Baseline MMSE Research Articles

Association of modifiable risk factors with progression to dementia in relation to amyloid and tau pathology

BackgroundDementia preventive interventions targeting multiple modifiable risk factors are a promising approach. However, the impact of modifiable risk factors in the presence of beta-amyloid or phosphorylated-tau (p-tau) pathology is unclear.MethodsThe objective of the study was to examine the role of modifiable risk factors (vascular factors, depression, and smoking) in the progression to mild cognitive impairment (MCI) or dementia among 434 cognitively unimpaired (CU) and 611 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Vascular risk factors were summarized with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, dichotomized into higher versus lower risk. Depression and smoking (yes/no) were categorised according to medical history or current symptoms. Analyses were stratified by beta-amyloid negative (A-) and positive (A +), p-tau negative (T-) and positive (T +), or beta-amyloid and p-tau negative (A-T-) and positive (A + T +) biomarker status. Cox proportional hazard models were adjusted for age, sex, education, baseline MMSE score, baseline hippocampal volume and ApoE4 carrier status.ResultsHigher CAIDE score was associated with increased risk of progression to all-cause dementia in most MCI subgroups: adjusted hazard ratios (aHR) [95% CI] were 3.1 [1.43; 6.53] in the A- subgroup, 1.7 [1.20–2.27] in T + , 2.6 [1.06–6.59] in A-T-, and 1.6 [1.15–2.22] in the A + T + subgroup. Smoking (yes/no) was associated with increased dementia aHR in the A + MCI subgroup: 1.6 [1.07–2.34]. Depression increased dementia aHR in the T + MCI subgroup: 1.5 [1.06–2.02]. No significant associations were found in the CU biomarker subgroups.ConclusionAddressing modifiable risk factors carries an important potential for reducing the risk of dementia even after the onset of Alzheimer's pathology. Knowledge of biomarker status can further optimize prevention strategies.

CAPS: a simple clinical tool for β-amyloid positivity prediction in clinical Alzheimer syndrome.

With the advent of anti-β-amyloid therapies, clinical distinction between Aβ + and Aβ- in cognitive impairment is becoming increasingly important for stratifying referral and better utilization of biomarker assays. Cognitive profile, rate of decline, neuropsychiatric inventory questionnaire (NPI-Q), and imaging characteristics were collected from 52 subjects with possible/probable AD. Participants with Aβ+ status had lower baseline MMSE scores (24.50 vs. 26.85, p = 0.009) and higher total NPI-Q scores (2.73 vs. 1.18, p < 0.001). NPI-Q score was found to be the only independent predictor for β-amyloid positivity (p = 0.008). A simple scoring system, namely Clinical β-Amyloid Positivity Prediction Score (CAPS), was developed by using the following parameters: NPI-Q, rapidity of cognitive decline, and white matter microangiopathy. Data from 48 participants were included in the analysis of accuracy of CAPS. CAP Score of 3 or 4 successfully classified Aβ + individuals in 86.7% cases. Clinical β-Amyloid Positivity Prediction Score is a simple clinical tool for use in primary care and memory clinic settings to predict β-amyloid positivity in individuals with clinical Alzheimer Syndrome can potentially facilitate referral for Anti Aβ therapies.

Combined Neuroinflammation and Amyloid PET Markers in Predicting Disease Progression in Cognitively Impaired Subjects.

Neuroinflammation in Alzheimer's disease is known as an important process in the disease, yet how microglial activation affects disease progression remains unclear. The current study aims to interrogate the predictive value of neuroinflammation biomarker (11C-PBR28 PET), together with A/T/N imaging markers on disease deterioration in a cognitively impaired patient cohort. The study included 6 AD and 27 MCI patients, who had MRI, 11C-PBR28, 18F-flutemetamol (amyloid marker), 18F-AV1451 (tau marker) PET scans, and were followed up with multiple neuropsychological assessments for at least one year (1.6 and 2.8 years on average for AD and MCI). The predictive values of imaging biomarkers on baseline and longitudinal cognition were interrogated using linear regression to identify the biomarkers that could explain disease progression. Linear mixed models found the average intercepts (baseline) MMSE were 23.5 for AD and 28.2 for MCI patients, and the slope of MMSE (annual change) were -0.74 for AD and -0.52 for MCI patients. White matter microstructural integrity was predictive of baseline cognition, while PET markers of amyloid, tau and neuroinflammation were predictive of longitudinal cognitive decline. Both amyloid and neuroinflammation PET markers were predictors independent of each other. And a sub-group analysis showed the predictive effect of neuroinflammation on cognitive decline is independent of amyloid and tau. Our study highlights the prognostic value of disease specific markers (amyloid, tau and neuroinflammation) in clinically diagnosed AD and MCI patients and suggests that the effects of these molecular markers are mediated by structural damage to the brain.

Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Cerebrospinal fluid NPTX2 changes and relationship with regional brain metabolism metrics across mild cognitive impairment due to Alzheimer's disease.

Neuronal pentraxin-2 (NPTX2), crucial for synaptic functioning, declines in cerebrospinal fluid (CSF) as cognition deteriorates. The variations of CSF NPTX2 across mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and its association with brain metabolism remain elusive, albeit relevant for patient stratification and pathophysiological insights. We retrospectively analyzed 49 MCI-AD patients grouped by time until dementia (EMCI, n = 34 progressing within 2years; LMCI, n = 15 progressing later/stable at follow-up). We analyzed demographic variables, cognitive status (MMSE score), and CSF NPTX2 levels using a commercial ELISA assay in EMCI, LMCI, and a control group of age-/sex-matched individuals with other non-dementing disorders (OND). Using [18F]FDG PET scans for voxel-based analysis, we explored correlations between regional brain metabolism metrics and CSF NPTX2 levels in MCI-AD patients, accounting for age. Baseline and follow-up MMSE scores were lower in LMCI than EMCI (p value = 0.006 and p < 0.001). EMCI exhibited significantly higher CSF NPTX2 values than both LMCI (p = 0.028) and OND (p = 0.006). We found a significant positive correlation between NPTX2 values and metabolism of bilateral precuneus in MCI-AD patients (p < 0.005 at voxel level, p < 0.05 with family-wise error correction at the cluster level). Higher CSF NPTX2 in EMCI compared to controls and LMCI suggests compensatory synaptic responses to initial AD pathology. Disease progression sees these mechanisms overwhelmed, lowering CSF NPTX2 approaching dementia. Positive CSF NPTX2 correlation with precuneus glucose metabolism links to AD-related metabolic changes across MCI course. These findings posit CSF NPTX2 as a promising biomarker for both AD staging and progression risk stratification.

DO DEPRESSIVE SYMPTOMS MEDIATE SEGREGATION’S IMPACT ON COGNITIVE AGING IN OLDER MEXICAN AMERICANS?

Abstract Segregation in the United States has important implications for cognitive aging among Mexican Americans as a social determinant of health. Because segregation is systemically engrained, identifying more immediately modifiable mechanisms, such as depressive symptoms, that may underly segregation-cognition associations could point to intervention targets to reduce cognitive aging disparities. We used path mediation modeling to test whether depressive symptoms mediated (indirect effect) the segregation-cognition associations. We used H-EPESE data on older Mexican Americans from the first (n=3,050) wave and returning at wave 5 (n=1,167) combined with Census data from the National Neighborhood Data Archive, which provided indicators for county level segregation (isolation, interaction, dissimilarity). Cognition was operationalized as baseline MMSE, MMSE at wave 5, and change between baseline and wave 5. Depressive symptoms were measured by the CESD at baseline. Covariates included age, sex, and years of education. The sample was 58% female with an average age of 73.6 (SD=6.2) and an average 5-years education (SD=3.9). Higher dissimilarity (i.e., less exposure to non-Hispanic Whites) was associated with better baseline (B=.078, SE=.031, p=.012) and wave 5 cognition (B=.130, SE=.037, p&amp;lt;.001), independent of depressive symptoms. More depressive symptoms were associated with worse baseline and wave 5 cognition, independent of segregation indices (CESD B values range from -.063 to -.142, ps &amp;lt;.05). Depressive symptoms did not mediate segregation-cognition associations. Results suggest that there may be an enclave effect that is protective for both depressive symptoms and cognition in older Mexican Americans. Future research should examine additional biopsychosocial mechanisms underlying segregation-cognition associations.

Predicting cognitive decline in amyloid‐positive patients with mild cognitive impairment or mild dementia

AbstractBackgroundCognitive decline rates in Alzheimer’s disease (AD) vary greatly. Disease‐modifying treatments (DMT) may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid‐positive patients with mild cognitive impairment (MCI) or mild dementia.MethodsFrom the Amsterdam Dementia Cohort, we selected amyloid‐positive participants with MCI (n = 317, 66±7yrs, 45%Female, baseline MMSE 26±2) or mild dementia (n = 666, 65±7yrs, 49%Female, MMSE 22±4) and ≥2 annual MMSEs. Follow‐up was 3±2yrs with 4±2 MMSEs. Amyloid positivity was based on cerebrospinal fluid (CSF) AD biomarker concentrations or amyloid PET. We used linear mixed modelling to predict MMSE over time. First, decline trajectories were described with cubic time curves (S‐shaped). Then, we backwards selected predictors from baseline MMSE, age, sex, APOE ε4 dose, magnetic resonance imaging (MRI; visual scores: medial temporal lobe [MTA], global atrophy), CSF concentrations (phosphorylated tau [pTau], Aβ1‐42), and their interactions with linear time. MCI and mild dementia were modelled separately as stratification increased log‐likelihood.ResultsFor MCI and mild dementia, rates of cognitive decline increased over time. In MCI, average MMSE declined from 26.4(95%CI:26.2‐26.7) to 25.8(25.5‐26.1) after 18 months, to 24.2(23.7‐24.6) after three years, and to 21.0(20.1‐21.7) after five years. In mild dementia, MMSE declined from 22.4(95%CI:22.0‐22.6) to 19.8(19.4‐20.2), 15.3(14.6‐15.9), and 7.8(6.7‐8.9). For MCI, selected predictors of future MMSE were baseline MMSE, and interactions of time with age, MTA and pTau (table 1). For mild dementia, additional selected interactions with time were baseline MMSE, Aβ1‐42, and APOE ε4. Figure 1 shows the predicted decline distribution. As an example; predicted MMSE after three years for a 65yrs female MCI patient with baseline MMSE 27, would be 26.3 with MTA 0 and pTau 20pg/ml, compared to 23.8 with MTA 1 and pTau 40pg/ml (figure 2a;2b). In the latter case, 27% slower decline would lengthen follow‐up to a predicted MMSE of twenty by fourteen months.ConclusionWe constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and aid in conversations about DMT initiation and the evaluation of their potential effect.

Topline results of INTERCEPT‐AD: A phase I trial of Aβ oligomer‐targeting ACU193 in early Alzheimer’s disease

AbstractBackgroundACU193 is a humanized IgG2 subclass monoclonal antibody targeting soluble amyloid‐beta oligomers (sAβOs). Growing evidence supports the view that sAβOs may be the most toxic and pathogenic form of Aβ relative to Aβ monomers and amyloid plaques and are one of the primary drivers of Alzheimer’s disease (AD) neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 is a promising approach for treating AD.MethodINTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐ ascending dose (SAD/MAD) study of the safety, tolerability, and pharmacokinetics (PK) of intravenous ACU193 in participants with early AD, i.e., mild cognitive impairment or mild dementia due to AD. Key inclusion criteria are 55‐90 years of age, confirmation of amyloid pathology with a PET scan, MMSE score of 18‐30, and CDR‐Global score (CDR‐GS) of 0.5 or 1.0. The MAD portion of the study includes three administrations of ACU193 at doses of 10, 25, or 60 mg/kg. In addition to standard safety measures, MRI is assessed periodically. Cerebrospinal fluid is collected to assess PK and evidence of target engagement. The study also includes exploratory measures such as standard cognitive and functional assessments, a computerized cognitive test battery, measures of cerebral blood flow via arterial spin labeling on MRI, and various plasma biomarkers.ResultSixty‐five participants from 17 U.S. study sites were randomized to INTERCEPT‐AD, with 53% female and baseline age of 72.1 ± 7.8 years (mean ± SD). The baseline MMSE was 24.2 ± 3.6, CDR‐GS was 0.64 ± 0.27, and CDR‐Sum of Boxes was 3.5 ± 1.8. In addition to baseline characteristics, the presentation will provide topline safety results, frequency of amyloid‐related imaging abnormalities (ARIA), PK assessments, and evidence of target engagement. Some exploratory measures including cognitive and functional assessments, computerized cognitive testing, and endpoint florbetapir PET results will also be presented.ConclusionWe will present topline results, along with key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. The data generated from this trial will guide further development of ACU193 in a subsequent trial to test the novel mechanism of action of ACU193 in the treatment of early AD.

Apathy and dysfunction in Lewy Body Disease

AbstractBackgroundStudies in Alzheimer’s disease and frontal temporal lobe dementia have shown high prevalence and persistence of apathy at different disease stages and its strong association with functional decline. Here we use well‐established methods to examine the relationship between apathy and function in a cohort of well‐characterized patients with Lewy Body Disease (LBD) who had regular assessments over time.MethodSample includes participants in the National Alzheimer’s Coordinating Center Uniform Data Set (NACC‐UDS, 9/2005‐12/2019) who had at baseline (1) cognitive status of mild cognitive impairment (MCI) or dementia, (2) presumed etiologic diagnosis of LBD, and (3) ≥1 follow‐up. Baseline diagnosis of Parkinson’s disease (PD) was assessed. Apathy was identified using clinician judgment. Participants’ function was measured using the Functional Assessment Questionnaire (FAQ). Multivariable linear mixed model (LMM) was used to estimate relationships between apathy, cognitive status (baseline MCI vs dementia), and function over time.ResultThe sample included 339 participants with MCI and 748 with dementia. Average age = 72.7±8.3, 74% male, 86% non‐Hispanic white, 15.4±3.4 years of education, baseline MMSE = 23.7±5.8, with 3.4±1.7 years of follow‐up. Proportion of participants who reported difficulty with function at baseline ranged according to task complexity from 48% (Heating water, making a cup of coffee, turning off stove after use) to 85% (Assembling tax records, business affairs, or papers); with total FAQ = 13.0±9.1. Presence of apathy increased from 52% at baseline to 60% at visit 4. Across all follow‐ups, 24% of the participants were never apathetic, 13.7% had apathy intermittently (&lt;50% of all visits), 28.3% persistently (≥50% of all visits), and 34.0% were apathetic at all visits. LMM estimation results showed that, compared to participants who were never apathetic, FAQ was 3.8±0.8 points higher, i.e., greater dysfunction, at baseline in participants who were always apathetic, and 3.3±0.7 points higher in those who had intermittent/persistent apathy (both p&lt;0.001). Rate of functional decline was 0.41±0.3 points faster each year in those always apathetic compared to never apathetic (p&lt;0.1).ConclusionApathy is highly prevalent in individuals with LBD. Independent of cognitive status, more persistent apathy was strongly associated with worse function.

Associations between neuropsychiatric symptoms, pathology in neuropathological cohorts of Alzheimer’s disease, Alzheimer’s disease with Lewy bodies and Dementia with Lewy bodies

AbstractBackgroundNeuropsychiatric symptoms (NPS) are frequent in Alzheimer’s Disease dementia (ADD) but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co‐occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). Previous studies have shown that both ADLB and DLB cases have faster cognitive and/or functional decline compared to AD. However, the differences in NPS severity over disease course and survival in these pathologic subgroups is not well understood.MethodCases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a final neuropathologic diagnosis of DLB (±AD co‐pathology; n = 65), ADLB (n = 89), AD (without LB) (n = 140), and controls (no neuropathological diagnosis) (n = 82) were included. Total NPI‐Q (scores ranging from 0‐36) at time of enrollment and within 2.5 years of death were calculated for all groups. Statistical analysis utilizing ANCOVA (adjusting for age, sex, baseline MMSE and cognitive symptom duration) with pairwise comparisons, and Kaplan‐Meier curves were completed.ResultAge at onset of cognitive symptoms was not different between pathology groups. NPI‐Q scores at enrollment were highest in ADLB (7.33 ± 4.85), and higher (p&lt;0.001) than DLB (5.10 ± 3.37), AD (4.54 ± 3.63) and controls (1.78 ± 1.70). At final evaluation, NPI‐Q scores were highest in DLB (10.04 ± 6.28), followed by ADLB (8.0 ± 4.), and ADD (7.61 ± 5.05) when compared to controls (2.78 ± 3.97) (all p&lt;0.001). DLB and AD demonstrated significant increases in NPI‐Q severity during follow up (p &lt; 0.001). AD had longer survival time (5.8 years) compared to ADLB (4.0 years) and DLB (3.9 years). Subjects with NPS had a shorter median survival time (3.4 years) compared to subjects without NPS (6.5 years; p = 0.002).ConclusionA higher NPS burden and shorter survival is seen in both DLB and ADLB, as compared with AD. This suggests that diffuse neocortical LB pathology is not the major driver of either NPS or survival.

Decline in cognitive trajectories in the neuropathological spectrum of Lewy Body disease

AbstractBackgroundPathological Lewy body disease (LBD) may commonly present clinically as Parkinson’s disease dementia (PDD), Dementia with Lewy bodies (DLB) or Alzheimer’s disease dementia (ADD). Neuropathological definitions also include a group in which ADD is present, but the postmortem Lewy pathology does not meet threshold density and distribution levels for the neuropathological diagnosis of DLB (ADLB). Little is known about the cognitive profiles of patients with ADLB and despite common underlying pathology, studies delineating neuropsychological profiles in LBD are fraught with inconsistencies. We characterized the longitudinal cognitive trajectories defined by neuropsychological profiles in cases along the pathological spectrum of LBD.MethodCases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a cognitive diagnosis of dementia at death and who at minimum, had two neuropsychological evaluations were included. Final neuropathological diagnosis was determined as LBD (neocortical or limbic LB ± AD), ADLB, and AD pathology only. LBD cases were categorized by their cognitive clinical syndromes as PDD and DLB. Global cognition was evaluated using MMSE. Neuropsychological domains of Memory, Executive function, language, attention, and visuospatial were evaluated. Mixed linear methods were used to predict longitudinal change for a given baseline MMSE.Result287 participants and 1874 participant‐years of data were included in this study. LBD (n = 115), and ADLB (52) groups were predominantly male, while AD (n = 114) group was primarily female. Baseline MMSE was similar across all pathologic groups. Linear mixed modelling methods showed faster decrease in memory domain scores (decreasing 0.22 units/year – 0.42 units/year faster, p = 0.01) in ADLB group compared to other groups. Significantly faster decline was noted in LBD and ADLB group in clock drawing (p&lt;0.001), fluency scores (declining 1.02 unit/year faster p&lt;0.001) compared to AD group. There was no difference between PDD and DLB clinical subgroups.ConclusionIn autopsy confirmed cases, ADLB had an accelerated trajectory of decline in memory tasks, while AD, and LBD appeared to have similar trajectories. In contrast, all groups with Lewy bodies progressed faster and showed accelerated decline compared to AD in measures of frontal‐subcortical functions. These results may inform antemortem classification of patients and diagnostic accuracy in these groups.

Longitudinal robustness of resting‐state functional connectivity signatures across different stages of the Alzheimer’s disease continuum

AbstractBackgroundA growing number of resting‐state fMRI (rs‐fMRI) studies report changes in network activity to be a frequent and often early pathological feature in many neurodegenerative conditions. The majority of studies have primarily focused on changes in group averages, failing to account for individual functional connectivity (FC) idiosyncrasies that have been shown to provide a unique identifier or “fingerprint” in healthy individuals (Finn et al., 2015). It thus remains unclear to what extent FC‐signatures are stable in the context of cognitive decline and Alzheimer’s Disease (AD) pathology (e.g., β‐amyloid [Aβ] and tau). We studied the robustness of subject‐specific FC in a longitudinal cohort covering the AD spectrum.Method275 participants with longitudinal rs‐fMRI data—baseline plus a follow up after approximately two‐years—were selected from the Swedish BioFINDER‐2 cohort, split into six groups: cognitively normal (CN) Aβ‐, subjective cognitive decline (SCD) Aβ‐, SCD Aβ+, mild cognitive decline (MCI) Aβ‐, MCI Aβ+, and AD Aβ+. FC matrices were derived from each subject rs‐fMRI session using the Schaefer cortical parcellation (200 and 400 ROIs), and consequently, a 275×275 identifiability matrix (IM) was derived; see Fig. 1B. For each subject, two fingerprinting measures were extracted from the IM: self identifiability (I‐self) and differential identifiability (I‐diff); see Fig.1B.ResultI‐self and I‐diff show varied distributions across the six groups, but values remain notably high even within the AD Aβ+ (Fig.2A). Both I‐self and I‐diff show significant differences between CN Aβ‐ and AD Aβ+ (Fig.2B). SCD Aβ‐ not only show a greater difference to AD Aβ+, but also to SCD Aβ+ and MCI Aβ+; see Fig.2B. Baseline tau‐PET was associated with I‐self (r = ‐0.1928,p = 0.0014) and to a lesser degree with I‐diff (r = ‐0.1293, p = 0.0334), whereas baseline MMSE was only found associated to I‐self (r = 0.1671,p = 0.0055); neither I‐self nor I‐diff were associated with age (Fig.3).ConclusionOur results suggest that resting‐state FC is mostly stable under cognitive decline and presence of AD pathology. FC was most notably differentiable for SCD Aβ‐, suggesting it as a potential signature to decipher underlying cognitive status and to predict likelihood of future conversion to AD.

PK/PD analyses of ARIA‐E and isolated ARIA‐H in Lecanemab Clarity AD study

AbstractBackgroundClinical efficacy of lecanemab was confirmed in a Phase 3 trial (Clarity AD, NCT03887455), reducing markers of amyloid in early Alzheimer’s disease and slowing cognitive and functional decline as compared to placebo. However, some subjects experienced amyloid‐related imaging abnormalities (ARIA) associated with edema/effusion (ARIA‐E) or hemorrhage (ARIA‐H). PK/PD analyses were performed to explore the potential relationship between ARIA‐E and isolated ARIA‐H incidences with lecanemab exposure and key covariates.MethodThe Clarity AD trial randomized 1795 participants to receive lecanemab (N = 898, 10 mg/kg bi‐weekly) or placebo (N = 897). A total of 177 ARIA‐E incidences were observed from pooled Phase 2 (NCT01767311) and Phase 3 (Clarity AD) data. Additionally, a total of 150 participants from Clarity AD trial experienced treatment‐emergent isolated ARIA‐H (an ARIA‐H event without concurrent ARIA‐E). The ARIA‐E incidence rate was modeled as a function of lecanemab steady state exposures, and effects of potential covariates were explored. Graphical PK/PD analysis was performed to examine the relationship between isolated ARIA‐H and lecanemab steady‐state exposures.ResultThe observed ARIA‐E incidence was best modeled using lecanemab maximum concentration at steady‐state (Css,max) with ApoE4 genotype identified as a significant covariate. The model indicates a higher ARIA‐E incidence in homozygous carriers compared to non‐homozygous carriers or noncarriers (p&lt;0.0001). At mean lecanemab Css,max = 305 µg/ml in subjects receiving 10 mg/kg bi‐weekly in Clarity AD, the model predicted a 5.45% (95% CI: 3.75% ‐ 7.84%) incidence of ARIA‐E in noncarriers, 9.85% (95% CI: 7.96% ‐ 12.1%) in heterozygous, and 28.0% (95% CI: 22.6% ‐ 34.1%) in homozygous carriers. No other covariate explored (age, sex, race, baseline MMSE, or occurrence of anti‐drug antibodies) had a statistically significant effect on ARIA‐E incidence. For isolated ARIA‐H, the graphical analysis identified no apparent relationship between isolated ARIA‐H incidence with lecanemab exposure. Isolated ARIA‐H incidence was associated with ApoE4 genotype, with homozygous having the highest isolated ARIA‐H incidence.ConclusionThe incidence of ARIA‐E increased with lecanemab Css,max. The incidence rate of isolated ARIA‐H was demonstrated independent of lecanemab exposure. The ApoE4 genotype impacts both ARIA‐E and isolated ARIA‐H, with increased incidences in homozygous carriers compared to heterozygous carriers or non‐carriers.

Exposure‐response modeling to describe the change in brain amyloid following lecanemab administration in patients with early Alzheimer’s disease

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. Lecanemab has been tested as a disease‐modifying treatment for early Alzheimer’s disease in two clinical studies (NCT01767311 and CLARITY‐AD, NCT03887455). As part of these studies, amyloid PET scans were collected in a subset of patients, demonstrating that lecanemab leads to pronounced reduction in brain amyloid.MethodA model describing the relationship between serum lecanemab exposure and brain amyloid reduction from baseline was developed using data pooled from Phase 2 and 3 studies. Individual serum lecanemab exposure was estimated using a population PK model and correlated with amyloid PET using an indirect response model, with a lecanemab‐dependent increase in the degradation rate of amyloid, introduced as linear function. The model was parametrized in terms of baseline amyloid load, elimination rate constant for amyloid removal (Kout) and exposure effect (DESLP). Inter‐subject variability was estimated for each of the model parameters. Covariates were included in the model using a forward‐inclusion (p&lt;0.01) /backwards‐elimination (p&lt;0.001) approach.ResultA total of 4129 observations from 1088 subjects were included in the dataset. The model estimate of Kout was 0.0496 yr−1 (95% confidence interval: 0.0206, 0.0827), suggesting a re‐accumulation half‐life of brain amyloid of ∼14 years. APOE4 carrier status (homozygous and heterozygous together) was a statistically significant predictor of baseline amyloid (APOE4 noncarriers: 65 CL; APOE4 carriers: 83 CL). Age was a significant covariate on DESLP, with older patients removing amyloid at a faster rate than younger patients. None of the other covariates explored, including presence of antidrug antibodies or baseline MMSE score, had a statistically significant effect on any model parameter.ConclusionAn exposure‐response model has been developed that describes the change in brain amyloid over time during treatment with lecanemab and after stopping lecanemab treatment. This model provides additional insights into factors that may drive differences in the rate of brain amyloid removal between patients.

Neuropsychological and biomarker predictors of conversion to dementia in young‐onset Mild Cognitive Impairment

AbstractBackgroundMild Cognitive Impairment (MCI) is a clinical condition that captures the stage between normal aging and dementia along the continuum of cognitive impairment. While it is usually thought to be precursor of Alzheimer’s Disease, when occurring at young ages (i.e., before 65 years old) it may increase the risk of all forms of neurodegenerative dementing diseases. We studied which neuropsychological and biomarker characteristics are predictors of conversion to dementia in a sample of patients with young‐onset MCI.MethodSubjects with a diagnosis of MCI and early‐onset of cognitive symptoms (&lt; 65 yo) were recruited in a prospective longitudinal study. They underwent extended neuropsychological assessment, Magnetic Resonance Imaging with measurement of hippocampal volume, and lumbar puncture with measurements of cerebrospinal fluid (CSF) light‐chain neurofilaments (NFL), beta‐amyloid 1‐42, total‐ and phosphorylated‐tau. They were followed‐up clinically and repeated the neuropsychological evaluation at 18 months from the baseline. Statistical analyses were performed with Stata15. Each biomarker and neuropsychological variable were added in multivariate Cox regression models with age, sex, and education.Result84 young‐onset MCI patients were recruited. After 18 months, 26 converted to dementia while 58 remained stable (i.e., MCI). Preliminary analyses showed that baseline smaller bilateral hippocampal volumes, lower baseline MMSE scores, baseline worst performances in tests of language, verbal long‐term memory, and executive functions, as well as baseline elevated levels of CSF NFLs increased the risk of conversion to dementia. Among them, the higher risk was given by the Free and Cued Selective Reminding Test (FCSRT), the Corsi Supraspan, the Frontal Assessment Battery, and the CSF NFLs levels, as shown by spline regression analyses (Figure 1). Of note, the FCSRT delayed recall showed a U‐shaped relationship with the risk of conversion (i.e., not only low/bad performance but also high/good performance were both related to a higher risk of conversion) suggesting that the types of predicted conversion may be different.ConclusionOur results suggest that, in young‐onset MCI, a combination of CSF‐NFLs levels and baseline performance at long‐term memory tests may be predictive of conversion to dementia, either AD or FTD.

Do Subjects Not Meeting Screening Inclusion Criteria at Baseline Differ in Screening Performance in Diagnostic Tests in Early Dementia Clinical Trails?

AbstractBackgroundThe success of any clinical trial begins with ensuring that participants entering the trial meet the inclusion criteria and disease severity. Score manipulation to meet eligibility criteria may contribute to loss of signal in clinical trials. Based on our prior analyses of early Alzheimer’s disease (AD) clinical trials, over 10% of randomized participants likely had inflated MMSE scores at inclusion determination. In addition to ‘traditional’ instruments such as the MMSE or CDR, other ‘diagnostic’ instruments such as the RBANS, FCSRT and Wechsler Memory Scale are often used to select the study population. In the current analysis we explore the relationship between the performance on the diagnostic tests and the likely inflation in MMSE.MethodBaseline MMSE scores and Screening diagnostic tests results were pooled from 6,387 subjects from multiple clinical trials in early AD. Within each trial, participants’ performance on the diagnostic tests was broken into quartiles – best performers, second best, second worst and worst performers. Participants were also classified by their Baseline MMSE score as either meeting or being below the Screening MMSE inclusion criteria. A logistic regression was used to explore the association of the diagnostic test performance quartiles and Baseline MMSE score categories correcting for Screening MMSE score.Result1223 (19.2%) participants comprised the best performing quartile on the diagnostic tests. Comparatively, with each subsequent quartile, the odds of not meeting the Screening inclusion criteria at Baseline increased significantly ‐ by 1.4x in the 1666 participants (26.1%) in the second best, by 2.0x in the 1696 (26.6%) in the second worst, and by 2.4x in the 1800 (28.2%) in the worst quartile.ConclusionThis post‐hoc analysis identified increasingly significant odds of not meeting Screening MMSE related inclusion criteria at Baseline for each progressive quartile of worsening diagnostic test performance, when correcting for the Screening MMSE score. We suggest that despite the limitations of this post‐hoc analysis, outlying poor performance on the diagnostic tests should be considered a risk marker for possible score inflation and assessed in the whole context of the available data. Further work is necessary.

Serum brain-derived neurotrophic factor levels as a predictor for Alzheimer disease progression.

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of Alzheimer's disease (AD), and decreased peripheral levels of this protein are associated with an increased risk of developing the disease. This study focuses on whether serum BDNF levels could be used as a predictor of AD progression. In this longitudinal observational study, we recruited cognition normal participants (N=98) and AD (N=442) from the Clinic at the Taipei Veterans General Hospital. We conducted a mini-mental status exam, a 12-item memory test, a categorical verbal fluency test, and a modified 15-item Boston naming test. A Serum BDNF level and Apolipoprotein E (APOE) allele status were measured. The AD patients were followed prospectively. Based on the difference of MMSE scores, these patients were divided into fast decliners (decline ≧ 3/year) and slow decliners (MMSE decline < 3/year). Logistic regression was conducted to examine the impact of serum BDNF levels and other factor on the likelihood of AD patients being slow decliners. Pearson's correlation was used to estimate the relationship between serum BDNF levels and the score of neuropsychological tests. In a logistic regression model containing serum BDNF levels, age, sex, APOE4 carrier status, education levels, and baseline MMSE score, higher serum BDNF levels were associated with a slower rate of cognitive decline in the AD group. Serum BDNF levels positively correlated with the results of multiple neuropsychological tests. BDNF is a protective factor against AD progression and likely plays a role in establishing a link between AD pathology and clinical manifestations.

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.