Clinical Dementia Rating Sum Of Boxes Research Articles

Towards the future of ADRD diagnosis: combination of a brief digital cognitive battery and plasma biomarkers for diagnosis and prognosis of disease

AbstractBackgroundScalable and accurate diagnostic markers of Alzheimer’s disease and related dementias (ADRD) are urgently needed. A combination of a sensitive brief digital cognitive assessment and plasma biomarkers could represent a promising scalable alternative to standard diagnostic procedures. We evaluated the performance of the TabCAT Brain Health Assessment Cognitive Score (BHA‐CS) and plasma Aβ42/40, pTau‐181, NfL, and GFAP at predicting concurrent Aβ positivity on CSF or PET, concurrent disease severity, and future functional decline.MethodParticipants were 309 subjectively or objectively impaired older adults enrolled in longitudinal observational studies at UCSF (Table 1), who completed a blood draw and TabCAT‐BHA at baseline. Biomarker concentrations were measured using commercially available Quanterix kits. Receiver operating characteristic analyses were used to determine the accuracy of combined BHA‐CS and plasma biomarkers in discriminating between Aβ+/‐ status on CSF/PET at baseline. Multiple regressions were used to examine baseline associations of BHA‐CS and plasma markers with disease severity measured by Clinical Dementia Rating Sum of Boxes (CDR‐SB). Linear mixed effect models were used to examine the associations of baseline BHA‐CS and biomarker values with longitudinal decline on CDR‐SB. All analyses controlled for age, sex, education, and baseline diagnosis.ResultpTau‐181 was the strongest predictor of Aβ positivity (AUC = .745; 95%CI: .656‐.833), with no significant improvements in the AUC with the addition of any combination of markers (Figure 1). In a combined model with all markers included simultaneously, BHA‐CS (B = ‐0.678, P<.001) and plasma NfL (B = 0.625, P = .01) were the only unique significant predictors of concurrent CDR‐SB. In a combined mixed model with all markers included simultaneously, baseline BHA‐CS, pTau‐181, NfL, and GFAP were unique significant predictors of CDR‐SB decline (Figure 2), and together accounted for 27% of longitudinal variance in CDR‐SB.ConclusionOur findings indicate unique and complementary roles of scalable digital cognitive and plasma biomarkers as diagnostic and prognostic markers of ADRD. At baseline, whereas pTau‐181 was most accurate at predicting Aβ positivity, a combination of BHA‐CS and NfL was most accurate at predicting concurrent disease severity. In longitudinal analyses, a model that combined baseline cognitive testing results and plasma pTau‐181, NfL, and GFAP was most accurate at predicting future decline.

GRADUATE I AND II: Factors that may influence participant response to subcutaneous gantenerumab

AbstractBackgroundGRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two Phase III trials that investigated the efficacy and safety of gantenerumab, a subcutaneous fully human monoclonal antibody that binds aggregated forms of amyloid‐beta, in participants with early Alzheimer’s disease (AD). Although the studies did not meet their primary endpoints, participant characteristics that might influence response to gantenerumab were evaluated.MethodEligible participants with early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) were randomized 1:1 to receive gantenerumab or placebo. Gantenerumab‐treated participants were up‐titrated to 510 mg subcutaneous gantenerumab every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Secondary endpoints of cognition (ADAS‐Cog13) and function (ADCS‐ADL, FAQ) were assessed. Pre‐specified and exploratory post‐hoc subgroup analyses on these endpoints were performed.ResultAcross endpoints, there were consistent trends towards larger point estimates of gantenerumab treatment effect compared with placebo at Week 116 in males (using CDR‐SB as representative example: GRADUATE I: 16% relative reduction (RR); GRADUATE II: 17% RR) vs females (GRADUATE I: 3% RR; GRADUATE II: –2% RR) and participants with MCI (GRADUATE I:15% RR; GRADUATE II:10% RR) vs mild AD (GRADUATE I: 4% RR; GRADUATE II: 2% RR). This pattern was not consistently seen when using CDR‐Global Score (0.5 vs >0.5) to define disease stage. Compliers, defined as participants who received ≥90% of the intended cumulative dose, had an increased point estimate of treatment effect (CDR‐SB: GRADUATE I: 17% RR; GRADUATE II: 18% RR) vs non‐compliers (CDR‐SB: GRADUATE I: –1% RR; GRADUATE II: –3% RR). In a pooled analysis, a larger point estimate of treatment effect vs placebo was observed in East‐Asian vs Non‐East‐Asian countries (CDR‐SB: RR 38% vs 5%). The East‐Asian population had lower baseline weight, greater treatment compliance, and accordingly higher plasma exposure, than the Non‐East‐Asian population, suggesting this observation is not driven by racial differences in treatment response.ConclusionSubgroup analyses in the GRADUATE studies provide insights into participant characteristics that may influence the degree of clinical response to gantenerumab treatment. Higher gantenerumab exposure may result in greater clinical efficacy.

Developing Topics.

Alzheimer's disease (AD) is a multifactorial disease including pre-clinical, prodromal and clinical phases. CSF "A/T/N" (Ab42, pTau181, tTau) biomarkers help characterize the biological state of AD. The primary aim was to assess contributions of eight CSF markers for predicting changes in cognition. CSF from 237 participants (CN: 176[74.3%], MCI: 33[13.9%], AD: 28[11.8%]) of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing was used to measure Ab42 (GenII assay), pTau181, and tTau (Elecsys®) along with neurogranin, neurofilament light (NFL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells-2 (sTREM2), s100 calcium-binding protein B (s100B), and interleukin-6 (IL-6) from the NeuroToolKit (NTK) panel of exploratory prototype assays (all Roche Diagnostics International Ltd). NTK biomarker concentrations were measured amongst each of four ATN groups at baseline; 1) A-/T-/N- (reference group), 2) A+/T±/N± (amyloid+), 3) A-/T±/N± (amyloid-), and 4) A+/T+/N+. Change in cognition was assessed using the pre-clinical Alzheimer's cognitive composite (PACC) and the clinical dementia rating sum of boxes (CDR-SB) scores, in all four ATN groups, stratified by low/high NTK biomarker over a minimum of 36 months. The primary outcome was defined as change in cognition in amyloid+ participants modulated by the addition of NTK markers to ATN groups. A+/T+/N+ participants had faster cognitive decline on both PACC and CDR-SB over time compared to all other groups (Figure 1A, PACC; Figure 1B, CDR-SB). Within the amyloid+ group, participants with high sTREM2 (K+) had a faster rate of decline in PACC compared to those with low sTREM2 (K-, p = 0.04; Figure 1C), whilst participants with high α-synuclein had a faster increase in CDR-SB compared with those with low α-synuclein (p = 0.005; Figure 1D). Amongst participants who were A+/T+/N+, those with high YKL40 had a significantly faster rate of decline in PACC (p = 0.017; Figure 1E), and a faster increase in CDR-SB, (p = 0.017; Figure 1F) compared with those who with low YKL40. Biomarkers of microglial activation (sTREM2), synaptic function and synuclein metabolism (α-synuclein), and astrocytic activation (YKL-40) may be appropriate to discern rates of cognitive change within amyloid+ participants. Findings are being validated in a separate population.

Efficacy results from the unique long‐term randomised controlled double‐blind LipiDiDiet trial with a multinutrient intervention in prodromal AD/MCI_AD

AbstractBackgroundLifestyle factors such as nutrition and diet are modifiable risk factors for the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). A small number of interventions recently showed cognitive and functional benefits. It is unclear however how long these benefits will last, requiring long‐term studies.LipiDiDiet was the first AD double‐blind, placebo‐controlled trial clinical trial to show a significant and sustainable benefit, including a 45% reduction in decline on CDR‐SB performance in a prodromal study population evaluating a multinutrient formulation (Soininen Lancet Neurology 2017; Soininen Alz&Dem 2021). We now extended the analysis from 3 years to up to 6 years of active intervention to investigate long‐term effects.MethodLipiDiDiet is a 6‐year randomised, double‐blind, placebo‐controlled trial, investigating the effects of a nutritional intervention in individuals with prodromal AD/MCIAD. 311 individuals with prodromal AD (IWG‐1) were randomized to active (125ml once‐a‐day drink; Fortasyn Connect [Souvenaid]) or a calorie‐matched control. Following the first 2 years of intervention, participants could opt‐in for annual extensions up to a maximum of 6‐year double‐blind intervention. Individual participants progressing to mild dementia were provided AD medication and/or open‐label active product and could continue in the trial. Main outcomes included Neuropsychological Test Battery (NTB) composites on cognition and memory, and the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Modified intention‐to‐treat analyses were performed over 4‐6 years of intervention using a joint model combining longitudinal and survival data.ResultAdding data from all participants who completed the 4‐year visit while still on double‐blind treatment (n = 38) to the previously performed joint model analyses on the 3‐year data showed that the initially observed benefits on cognition, memory, and CDR‐SB appear to have continued beyond 3 years. These and other ongoing analyses are addressing the statistical challenges specific to long‐term AD trials including non‐random patterns of missing data.ConclusionIn addition to the already demonstrated sustainable benefits of Fortasyn Connect in individuals with prodromal AD/MCIAD, combined with feasibility of its long‐term use without indications for health concerns, we now report first results indicating that benefits on cognition, memory, and CDR‐SB are sustained over 4 years.

Changing the trajectory of Alzheimer’s disease: What is a meaningful delay in disease progression?

AbstractBackgroundRecent trials of anti‐amyloid therapies have shown it is possible to change the course of early symptomatic Alzheimer’s disease (AD). However, the limited durations of these trials with the associated limited decline in the patient populations have left questions about the clinical meaningfulness of the observed treatment differences. Through progression analysis, one can quantify trial results in terms of time delay of progression. Compared to treatment differences on clinical scales, time delays are arguably more interpretable to patients and their families. However, it is yet to be established what constitutes a meaningful time delay in AD progression.MethodAssess how different hypothetical delays in disease progression in early symptomatic AD translate into treatment differences on the Clinical Dementia Rating Sum of Boxes (CDR‐SB) based on published results placebo‐arm trajectories in recent anti‐amyloid trials. Estimates are compared to published estimates of minimal clinically important differences (MCIDs) in AD and meaningful delays in progression in other diseases.ResultBased on placebo arms from six recent trials of anti‐amyloid antibodies, a 6‐month delay over 18 months (33% slowing) corresponded to treatment differences on CDR‐SB between ‐0.5 and ‐0.8, a 12‐month delay (67% slowing) corresponded to treatment differences between ‐1.0 and ‐1.7, and completely stopping progression (18‐month delay) corresponded to treatment differences between ‐1.6 and ‐2.3 (Figure 1, Table 1). Observed treatment effects in the EMERGE, CLARITY‐AD and TRAILBLAZER‐ALZ trials are consistent with approximately 4‐6 months delay of progression (22‐30% slowing, Figure 1). Established MCIDs in CDR‐SB in early AD range between 1.0 and 1.6, suggesting that a 12‐month delay or 67% slowing of disease progression in an 18‐month trial would be considered borderline in terms of clinical meaningfulness.ConclusionQuantifying treatment effects in progressive diseases such as AD in terms of time delays or slowing of progression may offer a more meaningful interpretation of the treatment effects. Based on the trajectories of placebo group in recent trials, we found that treatment effects matching conventionally used MCIDs in AD would correspond to a very substantial slowing of disease (>67%), suggesting that current MCIDs for CDR‐SB are likely inflated.

Clinical and neuroimaging predictors of Alzheimer’s Dementia Conversion in patients with mild cognitive impairment using 18F‐Florapronol amyloid PET by quantitative analysis over 2 years

AbstractBackgroundPatients with mild cognitive impairment(MCI) are a clinically important group because of the increased risk for the progression to Alzheimer’s dementia(AD). Amyloid positron emission tomography(PET) was useful as a predictor for identifying AD pathology in the pre‐dementia stage. We determined the rates of conversion to AD in MCI patients based on amyloid positivity by visual and quantitative analysis over 2 years. We also investigated the clinical and neuroimaging predictors for conversion to AD.MethodIndividuals aged 50 and above with MCI according to Petersen’s criteria were eligible. Subjects underwent laboratory tests including APOE genotyping, neuropsychological tests, brain magnetic resonance imaging(MRI), and amyloid PET assessed by 18F‐FC119S. Amyloid positivity was determined in each lobe of the brain and quantitatively analyzed. The follow‐up period was at least 2 years. Cox regression analysis was performed to identify prognostic factors which are independently related to time to AD conversion.ResultWe recruited 50 patients and 39 subjects were enrolled. 5 patients dropped out at 2 years, so 34 subjects were finally included. 13 of 34(38.2%) by visual analysis and 12 of 34(35.3%) by quantitative analysis of 18F‐FC119S PET showed amyloid positive. The basic demographics were not significantly different between the groups except for Korea‐Instrumental Activities of Daily Living(K‐IADL) at baseline(p = 0.004) and 1 year(p = 0.001), Mini‐mental State Examination(MMSE) at 2 years(p = 0.047) and Global Deterioration Scale(GDS) at 2 years(p = 0.029). 4 of 13(30.8%) by visual analysis, 4 of 12(66.7%) by quantitative analysis amyloid‐positive MCI patients converted to AD. Amyloid positive in posterior cingulate was marginally significant(p = 0.066). AD conversion group had a higher Clinical Dementia Rating‐Sum of box(CDR‐SOB) at baseline(p = 0.002) compared with remained MCI group. In multivariate cox regression, CDR‐SOB at baseline, MMSE at 1 year and K‐IADL at 2 years were included.ConclusionAmyloid‐positive MCI group was more likely to progress to AD. But long‐term follow‐up was required. By quantitative analysis of 18F‐FC119S PET, amyloid deposition in posterior cingulate was highly associated with the AD conversion group. CDR‐SOB at baseline, MMSE at 1 year and K‐IADL at 2 years were considered as clinically valuable prognostic predictors of disease progression. Especially, CDR‐SOB is important as a predictive biomarker in the pre‐dementia stage.

Re‐estimation of drug‐specific amyloid removal parameters and the rate constant for pathogenic tau turnover brings the Q‐ATN model into better alignment with recent phase 3 data from gantenerumab and lecanemab

AbstractBackgroundThe Q‐ATN model (Mazer et al., Alzheimer’s & Dementia. 2022; https://doi.org/10.1002/alz/12877) is a quantitative semi‐mechanistic representation of the A (amyloid)/T (tau)/N (neurodegeneration) framework for simulating the natural history of Alzheimer’s disease and the effects of anti‐amyloid treatment. The recently reported phase 3 trials of gantenerumab (GRADUATE 1&2) and lecanemab (CLARITY) provide additional data to update model parameters and assess the assumptions of the model.MethodThe drug‐specific amyloid removal parameters (αrem) for gantenerumab and lecanemab were re‐estimated from the mean amyloid PET data in GRADUATE 1&2 and CLARITY. Using the new αrem values, Q‐ATN simulations of the Clinical Dementia Rating – Sum of Boxes (CDR‐SB) and tau PET trajectories were made for each study. The rate constant for pathogenic tau turnover (ktau), which was uncertain due to limited data, was re‐estimated using a sensitivity analysis of the CDR‐SB treatment effects. Results from the aducanumab EMERGE and ENGAGE studies were also included in the analysis.ResultThe simulated increase in amyloid PET agreed well with the mean data from the placebo groups. For GRADUATE 1&2, αrem was 34% and 41% lower, respectively, than the prior value (0.0137 Yr−1/(ug/mL)) estimated from the gantenerumab open‐label extension studies. For CLARITY, αrem was 26% lower than the prior value (0.0109 Yr−1/(ug/mL)) estimated from the lecanemab phase 2 study. For GRADUATE 1&2, the simulated CDR‐SB trajectories for the placebo groups were in good agreement with the observed increases from baseline. For CLARITY, the simulation overestimated the observed increase. The re‐estimated value of ktau (0.2 Yr−1), which corresponds to a 3.5 Yr half‐life, yielded treatment effect sizes on CDR‐SB within the 95% confidence intervals for all treatment arms (N = 7). The prior value (0.5 Yr−1) yielded treatment effect sizes that were too large in three cases (see Figure). Tau PET simulations (with ktau = 0.2 Yr−1) were consistent with medial temporal ROI data from lecanemab and aducanumab; tau PET data from gantenerumab are pending.ConclusionThe updated αrem and ktau parameters bring the Q‐ATN model into better alignment with recent phase 3 data. Forthcoming data from the Donanemab TRAILBLAZER‐ALZ 2 study could further help assess the model assumptions.

Interpreting trial results in an era of disease‐modifying therapies: Efficacy of approved anti‐amyloid drugs in the context of the long‐term Alzheimer’s trajectory

AbstractBackgroundEarly‐stage Alzheimer’s disease (AD) typically presents with slow progression of clinical symptoms. Approved high‐potency anti‐amyloid‐β (Aβ) therapies have demonstrated changes in the disease trajectory in these early stages and offer potential benefits beyond the period for which they have been studied in trials.MethodsBased on published results, the time‐slowing of disease progression based on change in CDR sum of boxes (CDR‐SB) was approximated. Disease progression modeling using long‐term cohort data was used to estimate the natural history trajectory of CDR‐SB in AD from the preclinical stages to severe dementia. Modeling of trial inclusion criteria was used to estimate the interval of the natural history trajectory of AD that were included in trials and different scenarios for long‐term treatment effects were explored.ResultsIn positive phase 3 studies, the high‐potency anti‐Aβ therapies appeared to slow disease progression 20‐30% resulting in a 4‐6‐month delay of progression during the 18‐month study period. Included patient populations were found to differ substantially, with the EMERGE and ENGAGE studies including an earlier group of patients than CLARITY‐AD. Consistent with trial subgroup analyses, natural‐history modeling suggested that more progressed patients would see an apparent greater absolute benefit during 18 months, but less absolute benefit over longer durations. Under an assumption of continued slowing beyond the study period, a treatment slowing disease progression by 30% (5.4 months delay in disease progression after 18 months) would lead to treatment differences on CDR‐SB of ‐0.42 and ‐0.72 points for typical MCI and mild dementia patients. With continued slowing beyond the length of the trial, typical MCI patients would have a treatment effect of ‐0.96 points once reaching the same disease stage as the mild dementia patients. Five‐year treatment differences would be approximately ‐2.5 and ‐3.2 points, well beyond all estimates of clinically meaningful differences. Even in the most conservative disease‐modifying scenario assuming no increased time delay after 18 months, observed treatment differences would still increase beyond 18 months due to the nonlinear trajectory of CDR‐SB.ConclusionDisease‐modifying effects of the magnitude observed in recent trials can potentially translate into clearly meaningful differences over a longer duration.

Plasma p‐tau and brain‐derived total tau biomarkers predict longitudinal changes in Aβ, tau, and cognition across the AD continuum

AbstractBackgroundRecent studies have suggested that plasma p‐tau biomarkers are associated with cross‐sectional brain amyloid(Aβ) rather than tau tangle pathology. However, it is still unclear if plasma tau biomarkers are closely related to changes in AD pathophysiology over time. In this work, we aimed to determine if cross‐sectional measures of plasma tau biomarkers are associated with longitudinal changes in Aβ‐PET, tau‐PET, and cognition across the AD spectrum.MethodWe evaluated 157 individuals(96 cognitively unimpaired(CU) and 61 cognitively impaired (CI)) with available baseline measures of plasma Aβ42/40, p‐tau(at threonine 181, 217+, and 231), N‐terminal tau fragments(NTA, a new brain derived tau marker), and glial fibrillary acidic protein(GFAP) and with longitudinal [18F]AZD4694 Aβ‐PET, [18F]MK6340 tau‐PET and Clinical Dementia Rating sum of boxes(CDR‐SB) score from the TRIAD cohort. We also included 321(118 CU and 203 CI) individuals from the ADNI cohort with baseline plasma p‐tau181 and [18F]florbetapir Aβ‐PET and longitudinal CDR‐SB. Using linear regressions adjusted for age and sex we tested the associations between plasma biomarkers and longitudinal changes in Aβ‐PET, tau‐PET, and CDR‐SB.ResultIn CU, changes in tau‐PET were significantly associated only with plasma p‐tau217+(β = 0.331, p<0.01,Figure1A). Changes in Aβ‐PET were significantly associated with p‐tau181(β = 0.594, p<0.01,Figure2A), p‐tau217+(β = 0.311, p = 0.02) and NTA(β = 0.435, p<0.01), while no plasma biomarker was associated with changes in cognition in CU(Figure3A). In CI, changes in tau‐PET were significantly associated with plasma p‐tau181(β = ‐0.338, p = 0.03,Figure1B) and NTA(β = ‐0.379, p = 0.03), while no plasma biomarker was significantly associated with changes in Aβ‐PET. Changes in cognition were significantly associated with plasma p‐tau181(β = 0.340, p = 0.01, Figure3B), p‐tau217+(β = 0.54, p<0.01), and NTA(β = 0.530, p<0.01). Similarly, in the ADNI cohort, plasma p‐tau181 was associated with longitudinal changes in cognition in CI (β = 0.247, p<0.01,Figure3D).ConclusionWe demonstrate that cross‐sectional measures of plasma p‐tau and NTA biomarkers were associated with longitudinal Aβ deposition and tau accumulation in CU, while in CI they were only associated with tau accumulation. Interestingly, plasma tau biomarkers were also associated with changes in cognition in CI individuals. The fact that abnormal levels of plasma tau biomarkers are associated with longitudinal changes in AD pathophysiology has implications for the use of these markers in clinical trials and practice.

Impact of sex and ApoE4 on the longitudinal association of plasma ptau‐181 and NFL with cognitive decline in non‐demented older adults

AbstractBackgroundAPOE4 is a strong genetic risk factor for Alzheimer’s disease (AD). Sex‐dependent differences has been shown in AD pathophysiology and clinical course. Here, we aim to assess the association between longitudinal changes in ptau‐181 and neurofilament light protein (NfL) and concurrent changes in cognitive measures in non‐demented individuals and to evaluate if this association is impacted by sex and ApoE4 status.MethodParticipants (N = 738) were non‐demented (cognitively unimpaired or mild cognitive impairment) older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 738) with up to 4ys of longitudinal data. Linear Mixed Effects (LME) models were used to study the effect of ptau‐181 and NFL on cognition as measured by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐cog11; Range 0‐70) and Clinical Dementia Rating, sum of boxes (CDR‐SB). Sex by time and APOE4 by time interactions were assessed in the models for the entire sample. Analyses was repeated after separately stratifying sample by sex and APOE4.ResultAt baseline, both ADAS‐11 and CDRSB values correlated with plasma p‐Tau181 and NfL measures (Table 1). The longitudinal change in plasma p‐Tau181 correlated only with baseline CDR‐SB while that of NfL correlated with baseline ADAS‐11. The APOE4*time interaction, but not sex‐time interaction, were significant in LME models of both p‐Tau181 and NFL (Table 2). When stratified by sex, in females longitudinal increase in p‐Tau181 was associated with cognitive decline measured by both ADAS‐11 and CDR‐SB. In males, longitudinal increase in p‐Tau181 was associated with increase in ADAS‐11 scores and NfL was associated with cognitive decline on both outcomes. When stratified by APOE4 status, longitudinal changes in plasma biomarkers were only associated with cognitive decline in the APOE4+ subsample.ConclusionPlasma NfL and pTau increase during early AD and can be used to monitor disease progression. The relationship between increase in plasma ptau‐181 and NFL levels and worsening of cognition is affected by APOE4 status.

Correlations between daily activities and the Korean‐Everyday cognition, and the Gottfreis‐Bråne‐Steen scale in the patient complaint with cognitive decline

AbstractBackgroundTo get the right diagnosis of dementia, clinicians need a wealth of information from the patient and their caregivers, as well as objective examinations. Some questionnaires may provide sufficient information to be obtained by interviewing. The Everyday Cognition (ECog), and the Gottfreis‐Bråne‐Steen (GBS) scale were developed to measure functional changes in cognitive decline patients through the caregiver’s report. This study aims to evaluate the usefulness of theses scales in the dementia clinic.MethodThe Korean‐ECog (K‐ECog), and GBS scale was answered by 100 caregivers from patients with cognitive decline. Results of neuropsychological tests, and clinical information were collected. Correlation analyses were conducted between K‐ECog, GBS, Korean version of instrumental activities of daily living (K‐IADL), Clinical dementia rating‐sum of boxes (CDR‐SB), global deterioration scale, and other detailed cognitive tests.ResultThis study included 97 patients, including 54 dementia, 34 mild cognitive impairment, and 9 subjective memory impairment. The K‐ECog, and GBS had moderate correlations with K‐IADL, and CDR‐SB. The K‐ECog and GBS had strong correlation each other. And GBS score was effectively differentiated dementia patients from non‐demented patients, respectively.ConclusionThe two scales, the K‐ECog, and GBS, are well represented cognitive dysfunctions of the daily activities in the patients with cognitive decline, as with the K‐IADL, CDR‐SB. Therefore, these scales can make it easier to understand the patient’s daily cognitive state and diagnose the disease relatively quickly and with little effort.

Blood‐based biomarkers of Alzheimer disease as measured by a mass spectrometry assay are as accurate as CSF tests

AbstractBackgroundEspecially because disease‐modifying treatments (DMTs) for Alzheimer disease (AD) are likely to become more available soon, highly accurate AD blood tests for use in clinical diagnosis are critically needed. Although amyloid PET scans and cerebrospinal fluid (CSF) tests are highly accurate in the identification of individuals with brain amyloidosis, blood tests are likely the only test modality that will enable an adequate scale of AD biomarker testing. Mass spectrometry‐based AD blood tests have consistently demonstrated very high performance.MethodsResearch participants enrolled in studies at the Knight Alzheimer Disease Research Center who underwent amyloid PET and measurement of established CSF biomarkers of AD with Lumipulse automated assays were included. The presence and severity of dementia was evaluated with the Clinical Dementia Rating® (CDR®) and Clinical Dementia Rating Sum of Boxes (CDR‐SB). Plasma samples collected at the same session as CSF underwent analysis for specific phosphorylated and non‐phosphorylated tau species with an immunoprecipitation‐mass spectrometry assay. Plasma T217 occupancy was calculated as the percent of phosphorylated to non‐phosphorylated tau at threonine 217.ResultsThe study cohort included 337 individuals with an average age of 69.8 ± 8.3 years (mean ± standard deviation); 175 (52%) were female, 128 (38%) were APOE ε4 carriers, 112 (33%) were amyloid PET positive, and 50 (15%) were cognitively impaired. Classification accuracy of amyloid PET status was equivalent for plasma T217 occupancy (AUC 0.973) and CSF Aβ42/Aβ40 (AUC 0.970), (p = 0.72 for the difference). Interestingly, plasma T217 occupancy more accurately classified individuals as cognitively impaired (CDR>0) or cognitively unimpaired (CDR 0), with an AUC of 0.876 versus 0.814 for CSF Aβ42/Aβ40 (p = 0.006 for the difference). Further, plasma T217 occupancy was better correlated with dementia severity as measured by the CDR‐SB (Spearman ρ = 0.455 versus ‐0.338 for CSF Aβ42/Aβ40, p = 0.02).ConclusionPlasma T217 occupancy as measured by mass spectrometry had equivalent classification accuracy of amyloid PET status compared to Lumipulse CSF Aβ42/Aβ40. Notably, plasma T217 occupancy was more strongly associated with cognitive impairment and dementia severity than CSF Aβ42/Aβ40. Overall, these data suggest that some AD blood tests have equivalent or better performance characteristics than clinically used CSF tests.

A polygenic risk score (PRS) predicts cognitive decline in the APOE3 population in an early Alzheimer’s disease clinical trial cohort

AbstractBackgroundAlzheimer’s disease (AD) is one of the most common forms of dementia globally and is defined by accumulation of extracellular amyloid plaques and intracellular tau‐containing neurofibrillary tangles in neuronal cells. These pathological changes occur more than a decade prior to symptom onset. Given that disease modifying therapies are geared towards asymptomatic/early AD patients, identification of asymptomatic individuals at risk of progression is key. Genome‐Wide Association Studies(GWAS) for AD have implicated many single nucleotide polymorphisms (SNPs) associated with disease risk. Whereas a minority of early onset AD cases are driven by mutations in genes, sporadic AD cases have complex genetic architecture and are highly heritable. Polygenic Risk Scores (PRS), which aggregate genome‐wide risk loci, have been shown to predict AD onset with AUCs of 75‐84%.MethodsThe PRS approach used in this study is built from a sum of weighted contributions of over 100,000s SNPs associated with disease. We utilized PRS (genoSCORE™) to predict cognitive function decline in a cohort of 280 AD patients in a Ph2 clinical trial for Tilavonemab, a monoclonal antibody targeting the N‐terminus of human tau. Additionally, genoTOR™ was calculated to identify pathways most impacted by the genetic variants enriched in the cohort.ResultsGiven that tilavonemab did not alter Clinical Dementia Rating‐Sum of Boxes(CDR‐SB), we tested differences in cognitive decline between high PRS and low PRS individuals defined using a threshold of 0.6 in the entire cohort and found no difference. Upon stratification by APOE status, higher PRS(> = 0.6) predicted an increase in CDR‐SB of an average of 1.0 at week 72 (p<0.1) and week 96 (p<0.05) compared to participants with lower PRS(<0.6) within the APOE3 population. Additional analyses of the genoTOR™ signaling pathways are ongoing.ConclusionsThe results of these analyses demonstrate that genoSCORE™ may be helpful to enrich for APOE3 individuals most susceptible to cognitive decline over time. Since the majority of genetic risk studies have focused on an APOE4 population, this method provides a novel tool to enrich for individuals at high risk for cognitive decline over time in a less studied population in which there is difficulty with prediction of disease progression.

Evaluation of NLRP3 and NLRP1 inflammasome pathways in patients with Alzheimer’s disease: a clinicopathological study

AbstractBackgroundA growing body of evidence has suggested a detrimental role of NLRP1 and NLRP3 inflammasome in experimental AD. However, the characterization of these pathways in AD human brains is still missing. We aimed to characterize the hippocampal expression of the NLRP1 and NLRP3 inflammasomes in individuals with AD neuropathological change (ADNC) compared to age‐ and sex‐matched controls. We also sought to investigate the association of the expression of these proteins with cognitive abilities and AD‐pathology.MethodThe expression of NLRP1, NLRP3, caspase‐1, ASC, and hyperphosphorylated tau (p‐tau) was evaluated in the cornu ammonis (CA), dentate gyrus (DG), and subiculum (SUB) of individuals with pure AD and controls (n = 28 per group), using immunohistochemistry. The percentage of the immunostained area (IA) and the optical density (OD) of the staining were quantified through semiautomatic morphometry. Cognitive abilities were evaluated using the Clinical Dementia Rating – sum of boxes (CDR‐SB) and the AD‐pathology was based on Braak staging and the Consortium to Establish a Registry for AD (CERAD) criteria. We applied the Mann‐Whitney test to compare control with ADNC hippocampi, linear regression to examine the association of inflammasome proteins with cognition and AD‐pathology, and Spearman coefficient to examine the correlation of these proteins with p‐tau.ResultSociodemographic and clinical variables were similar between the groups (Table 1). NLRP1 and caspase‐1 expression was predominant in neurons, while ASC was detected in glial cells. NLRP3 was expressed in neurons and glia. NLRP1 and NLRP3 deposits were observed in neuritic plaques. Except for NLRP1, all the inflammasome proteins were overexpressed in CA and SUB of individuals with ADNC compared to controls (p<0.05) (Figure 1). CDR‐SB and CERAD criteria were associated with increased IA for NLRP3, caspase‐1, and ASC; the Braak stage was associated with higher expression of caspase‐1 and ASC (p<0.05, Table 2). Interestingly, NLRP3 (r = ‐0.52, p = 0.009) and ASC expression (r = ‐0.43, p = 0.004) correlated negatively with OD of p‐tau immunostaining in the CA of individuals with ADNCConclusionNLRP3 inflammasome pathway is up‐regulated in the ADNC hippocampi and was associated with AD‐pathology. Our results suggest that NLRP3 inflammasome contributes to cognitive impairment in AD.

Clinical Manifestations.

It is unclear whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) represent the two ends of a clinical continuum or exist as distinct syndromic entities with specific pathologic/prognostic correlates. We aimed to characterize the main clinical features along the spectrum of progressive non-fluent speech-language disorders (nf-SLD) and explore the existence of data-driven symptom clusters with etiological/prognostic value. We included 98 participants presenting with progressive motor speech impairment and/or agrammatism, of which 43 had an autopsy-confirmed neuropathological diagnosis. Speech pathologists rated motor speech features indicative of dysarthria and AOS. Quantitative measures of expressive/receptive agrammatism were obtained and compared with healthy controls. Baseline and longitudinal disease severity was assessed with the Clinical Dementia Rating sum-of-boxes (CDR-SB). We explored the clustering tendency of the data to form robust symptom clusters and used principal component analysis to extract data-driven clinical components. The longitudinal CDR-SB change was estimated with linear mixed-effects models. Ninety-one participants fitted previously reported clinical profiles (69 AOS+agrammatism, 18 PPAOS and 4 PAA), while 7 remained unclassifiable and were characterized by nonfluent speech and dysarthria in the absence of apraxia of speech or agrammatism. None of the baseline clinical features discriminated between FTLD subgroups. The Hopkins statistic ruled out the existence of syndromic clusters in the whole sample. Three data-driven components explained 71% of the variance ([i]severity-agrammatism, [ii]AOS, and [iii]dysarthria). The component characterized by prominent dysarthria was more specific to patients with Progressive Supranuclear Palsy while the component characterized by severity-agrammatism predicted a faster CDR-SB increase. Our results suggest that nf-SLD represents a clinical continuum. Splitting this continuum into different clinical phenotypes based on its major clinical features does not improve clinical-pathological correlations, stressing the need for new clinical and biological markers. The term nf-SLD could be used to group together these speech-language phenotypes strongly associated with FTLD.

Tau PET accumulation in Brodmann areas 35 and 36 is associated with individual differences in cognition in non‐demented older adults

AbstractBackgroundMounting evidence indicates that tau accumulation in the entorhinal cortex (EC) occurs early in the course of Alzheimer’s disease (AD). Recent advances in automated segmentation methods allow for the investigation of smaller regions of the medial temporal lobes (MTL), including subregions of the EC. This study examined tau deposition in relation to individual differences in cognition among older adults, assessing whether MTL subregions explained a greater proportion of variance in cognition, when compared to standard labeling methods.MethodAnalyses included 91 BIOCARD study participants who were cognitively unimpaired (CU; n = 82) or had mild cognitive impairment (MCI; n = 9). Stepwise linear regressions were used to examine the contributions of regional tau burden to individual differences in the CDR sum of boxes (CDR‐SB), MMSE, and composite scores of global cognition and memory. Other model variables included amyloid burden, APOE4 status, sex, and education. Amyloid burden was assessed by 11C‐PiB and regional tau was assessed by 18F‐MK‐6240 PET. SUVR values representing tau accumulation were extracted using two MRI segmentation methods: (1) the FreeSurfer‐derived EC label, and (2) Automatic Segmentation of Hippocampal Subfields (ASHS)‐derived MTL subregions, including the EC and Brodmann areas 35 and 36 (Br35, Br36) defined in 1mm‐MNI space. Partial volume correction was applied to the motion‐corrected PET data.ResultTau burden in the right Br35, right Br36, and age were significant predictors of CDR‐SB scores, with the greatest proportion of variance explained when all three were included. The FreeSurfer‐labeled EC and other variables did not significantly contribute to the model. Right Br36 and age were significant predictors of MMSE while right Br36 and APOE4 status were significant predictors of the global cognition composite score, and right Br36 was a significant predictor of the memory composite score. Follow‐up analyses showed that addition of the FreeSurfer EC region did not significantly contribute to any of the models.ConclusionQuantifying tau burden in Br35 and Br36 better accounted for individual variability in cognition, when compared to standard EC labeling approaches. This suggests tau burden in these subregions may help identify CU and MCI individuals who are on a trajectory of decline due to AD.

Sex‐specific plasma markers of cholesterol‐metabolism and plant sterols predict cognitive decline in older people – a ten years follow‐up study

AbstractBackgroundMultiple studies in clinical settings show that there is a link between a dysregulation of cholesterol metabolism and neurodegenerative pathologies and dementia. Diet‐based plant sterols may also interfere with neurodegeneration and cognitive decline through cholesterol‐lowering properties. In this study, we investigate whether circulating levels of cholesterol, its precursors, and metabolites, as well as triglycerides, and phytosterols predict cognitive decline ten years later in the general population. As a secondary objective we address the role of sex and the APOE genotype on these relationships.MethodWe considered 206 individuals aged 65 and older from a population‐based prospective study from Lausanne, Switzerland. A comprehensive cognitive assessment was performed at baseline and after ten years. We quantified the plasma levels of cholesterol, high‐density lipoprotein (HDL‐) cholesterol, triglyceride, cholesterol precursors (lathosterol, lanosterol, desmosterol, dihydrolanosterol), cholesterol derivatives (cholestanol), oxysterols (24S‐hydroxycholesterol [24S‐OHC], 7α‐hydroxycholesterol, 27‐hydroxycholesterol), and phytosterols (campesterol, campestanol, stigmasterol, sitosterol, sitostanol and brassicasterol) at baseline and after five years. Regression analysis (considering several possible confounder including APOE‐genotype) determined the relationship between baseline sterol levels, and their changes between baseline and five‐year follow‐up, with measures of cognitive decline (i.e. changes in Clinical Dementia Rating (CDR), Mini‐Mental State Exam and CDR Sum of Boxes) at ten years. Analyses were performed in the whole cohort, and in males and females independently.ResultHigher levels of baseline HDL‐cholesterol and lanosterol were associated with cognitive decline after ten years in the whole cohort. Decrease over time of 24S‐OHC was also associated with cognitive decline. In males, several cholesterol‐related sterols (cholestanol, lathosterol, lanosterol, 7α‐hydroxy‐cholesterol) and the phytosterol sitosterol were associated with cognitive decline. In females, only cholesterol and campestanol were associated with cognitive decline. The APOE genotype did not affect these associations.ConclusionIn this cohort of older people from the general population, plasma markers of cholesterol synthesis and metabolism and as well as phytosterols are associated with cognitive decline after ten years. These findings have potential relevance for sex‐specific risk assessment and prevention of cognitive decline in older people.

The relationship between executive dysfunction‐associated activities of daily living (ADL) and the pattern of Clinical Dementia Rating (CDR) in patients with vascular dementia and age‐matched patients with Alzheimer’s disease

AbstractBackgroundClinical dementia rating (CDR) scale was originally developed to stage the severity of Alzheimer’s dementia (AD) but is now used globally regardless of types of dementia. This study aims to investigate the relationship between the characteristic pattern of CDR domains, neuropsychological findings, and activities of daily living (ADL) in patients with vascular dementia (VaD), compared with age‐matched patients with AD.MethodVery mild to mild VaD and AD patients matched for age were recruited among the first visitors to a dementia clinic. All subjects were administered a standardized clinical interview, physical and neurological examinations, and laboratory tests including the brain MRI according to the protocol of the Korean version of the CERAD assessment battery.ResultOne hundred and five pairs of VaD and AD patients participated in this study. Although the adjusted scores on MMSE were similar between two groups and the performances on Boston naming, word list memory, word list recall, word list recognition, constructional recall test were better in VaD patients, the scores on global CDR, CDR sum of box (SOB), and ADL‐related CDR domains were higher in VaD patients than in AD patients (p<0.001). The poor performances on disability assessment for dementia scale, frontal assessment battery, executive clock drawing task, and Stroop tests were observed in VaD patients.ConclusionDespite similar general cognitive function and better memory function, patients with VaD tend to be staged as severer dementia on the CDR scale than patients with AD because of more impaired ADL associated with executive dysfunction.

Rate of clinical progression in mixed Limbic‐Predominant Age‐Related TDP‐43 Encephalopathy (LATE) and Alzheimer disease

AbstractBackgroundLimbic predominant age‐related encephalopathy neuropathologic change (LATE‐NC) is associated with amnestic type dementia. LATE‐NC frequently coexists with Alzheimer disease neuropathologic change (ADNC). It is unclear whether LATE and Alzheimer disease neuropathologic change interact or independently affect clinical disease progression.MethodsData was from 80 autopsied participants with TDP‐43 immunohistochemical studies from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention. We used linear mixed effects models to estimate associations of ADNC and LATE‐NC with rate of progression of Clinical Dementia Rating Sum of Boxes (CDR‐SB) and investigated whether co‐occurrence of these two pathologies would modify these trends.ResultsParticipants in our sample were 42% female with mean age at death of 77.8 years (SD 9.6). Neuropathologic diagnoses were low/intermediate ADNC in 20 (25%), high ADNC in 29 (36%), LATE‐NC in 8 (10%), and LATE‐NC + high ADNC in 23 (29%) participants. Clinical progression of cognitive impairment was faster in participants with high ADNC than in those LATE‐NC (Slopes:1.82 units/year [95% CI: 0.93‐2.71] vs 1.33 units/year [95% CI: 0.29‐2.38]) (Figure). Co‐occurrence of LATE‐NC + high ADNC predicted similar progression than high ADNC alone (Slope: 1.83 units/year [95% CI: ‐0.45 – 4.12]) demonstrating interaction (p = 0.013) between LATE‐NC and high ADNC.ConclusionLATE‐NC and ADNC are independently associated with clinical progression of cognitive impairment. Co‐occurrence of LATE‐NC and high ADNC is expected to have similar clinical progression than ADNC alone. Research is ongoing to examine differences among these groups using T1‐weighted volumetric imaging and CSF glial activation biomarkers.

CSF Plasminogen inhibitor 1(PAI‐1) levels are associated with dementia symptoms in Alzheimer disease

AbstractBackgroundThere are currently excellent fluid biomarkers of brain amyloidosis, including CSF Aβ42/Aβ40 and CSF pT217/T217 (%). However, many individuals with brain amyloidosis do not have symptoms of Alzheimer disease (AD). Biomarkers that are strongly associated not only with brain amyloidosis but also with symptomatic AD would be invaluable tool in clinical trials and clinical diagnosis. We evaluated whether CSF biomarkers in an immunoassay panel added value to existing biomarkers in prediction of cognitive impairment.MethodAn immunoassay panel from Rules Based Medicine was used to measure CSF levels of 52 proteins including plasminogen inhibitor 1 (PAI1). CSF Aβ42/Aβ40 was measured by Lumipulse, and CSF pT217/T217 (%) was measured by an immunoprecipitation‐mass spectrometry assay. Logistic regression and linear models were used to evaluate the association between biomarkers and cognitive status (cognitively unimpaired or symptomatic AD as defined by a Clinical Dementia Rating [CDR] of 0.5 or greater), the Mini‐Mental State Exam [MMSE] score, and CDR Sum of Boxes [CDR‐SB]. Models included the covariates of age, self‐identified gender, and years of education.ResultThe cohort included n = 179 older research participants (average age 73.0 years, standard deviation 6.6 years), of which 47 (26%) had cognitive impairment (CDR>0). Cognitively impaired individuals had higher levels of PAI1 (p = 1.18e‐05) (Fig. 1A). PAI1 levels predicted cognitive status in the entire cohort (p = 4e10−3) and the sub‐cohort with CSF Aβ42/Aβ40 levels consistent with brain amyloidosis (Aβ42/Aβ40<0.0673; p = 0.003). Even when CSF pT217/T217 (%) was included in the model of cognitive status, PAI1 was a significant independent predictor of cognitive status in both the entire cohort (p = 0.005) and the sub‐cohort with brain amyloidosis (p = 0.008) (Fig. 1B). Both the MMSE and CDR‐SB were associated with PAI1 in the entire cohort (p = 1.86e‐07 and p = 5.45e‐07), and the sub‐cohort with brain amyloidosis (p = 2.44e‐05 and p = 4.77E‐05) (Fig. 1C‐D). When CSF pT217/T217 (%) was included in the model, both the MMSE and CDR‐SB remained associated with PAI1 in the entire cohort (p = 8.85e‐06 and p = 3.02e‐05) and the sub‐cohort with brain amyloidosis (p = 0.0001 and p = 0.0003).ConclusionThese results demonstrate that CSF PAI1 is associated with symptomatic AD and adds value to CSF pT217/T217 in predicting AD symptoms.