).

Quantitative EEG Spectral and Connectivity Analysis for Cognitive Decline in Amnestic Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is considered to be the borderline of cognitive changes associated with aging and very early dementia. Cognitive functions in MCI can improve, remain stable or progress to clinically probable AD. Quantitative electroencephalography (qEEG) can become a useful tool for using the analytical techniques to quantify EEG patterns indicating cognitive impairment. The aim of our study was to assess spectral and connectivity analysis of the EEG resting state activity in amnestic MCI (aMCI) patients in comparison with healthy control group (CogN). 30 aMCI patients and 23 CogN group, matched by age and education, underwent equal neuropsychological assessment and EEG recording, according to the same protocol. qEEG spectral analysis revealed decrease of global relative beta band power and increase of global relative theta and delta power in aMCI patients. Whereas, decreased coherence in centroparietal right area considered to be an early qEEG biomarker of functional disconnection of the brain network in aMCI patients. In conclusion, the demonstrated changes in qEEG, especially, the coherence patterns are specific biomarkers of cognitive impairment in aMCI. Therefore, qEEG measurements appears to be a useful tool that complements neuropsychological diagnostics, assessing the risk of progression and provides a basis for possible interventions designed to improve cognitive functions or even inhibit the progression of the disease.

Association between Grip Strength and Future Cognitive Function in male

AbstractBackgroundFrailty is an aging‐related syndrome of physiological decline, and has been associated with cognitive function.Grip strength, could be used as a marker for frailty and older adult health status. Frailty has been associated with cognitive function. However, its mechanism has not been fully investigated.We aimed to investigate the association between grip strength with cognitive function.MethodWe prospectively recruited 184 participants who underwent a grip strength test, cognitive function test. Data was collected from the Korean Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study which started in 2014. Frailty was represented by grip strength (kg). Cognitive function was assessed using Mini‐Mental State Examination(MMSE) and The Consortium to Establish a Registry for Alzheimer’s Disease‐K(CERAD‐K).Multiple linear regression models were used to analyze the associations between grip strength and cognitive function. We adjusted age, gender, years of education, and BMI.ResultAmong 184 participants, 119 (64.7%) were cognitively normal. 32 (17.4%) were diagnosed with mild cognitive impairment and 33 (17.9) were a probable AD. Mean age of the participants was 69.4 (8.2) years. 43.5% of the participants were female. Grip strength was positively associated with MMSE at 1 year later in male (ß = 0.182 p = 0.004). In terms of cognitive domain, verbal and visual memory, language, visuospatial, and frontal‐executive functions were related to grip strength (vebal memory: ß = 0.037 p = 0.022, visual memory: ß = 0.046 p = 0.002, language: ß = 0.055 p&lt;0.001, visuospatial: ß = 0.068 p = 0.0213, frontal‐executive: ß = 0.050 p&lt;0.001).ConclusionWeakness of grip strength is associated with decreased future cognitive function. This support concept that grip strength could be a marker for cognitive decline.

Reconsideration of appropriate use criteria for amyloid PET based on real‐world experiences

AbstractBackgroundAmyloid PET can detect brain abnormality at very early stages of AD. However, deciding which patients should undergo amyloid PET requires careful consideration, because of its expense and the lack of treatment options. Until now, 2013 recommendations for appropriate use of amyloid PET, by Amyloid Imaging Taskforce, have been used widely. However, anti‐amyloid treatment is becoming available, so it is an appropriate time to reconsider the optimal criteria for amyloid PET use. In Korea, amyloid PET is widely used in clinical practice due to its low cost and easy accessibility. Therefore, we conducted a survey to investigate the current status of amyloid PET use by dementia experts in Korea, and considered what would be the optimal criteria for using amyloid PET in the real world.MethodThe survey consisted of 52 questions, conducted using an online platform, in 2022. Fifty‐six dementia experts (34 neurologists and 22 psychiatrists) participated, mainly working at university hospitals in Korea.ResultExperts responded positively that they would use amyloid pet in the following situations: cognitive complaint with objectively confirmed impairment (88.5%), persistent MCI (32%), progressive unexplained MCI (84.9%), possible AD or mixed pathology (63.5%), possibility to change medication (75%), among patients age under 65 in MCI (86.5%), and in AD (82.6%). In cases of probable AD, it is recommended not to take an amyloid PET scan, but only 25% of experts answered “no”. 36.4% answered positively that they would use amyloid PET, and if the patient was under 65 years old, 30.8% responded “always”. And, to the question ‘If anti‐amyloid treatment becomes available, would you be willing to perform amyloid PET scan?’, nearly 90% of experts answered that they would consider amyloid PET in MCI and Probable AD.ConclusionUnlike previous recommendations, amyloid PET scan is widely used in actual clinical practice in Korea. In particular, in the situation where the use of anti‐amyloid based disease modifying drugs has become a reality, contrary to the recommendations, it could be used more actively in patients with probable AD. Therefore, it is necessary to reconsider what is the appropriate amyloid PET use criteria.

Salivary tau as a probable diagnostic method for Alzheimer’s disease

AbstractBackgroundBiomarkers can be detected in blood levels and, more recently, the feasibility of identifying TAU protein in salivary samples was verified.MethodThis is a case‐control study carried out in patients diagnosed with probable AD and cognitively healthy and non‐AD patients who had research centers in the cities of Ribeirão Preto, Jaboticabal, Louveira and São Paulo, Brazil. For the quantification of t‐Tau by the ELISA method in the saliva of research participants, we used the Kit MBS022635 Human Tau Protein ELISA. And for the quantification of phosphorylated TAU (pTAU), the Kit E‐EL‐H5314 Human pMAPT pTAU (microtubule‐associated phosphorylated tau protein) ELISA Kit was usedResultTotal TAU protein concentrations showed no evidence for differences in concentrations in the three groups of patients, with and without Alzheimer’s disease. However, the phosphorylated TAU protein brings a very interesting finding, as it showed variations between young and elderly patients with and without the disease.ConclusionTotal TAU protein does not seem to be a likely biomarker to aid in the diagnosis of the disease. However, our results show that phosphorylated TAU was elevated in the elderly and, in the elderly with AD, it was even higher.

Measurement of amyloid beta in nasal secretions as a potential biomarker for Alzheimer’s disease

AbstractBackgroundWe investigated the level of amyloid beta (Aβ) in nasal secretions of patients with Alzheimer’s disease using multichannel impedance analyzer (ToAD) and electrical‐immunosorbent assay (El‐ISA), and determined the predictive value of Aβ in nasal secretions for AD diagnosis.MethodNasal secretions were obtained from 84 participants with probable AD dementia (ADD), 83 with amnestic mild cognitive impairment (MCI), 22 with cognitive decline associated with other neurological disorders (OND), and 62 cognitively unimpaired (CU) participants. Aβ oligomers in nasal secretions were analyzed using ToAD / El‐ISA analytical systems. Capture antibodies in El‐ISA kits specifically capture Aβ oligomer in nasal secretion, and then detection probes for El‐ISA method bind with amyloid beta oligomer sequentially. Finally, unbound free detection probes in solution was electrochemically measured by ToAD analyzer for quantifying Aβ oligomers. Because this analytical method is based on the back‐titration, the change of electrical signal is inversely proportional with the concentration of detectable Aβ oligomers. Electrical signals finally expressed to Cantis AD Index (CAI, 0∼99) which normalized by standards for system calibration.ResultThe CAI was higher in the probable ADD group than in the CU group (p &lt; 0.05). The accuracy of the CAI was fair in separating into the probable ADD and CU groups (AUC of the ROC curve = 0.665, 95% CI = 0.572‐0.758, SE = 0.047, p = 0.001). The accuracy of the CAI was fair in separating into the participants with positive amyloid PET scan and those with negative amyloid PET scan (area under curve [AUC] of the receiver operating characteristic [ROC] curve = 0.697, 95% confidence interval [CI] = 0.629‐0.766, SE = 0.035, p &lt; 0.001). The CAI has a negative correlation with Mini‐Mental State Examination score and positive correlations with Clinical Dementia Rating scale‐Sum of Boxes and amyloid PET centiloid scale scores.ConclusionThese results demonstrate that the level of Aβ in nasal secretions increases in AD and the detection of Aβ in nasal secretions using ToAD / El‐ISA analytical systems may be possible in predicting ADD.

Diferencias neuropsicológicas en la enfermedad de Alzheimer en función de la edad de presentación

IntroductionEarly-onset Alzheimer's disease (EOAD) has been defined as a dementia due to AD presenting before the arbitrarily established age of 65 (as opposed to late-onset Alzheimer's disease or LOAD). There is still little research about other age sub-groups, the use of so-called senile dementia has been banished, usually including it within the late-onset Alzheimer's dementia. To the extent of our knowledge, there are no studies comparing the neuropsychological features of very-late-onset patients with early and late-onset ones. MethodsWe retrospectively selected 359 patients with a diagnosis of probable AD dementia. We subdivided patients into three groups attending to the age of onset of the disease: early-onset AD (EOAD; younger than 65 years old), late-onset AD (LOAD; between 65 and 80) and very-late-onset AD (VLOAD; defined here as onset age older than 80), and then we compared their neuropsychological results. ResultsAD patients with a younger age at onset scored worse on attention, executive function and visuospatial skills, while older-onset patients scored worse in memory tasks and language. Patients with a very-late-onset differed from the late-onset ones in a greater impairment of semantic fluency and naming. ConclusionAlthough the point of separation between EOAD and later-onset forms of EA at the age of 65 is an arbitrary one, our study shows that there are significant differences between these groups from a neuropsychological point of view. However, these differences do seem to follow a linear trend with age, rather than representing fundamentally distinct clinical pictures.

A comparative study of Amyloid positive and negative individuals with “Alzheimer Syndrome”

AbstractBackgroundOutside academic centres, the diagnosis of probable Alzheimer’s Disease remains a clinical diagnosis supported by basic blood work and structural brain imaging. It has already been documented, approximately 1/3rd of individuals meeting clinical criteria for probable AD, do not show underlying amyloidopathy on PET or cerebrospinal fluid. Thus, the clinical “Alzheimer Syndrome” encompasses individuals with abnormal amyloid (Amyloid positive: A+), as well as “amyloid negative” individuals lacking amyloidopathy. Finding ways to distinguish these subgroups clinically will become increasingly important as anti‐amyloid therapies become more available. It is not yet clear if these two groups have any clinical or imaging features that might distinguish them. Our objective was to find out if there are any clinical or imaging pointers towards amyloid biomarker status.MethodsA retrospective chart review of 23 patients screened for anti‐amyloid clinical trials was performed, of whom 13 were (A+) and 10 were (A‐). The following information was collected from the chart review‐ demography, medical history, clinical presentation, course of disease and rate of progression, neuropsychological test scores, blood work, brain scans, and any other relevant investigations. Relevant data were subjected to appropriate statistical analysis.ResultsThis is an ongoing study and the results are derived from interim analysis. Comparison of the (A+) and (A‐) groups revealed no statistically significant difference in terms of age, sex, amnestic presentation and cognitive decline rate. We did not find evidence (in this small group) that (A‐) subjects had a greater vascular load ‐ no difference in Hachinski score or Fazekas score. The only statistically significant difference between the groups was found in their NPI scores, with the A+ group showing a higher score (2.92 versus 0.80, p = 0.008).ConclusionAmyloid positive individuals are more likely to have neuropsychiatric manifestations during the course of their cognitive decline than their Amyloid negative counterpart. Work is ongoing to delineate biological and biomarker differences that account for the cortical dementia (Alzheimer Syndrome) in Amyloid negative subjects. Delineating differences in clinical presentation may prove useful in specifying which of these individuals are actually Amyloid positive. Confirmation in a larger group of subjects will be necessary.

Lateral temporal atrophy is a better visual scale to predict MMSE score than hippocampal atrophy in Alzheimer’s disease: A retrospective cross‐sectional study

AbstractBackgroundMini‐Mental State Exam (MMSE) is helpful in the cognitive evaluation and staging of Alzheimer patients (AD), but its score could be affected by acute medical conditions, depression, or anxiety. Conversely, head magnetic resonance imaging (MRI) is an independent diagnostic tool to evaluate specific cerebral pathology in AD patients. Many studies have investigated the correlation between head MRI visual scales such as hippocampal atrophy and baseline MMSE to aid in the diagnosis of AD. However, there has not been a study that evaluates the correlation between a comprehensive head MRI visual scale with baseline MMSE in AD patients.MethodWe retrospectively collected records of outpatients diagnosed as probable AD according to DSM V criteria in two dementia wards. Patients with age of onset before 65 years old were considered early‐onset AD patients. The comprehensive visual rating scale (CVRS) was used to semiquantitative structural lesions, including hippocampal, cortical, subcortical atrophy, and small vessel disease. The relationship between MRI lesions and baseline MMSE was evaluated using Bayesian model averaging (BMA) to control confounders. Data analysis was done using R‐4.0.3.ResultWe collected 65 AD patients with 21 (32.31%) early‐onset AD. Lateral temporal atrophy, level of education, and late age‐onset were the strongest independent predictors of baseline MMSE, while other structural lesions were not significant in the BMA model. Furthermore, hippocampal atrophy was only correlated with delayed recall, while temporal atrophy was correlated with orientations, attentions, language, and visual‐spatial.ConclusionOur study suggests that the lateral temporal atrophy correlates more with the baseline MMSE score in patients with AD than the hippocampal atrophy.

Centiloid scale measure of amyloid PET by CT‐guided anatomic standardization

AbstractBackgroundCentiloid (CL) scaling has become a standardized quantitative measure in amyloid PET because it facilitates the direct comparison of results across institutions, even when different analytical methods or tracers are used. Standard volumes of interest must be used to calculate the CL scale after the anatomic standardization of amyloid PET images using coregistered MRI; if the MRI is unavailable, the CL scale cannot be accurately calculated. This study sought to determine the substitutability of CT, which is used to correct PET attenuation in PET/CT equipment, by evaluating the measurement accuracy when CT is used as an alternative to MRI in the calculation of the CL scale.MethodAmyloid PET images obtained using 11C‐PiB from 19 patients with possible or probable Alzheimer’s disease were processed to calculate the CL scale using 3D T1‐weighted MRI (Optima MR450w, 1.5T, GE healthcare) and CT of PET/CT (uMI780, United Imaging Healthcare). CLMRI and CLCT were respectively defined as the use of MRI and CT for anatomic standardization and compared. We followed the method advocated by the Global Alzheimer’s Association Interactive Network for the calculation of the CL scale. The whole cerebellum was chosen as a reference area for the CL calculation.ResultA Bland–Altman plot showed that CLCT did not significantly differ from CLMRI (mean ± standard deviation, −0.1 ± 1.5; p = 0.734). The 95% limits of agreement ranged from −0.8 to 0.6. Pearson correlation analysis showed a highly significant correlation of r = 0.999 between CLCT and CLMRI (p &lt; 0.001). The linear regression equation was CLCT = 0.992 × CLMRI + 0.144. In a Bland–Altman plot, Spearman correlation analysis did not identify a significant association between the difference in CLMRI versus CLCT and CL load (ρ = −0.045, p = 0.853).ConclusionCL scales based on CT show a highly significant positive correlation with those based on MRI, regardless of the degree of amyloid accumulation in possible and probable AD patients. A key advantage of the use of CT is the simultaneous acquisition of PET and CT. This method would be applicable to subjects who are unable to undergo MRI.

Evaluation of salivary levels of beta amyloid in patients with Alzheimer’s disease

AbstractBackgroundSalivary analysis of amyloid beta protein levels in Alzheimer’s disease patients and research participants without Alzheimer’s disease.MethodThis is a case‐control study carried out in patients with a diagnosis of probable AD and cognitively healthy patients without AD. There were 3 groups, totaling 76 people: group 1 with AD; Group 2 without AD (under 59 years old) and group 3 without AD (over 60 years old). Ethics committee opinion n° 3,130,636. Salivary analysis of Ab‐40 and Ab‐42 performed by the ELISA method.ResultOur investigations for salivary AB42 showed slightly higher levels in male and female AD patients compared to healthy ones. The general AB42 group for AD was superior to the general group of healthy ones, demonstrating the feasibility of using saliva as a diagnostic element for AD.ConclusionAmyloid beta protein in fractions 40 and 42 amino acids (Ab1‐40 and Ab1‐42) were expressed in higher concentrations in AD patients and reduced in healthy ones, strengthening the hypothesis of the use of this fluid as an adjuvant in the diagnosis of Alzheimer’s Disease.

Neuroimaging statistical approaches for determining neural correlates of Alzheimer's disease via positron emission tomography imaging

AbstractAlzheimer's disease (AD) is a degenerative disorder involving significant memory loss and other cognitive deficits, manifesting as a progression from normal cognitive functioning to mild cognitive impairment to AD. The sooner an accurate diagnosis of probable AD is made, the easier it is to manage symptoms and plan for future therapy. Functional neuroimaging stands to be a useful tool in achieving early diagnosis. Among the many neuroimaging modalities, positron emission tomography (PET) provides direct regional assessment of, among others, brain metabolism, cerebral blood flow, amyloid deposition—all quantities of interest in the characterization of AD. However, there are analytic challenges in identifying early indicators of AD from these high‐dimensional imaging data sets, and it is unclear whether early indicators of AD are more likely to emerge in localized patterns of brain activity or in patterns of correlation between distinct brain regions. Early PET‐based analyses of AD focused on alterations in metabolic activity at the voxel‐level or in anatomically defined regions of interest. Other approaches, including seed‐voxel and multivariate techniques, seek to characterize metabolic connectivity by identifying other regions in the brain with similar patterns of activity across subjects. We briefly review various neuroimaging statistical approaches applied to determine changes in metabolic activity or metabolic connectivity associated with AD. We then present an approach that provides a unified statistical framework for addressing both metabolic activity and connectivity. Specifically, we apply a Bayesian spatial hierarchical framework to longitudinal metabolic PET scans from the Alzheimer's Disease Neuroimaging Initiative.This article is categorized under: Statistical and Graphical Methods of Data Analysis &gt; Analysis of High Dimensional Data Statistical Learning and Exploratory Methods of the Data Sciences &gt; Modeling Methods Statistical Models &gt; Bayesian Models

Longitudinal Spatial Relationships Between Atrophy and Hypometabolism Across the Alzheimer's Disease Continuum.

The A/T/N framework allows for the assessment of pathology-specific markers of MRI-derived structural atrophy and hypometabolism on 18FDG-PET. However, how these measures relate to each other locally and distantly across pathology-defined A/T/N groups is currently unclear. To determine the regions of association between atrophy and hypometabolism in A/T/N groups both within and across time points. We examined multivariate multimodal neuroimaging relationships between MRI and 18FDG-PET among suspected non-Alzheimer's disease pathology (SNAP) (A-T/N+; n = 14), Amyloid Only (A+T-N-; n = 24) and Probable AD (A+T+N+; n = 77) groups. Sparse canonical correlation analyses were employed to model spatially disjointed regions of association between MRI and 18FDG-PET data. These relationships were assessed at three combinations of time points -cross-sectionally, between baseline visits and between month 12 (M-12) follow-up visits, as well as longitudinally between baseline and M-12 follow-up. In the SNAP group, spatially overlapping relationships between atrophy and hypometabolism were apparent in the bilateral temporal lobes when both modalities were assessed at the M-12 timepoint. Amyloid-Only subjects showed spatially discordant distributed atrophy-hypometabolism relationships at all time points assessed. In Probable AD subjects, local correlations were evident in the bilateral temporal lobes when both modalities were assessed at baseline and at M-12. Across groups, hypometabolism at baseline correlated with non-local, or distant, atrophy at M-12. These results support the view that local concordance of atrophy and hypometabolism is the result of a tau-mediated process driving neurodegeneration.

Visual-spatial processing impairment in the occipital-frontal connectivity network at early stages of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide, but its pathophysiological phenomena are not fully elucidated. Many neurophysiological markers have been suggested to identify early cognitive impairments of AD. However, the diagnosis of this disease remains a challenge for specialists. In the present cross-sectional study, our objective was to evaluate the manifestations and mechanisms underlying visual-spatial deficits at the early stages of AD. We combined behavioral, electroencephalography (EEG), and eye movement recordings during the performance of a spatial navigation task (a virtual version of the Morris Water Maze adapted to humans). Participants (69-88 years old) with amnesic mild cognitive impairment-Clinical Dementia Rating scale (aMCI-CDR 0.5) were selected as probable early AD (eAD) by a neurologist specialized in dementia. All patients included in this study were evaluated at the CDR 0.5 stage but progressed to probable AD during clinical follow-up. An equal number of matching healthy controls (HCs) were evaluated while performing the navigation task. Data were collected at the Department of Neurology of the Clinical Hospital of the Universidad de Chile and the Department of Neuroscience of the Faculty of Universidad de Chile. Participants with aMCI preceding AD (eAD) showed impaired spatial learning and their visual exploration differed from the control group. eAD group did not clearly prefer regions of interest that could guide solving the task, while controls did. The eAD group showed decreased visual occipital evoked potentials associated with eye fixations, recorded at occipital electrodes. They also showed an alteration of the spatial spread of activity to parietal and frontal regions at the end of the task. The control group presented marked occipital activity in the beta band (15-20 Hz) at early visual processing time. The eAD group showed a reduction in beta band functional connectivity in the prefrontal cortices reflecting poor planning of navigation strategies. We found that EEG signals combined with visual-spatial navigation analysis, yielded early and specific features that may underlie the basis for understanding the loss of functional connectivity in AD. Still, our results are clinically promising for early diagnosis required to improve quality of life and decrease healthcare costs.

Allopregnanolone as a Regenerative Therapeutic for Alzheimer’s Disease: Phase 2 proof‐of‐concept clinical trial using hippocampal volume as a surrogate endpoint

AbstractBackgroundGiven that hippocampal volume is a well‐established imaging biomarker predictive of cognitive decline although not itself a measure of cognition, we propose its use as a surrogate endpoint to test the efficacy of allopregnanolone as a regenerative therapeutic for mild AD.MethodPhase 2 multi‐center, double‐blind, parallel‐group, randomized‐controlled clinical trial. A total of 20 sites will recruit 200 participants with mild AD, 100 participants per treatment arm. Eligible participants are male or female, age 55 to 80 years old, diagnosed with probable AD, with a MMSE between 20‐26 and APOE ε4 genotype (3/4 and 4/4). Participants will be randomized to 4 mg Allo (administered intravenously over 30 minutes, once per week) or matching placebo, 1:1 allocation, for a 12‐month period. After 12 months, all participants in the placebo group will be crossed‐over to receive Allo for the remainder of the study (6 month open‐label phase). Brain imaging to evaluate the primary endpoint will be conducted at baseline, 6 and 12 months. A critical component of this trial is that all imaging sites participating in the trial are capable of performing both basic and advanced MRI sequences required in the protocol.ResultPrimary Endpoint is Mean rate of change in hippocampal volume at 12 months. Secondary Endpoints include mean rate of change in cognitive outcomes (CANTAB‐PAL, ADAS‐Cog11), functional outcomes (ADCS‐iADL) and safety outcomes at 12 months. Exploratory endpoints include other imaging outcomes (regional brain volumes, white matter fiber tract diffusion measures as determined by DTI, average intrinsic connectivity as determined by resting state fMRI, and cerebral region cerebral blood flow); blood‐based biomarkers of target engagement; other cognitive and functional outcomes (CDR‐SB score, ADAS‐Cog14 score, MMSE score, NPI‐Q score, EuroQol 5‐Dimension / 5‐Level (EQ‐5D‐5L) health‐related quality of life scale scores, QoL‐AD score, Zarit Burden Interview Questionnaire score at 12 and 18 months. Additionally, change from baseline to 6, 12 and 18 months in open‐label treatment participants switching from placebo to Allo at 12 months in the above endpoints.ConclusionResults from this study will validate previous findings indicating that allopregnanolone may exert both regenerative and neuroprotective effects on structure and connectivity in the Alzheimer’s brain.

Plasma amyloid‐β profiles and the correlation with neuropsychological performance in patients with cognitive decline

AbstractBackgroundThis study aimed to investigate the relationship between the level of plasma amyloid‐β (Aβ) and neuropsychological performance in patients with cognitive decline, classified according to amyloid PET positivity using a highly sensitive nano‐biosensing platform.MethodA total of 44 patients with cognitive decline who underwent plasma Aβ analysis, amyloid PET scanning, and detailed neuropsychological tests were recruited in this study. The participants comprised 20 patients with subjective cognitive decline, 7 with amnestic mild cognitive impairment, and 17 with probable AD dementia. Patients were classified into a normal control (NC, N = 25) or Alzheimer’s disease (AD, N = 19) group based on amyloid PET positivity. Multiple linear regression was performed to determine whether plasma Aβ (Aβ40, Aβ42, and Aβ42/40) levels were associated with neuropsychological test results.ResultThe plasma levels of Aβ42/40 were significantly different between the NC and AD groups and were the best predictor of amyloid positivity by receiver operating characteristic curve analysis. There were significant differences in the neuropsychological performance of cognitive domains (language, visuospatial, verbal/visual memory, and frontal/executive functions) between the NC and AD groups. However, in multivariate regression analysis, upon inclusion of age, education, vascular risk factors, and apolipoprotein E ε4 status, higher levels of plasma Aβ42/40 showed significant negative correlations with verbal and visual memory performance, including immediate recall, delayed recall, and recognition tests.ConclusionWe suggest that our study might have clinical significance because plasma Aβ analysis using a highly sensitive nano‐biosensing platform could not only be a useful non‐invasive method for diagnosing AD, but also showed a significant association with memory performance in patients with cognitive decline. Further investigations with a larger sample size are necessary to clarify the possible relevance of plasma Aβ as a blood‐based biomarker for precise AD diagnosis.

A novel, efficient and seamless Phase 2A‐2B design to test varoglutamstat in early AD: the VIVA‐MIND study

AbstractBackgroundImproved Phase 2 study designs may increase success rates in late stage AD trials. Varoglutamstat (PQ912) is an oral small molecule glutaminyl cyclase inhibitor designed to address several key disease mechanisms. A Phase 2A study (NCT02389413) of 120 early AD patients treated for 12 weeks provided preliminary evidence of safety and tolerability, and effects on working memory, CSF biomarkers, and synaptic function (EEG theta‐power).ObjectiveTo design a well‐powered, safe, and efficient study of varoglutamstat in early AD incorporating adaptive dose selection in Phase 2A, a futility analysis testing pharmacological, biological and cognitive criteria, and a seamless transition to a larger Phase 2B study investigating longer‐term efficacy and safety.MethodsAn efficient and safe selection rule across 3 descending doses (600mg, 300mg, 150 mg BID) was established using a continuously monitored Pocock safety boundary targeting a set of treatment emergent AE’s of interest. Well‐powered stage‐gate criteria at a planned interim futility analysis included thresholds for target occupancy in plasma, and would detect negative effects on a cognitive composite or absence of benefit on EEG theta‐power. The Phase 2B study was powered to detect an effect size of 0.7 points on the Clinical Dementia Rating – Sum of Boxes score at 18 months, an established approvable endpoint.ResultsThe on‐going Phase 2A adaptive dose‐finding trial (NCT03919162) is randomizing 180 subjects with MCI or mild probable AD, initially to 24+ weeks of 600mg varoglutamstat dose or placebo, BID. If the safety boundary is hit, the dose will be discontinued and all subjects titrated down, with similar sequential testing of lower doses as needed. The interim futility analysis will occur when the first 180 randomized subjects have been on study for at least 24 weeks. If this stage‐gate is passed, Phase 2B will enroll 234 additional patients to achieve 414 total patients treated for 72 weeks at full dose of varoglutamstat or placebo.ConclusionThis novel study design enables adaptive dose selection, an early interim futility analysis, and longer‐term determination of cognitive and functional efficacy, and should support robust proof‐of‐concept for varoglutamstat using a total sample of 414 subjects treated for 72 weeks.

Distribution of Cortical Atrophy Associated with Cognitive Decline in Alzheimer's Disease: A Cross-Sectional Quantitative Structural MRI Study from PUMCH Dementia Cohort.

Quantitative measures of atrophy on structural MRI are sensitive to the neurodegeneration that occurs in AD, and the topographical pattern of atrophy could serve as a sensitive and specific biomarker. We aimed to examine the distribution of cortical atrophy associated with cognitive decline and disease stage based on quantitative structural MRI analysis in a Chinese cohort to inform clinical diagnosis and follow-up of AD patients. One hundred and eleven patients who were clinically diagnosed with probable AD were enrolled. All patients completed a systemic cognitive evaluation and domain-specific batteries. The severity of cognitive decline was defined by MMSE score: 1-10 severe, 11-20 moderate, and 21-30 mild. Cortical volume and thickness determined using 3D-T1 MRI data were analyzed using voxelbased morphometry and surface-based analysis supported by the DR. Brain Platform. The male:female ratio was 38:73. The average age was 70.8 ± 10.6 years. The mild: moderate: severe ratio was 48:38:25. Total grey matter volume was significantly related to cognition while the relationship between white matter volume and cognition did not reach statistical significance. The volume of the temporal-parietal-occipital cortex was most strongly associated with cognitive decline in group analysis, while the hippocampus and entorhinal area had a less significant association with cognitive decline. Volume of subcortical grey matter was also associated with cognition. Volume and thickness of temporoparietal cortexes were significantly correlated with the cognitive decline, with a left predominance observed. Cognitive deterioration was associated with cortical atrophy. Volume and thickness of the left temporal-parietal-occipital cortex were most important in early diagnosis and longitudinal evaluation of AD in clinical practice. Cognitively relevant cortices were left predominant.

Comparison of Visual Rating Scale Based on Brain 18F-FDG-PET and Montreal Cognitive Assessment Test in Probable Alzheimer’s Disease

Objecives: Recently, imaging biomarkers like flouro-deoxi-glucose positron emission tomography (FDG-PET) become even more important for evaluation probable AD. The aim of this study was to evaluate the possible correlation between Montreal Cognitive Assessment Test (MoCA) and metabolic function of brain regions determined by FDG-PET in patients with probable AD. Materials and methods: Thirty seven (37) patients who had diagnosis of probable AD were included. MoCA test and metabolic measurements of brain regions by FDG-PET were performed in all patients. A visual scoring was performed to obtain the rates of hypometabolism in brain regions. Results: Median age of the patients was 77 (minimum 65-maximum 83) years. On the right hemisphere, MOCA test score decreased according to visual FDG-PET score of parietal lobe (15±5.1, 11.8±8.4 and 8.5±5.9; p=0.032). MOCA test score was 16±5.8, 13.1±7.6 and 9.1±6.1 in patients with left temporal lobe and 15.2±5.2, 11.8±7.8 and 8.5±5.9 in patients with left parietal lobe according to visual FDG-PET scores respectively (p=0.035; p=0.02). The comparison of the other right and left hemisphere regions and MOCA test scores were not significant. Conclusion: The present study is emphasized that the MoCA test which is easily applied in outpatient clinics can be demonstrated the hypometabolism of bilateral parietal and left temporal brain regions related with pathophysiology of AD.

The association of basal cortisol levels with episodic memory in older adults is mediated by executive function

Elevated basal cortisol levels in elderly may indicate dysregulation of the internal stress-related system, as well as dysfunction and structural alterations in brain structures necessary for cognition, such as hippocampus and prefrontal cortex. Because of the close relation of executive functions and episodic memory processing, in this study we explored whether the association of elevated cortisol levels on episodic memory could be partly attributed to cortisol effects on executive functions. In this cross-sectional study we analyzed data from a sample of 236 community-dwelling older adults from the Cretan Aging Cohort aged 75.56 ± 7.21 years [53 with dementia due to probable Alzheimer’s disease, 99 with Mild Cognitive Impairment (MCI) and 84 cognitively non-impaired participants (NI)]. Morning serum cortisol levels were higher in the probable AD as compared to the NI group (p = .031). Mediated regression models in the total sample supported the hypothesis that the negative association of basal cortisol levels with delayed memory was fully mediated by the relation of basal cortisol levels with executive functions and immediate memory (adjusted for age and self-reported depression symptoms). Moderated mediation regression models revealed that the direct effect of cortisol on executive function and the effect of executive function on delayed memory performance were statistically significant among participants diagnosed with MCI, while the immediate memory effect on delayed memory was more pronounced in AD patients, as compared to the NI group. The current findings corroborate neuroimaging research highlighting cortisol effects on executive functions and immediate memory and further suggest that dysregulation of systems involved in these functions may account for the purported detrimental long-term effects of high cortisol levels on delayed memory.