Biomarkers.

BackgroundSecond-generation tau tracers for positron emission tomography (PET) show high affinity for paired helical filaments tau deposits characteristic of Alzheimer´s disease and low off-target binding. Differences in their chemical structure though may lead to variations in their regional tau uptake and off-target signal. In this work, we aimed to compare the in-vivo uptake of tau tracers [18F]PI-2620 and [18F]RO948 in the early stages of the AD continuum.MethodsData from the TAU-PET FACEHBI clinical trial (EUDRA-CT 2021–000473-83) were analyzed. All participants were non-demented and underwent tau imaging with [18F]PI-2620 and [18F]RO948 PET within 3 months, amyloid imaging with [18F]Florbetaben and brain magnetic resonance imaging. Tau PET standardized uptake values ratios (SUVR) were calculated in Braak and typical off-target regions using the inferior cerebellar cortex as a reference region.ResultsThe cohort consisted of 18 individuals with subjective cognitive decline (n = 13) and mild cognitive impairment (n = 5), with centiloid values ranging from 17 to 159. Both tau tracers showed similar tau pathology distribution but presented a distinct off-target signal pattern on visual read. SUVR measurements for [18F]PI-2620 and [18F]RO948 were highly correlated in all Braak regions (R2 range [0.65–0.80]). Regarding off-target signal, [18F]PI-2620 had higher SUVRs in vascular structures, and [18F]RO948 had higher SUVRs in the skull/meninges.ConclusionsIn a cohort of individuals at early stages of the AD continuum, tau PET tracers [18F]PI-2620 and [18F]RO948 showed similar in-vivo uptake in all Braak regions and distinct off-target signal. These preliminary results support the development of standardized quantification scales for tau deposition that are tracer-independent.Trial registrationAEMPS EudraCT 2021–000473-83. Registered 30 December 2021.

Background and objectives: Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia, and can be divided into amnestic and non-amnestic types. Patients with amnestic MCI present with memory impairments that are often considered as the early manifestation of Alzheimer’s disease. Patients with amnestic MCI are more likely to progress to Alzheimer’s disease than patients with non-amnestic MCI. The U.S. Food and Drug Administration has not yet approved any drug that can treat amnestic MCI. Moxibustion is a common noninvasive traditional oriental intervention, which uses mainly the heat generated by burning herbal preparations containing moxa and mugwort (Artemisia vulgaris) to simulate acupoints for alleviating the symptoms. To date, many clinical studies have investigated the clinical use of moxibustion to improve memory impairments of Alzheimer’s disease, but these have failed to make a distinction between amnestic and non-amnestic MCI. Therefore, this trial has been designed to assess the effectiveness of moxibustion on amnestic MCI using the Montreal Cognitive Assessment Scale. We will also assess the safety of moxibustion in healthy controls, and analyze the variation of brain functional connectivity and effective brain networks in patients with amnestic MCI undergoing moxibustion using function magnetic resonance imaging. Design: This is a prospective, single-center, randomized controlled clinical trial. Methods: This study will enroll 64 patients with amnestic MCI and 48 healthy controls at Baoan People’s Hospital, Shenzhen, China. The first 64 recruited patients with amnestic MCI will be randomly divided into moxibustion, placebo moxibustion, drug, and control groups (n = 16 per group). In the moxibustion group, patients will be given moxa-wool moxibustion for 12 consecutive weeks. The placebo moxibustion group will receive placebo moxibustion on the same acupoints. Patients in the drug group will be given oral administration of donepezil hydrochloride tablets, 5 mg daily, for 12 consecutive weeks. The control group will receive no intervention. Forty-eight healthy controls will also be randomly assigned into moxibustion, placebo moxibustion, and control groups (n = 16 per group). Interventions will be the same as those received by the patients with amnestic MCI. Evaluators will be blind to group allocation. Outcome measures and preliminary results: The primary outcome measure will be the improvement in cognitive function 12 months after treatment. Secondary outcome measures will be the scores on the Montreal Cognitive Assessment Scale, Clinical Dementia Rating Scale, Mini-Mental State Examination Scale, and Activity of Daily Living Scale before treatment, after 12 weeks of treatment, and 6 months after the end of treatment, as well as brain function analysis before treatment and after 12 weeks of treatment and adverse events during treatment and follow-up. A correlation analysis between cognitive function scores and brain function results will be performed. Results of our preliminary study involving 60 patients with amnestic MCI who experienced moxibustion or received no treatment showed that moxibustion on acupoints significantly improved cognitive ability and quality of sleep in patients relative to the baseline and compared with the control group. Moreover, the scores on attention and delayed recall in the moxibustion group after treatment were significantly higher than those at base line. In the control group the scores on visual space, execution, and delayed recall were significantly lower than those at baseline. These findings indicate that moxibustion improves patient’s attention and delayed recall. If not, visual space, execution, and delayed recall in MCI patients tend to be declined over time. No obvious adverse responses to moxibustion treatment occurred in the preliminary study. Discussion: This proposed trial has the potential to uncover that moxibustion will enhance cognitive-related brain function connections and effector brain networks, which is not yet known. If moxibustion is shown to be an effective and safe treatment strategy in patients with amnestic MCI, then this may pave the way for use of this treatment in clinic amnestic MCI. Ethics and dissemination: This study was approved by the Medical Ethics Committee of the Chinese Clinical Trial Registry (approval No. ChiECRCT-2017018) in October 2016, and registered on April 2017. The study was designed in June 2016. Patient recruitment was initialized in October 2016. Data analysis will be completed in December 2019. Results will be disseminated through publication in a peer-reviewed journal. Protocol version: 1.0. Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-POC-17011162).

Neuropsychological comparison of incident MCI and prevalent MCI

The recently developed cognitive change checklist (3CL) is comprised of four scales titled memory, executive, language, and remote recall. A previous study demonstrated that the checklist met criteria for reliability and validity in characterizing cases of mild cognitive impairment (MCI) and early dementia in a memory disorder clinic sample. In this study we examined further the reliability, validity, and efficacy of the 3CL in distinguishing among groups of normal individuals, those with cognitive complaints, amnestic and non-amnestic MCI cases, and early-stage demented individuals. Scale validation study. Alzheimer's Disease Research Center One hundred and twenty-five individuals who completed extensive evaluations as part of a longitudinal study of cognitive change. Scale reliabilities were found to be well within guidelines to support their use in the clinical assessment of change in global and specific cognitive domains. The factor structure of the 3CL was found to be highly similar to that originally reported. Validation support was obtained from correlational analyses that showed significant scale relationships with neurocognitive measures and with MRI ratings of medial temporal atrophy. Informant 3CL scales were found to discriminate individuals with cognitive complaints but without clinical findings from those individuals with amnestic MCI or early dementia. Results extend the foundation of support for the use of the 3CL as a measure to facilitate identification of cases of MCI and early AD. Further examination of the diagnostic utility of the scale, and of its value in combination with cognitive screening measures, will also be required.

BackgroundHyperphosphorylated tau isoforms (p‐tau) in cerebrospinal fluid (CSF) and plasma represent promising measures to monitor Alzheimer disease (AD) pathological changes. Brain amyloid deposition precedes tau aggregation and associated clinical decline by two decades. Several CSF and plasma p‐tau isoforms have been described as potential surrogates for tau Positron Emission Tomography (PET) imaging, but p‐tau isoforms have a strong association with amyloid PET, and increase without tau pathology. In this study, we investigated the relationship between multiple CSF p‐tau isoforms and brain imaging measures in the Knight ADRC cohort.MethodWe analyzed 10 p‐tau isoforms by mass spectrometry in 1932 CSF samples (1173 participants). Associated data includes 1250 amyloid PET and 442 tau PET scans, as well as CSF Aβ42/Aβ40 by immunoassay for all samples. We measured phosphorylation occupancies (ptau/tau) at T111, T153, T175, T181, S199, S202, T205, S208, T217 and T231, together with corresponding p‐tau and tau concentrations. We compared the accuracy of CSF p‐tau isoforms in predicting amyloid PET and tau PET status stratified according to amyloid PET, tau PET and/or Clinical Dementia Rating (CDR) status.ResultsPT217/T217 best‐predicted abnormal amyloid PET (AUROC=0.980) or CSF Aβ42/Aβ40 (AUC=0.954). PT217/T217 predicted brain amyloidosis in asymptomatic and symptomatic participants with similar accuracy (AUC=0.979 and 0.986 respectively) and was correlated with amyloid PET centiloid and CSF Aβ42/Aβ40 (Spearman R=0.73 and ‐0.76, p<0.0001). Notably, the correlation between pT217/T217 and amyloid PET centiloid was higher in amyloid PET(+)/tau PET(‐) compared to amyloid PET(+)/tau‐PET(+) (R=0.77, p<0.0001 versus 0.16, p=0.007). PT205/T205 and pT217/T217 better predicted tau PET positivity in amyloid PET(+)positive participants (AUC=0.908 and 0.866). These markers were also associated with tau PET signal in tau PET(+) participants (R=0.53 and 0.55 p<0.0001). Other p‐tau isoforms also predicted amyloidosis, except for T175, S199, S202 and T205. Only pT205/T205 and pT217/T217 were correlated with tau‐PET in tau PET(+) participants.ConclusionThese results suggest that tau hyperphosphorylation, notably at T217, is more strongly associated with brain amyloid burden than tau deposition in tau PET(‐) individuals. After tau PET becomes positive, p‐tau217 and p‐tau205 are correlated with tau burden. Soluble p‐tau are markers of both amyloid and tau aggregation in the AD brain.

BackgroundGosuranemab is a humanized monoclonal antibody that is hypothesized to neutralize extracellular tau and prevent the trans‐neuronal propagation of tau pathology across the brain. The TANGO study is an ongoing randomized, placebo‐controlled, global Phase 2 study evaluating safety and clinical efficacy of gosuranemab in individuals diagnosed with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or mild AD dementia. The TANGO study included two biomarker sub‐studies: cerebrospinal fluid (CSF) sub‐study and Tau positron emission tomography (PET) sub‐study; the baseline characteristics of the Tau PET sub‐study are described below.MethodTANGO enrolled 654 individuals aged 50‐80 years, diagnosed with MCI or mild AD, who were amyloid positive as assessed by amyloid PET or CSF testing. Approximately 350 patients enrolled in the longitudinal 18F‐MK‐6240 Tau PET sub‐study. Randomization was stratified by biomarker sub‐study participation among other factors. Baseline standardized uptake value ratio (SUVR) was measured in composite brain regions of interest (ROIs) corresponding to Braak I‐II, Braak III‐IV, and Braak V‐VI regions using superior‐eroded cerebellum as the reference region. Tau extent (percentage of supra‐threshold voxels within an ROI relative to reference region), an exploratory measure of the spatial extent of 18F‐MK‐6240 binding, was also investigated.ResultThe baseline demographics of the Tau PET sub‐study population were consistent with the overall TANGO study population including clinical stage (MCI vs. mild AD), age, gender, APOE4, and clinical scores. At baseline, average SUVR (±SD) was 1.92±0.6 in Braak I‐II, 1.90±0.7 in Braak III‐IV and 1.75±0.8 in Braak V‐VI composite ROIs. The Braak composite SUVRs were positively associated with disease stage (i.e. higher SUVR with increasing disease severity). Exploratory analyses of extent were supportive of the SUVR results.ConclusionAt study baseline, tau SUVR was highest in Braak I‐II, followed by Braak III‐IV, then Braak V‐VI. Cross‐sectionally, higher tau PET SUVR was associated with increasing disease severity and worse clinical scores, as expected. The TANGO Tau PET sub‐study will aid our understanding of gosuranemab’s effect on tau pathology and further inform on the value of tau PET in clinical trials.

Objective To identify the differences inneuropsychological characteristics between amnestic(AMCI)and vascular mild cognitive impairment(VMCI). Methods Totally 297 old community residents with mild cognitive impairment(MCI)were divided into amnestic MCI(AMCI)and vascular MCI(VMCI)subgroup from Guangzhou MCI prevalence survey.The elderly with MCI were interviewed and tested with the Chinese version of Montreal Cognitive Assessment(MoCA), the Mini-Mental state examination(MMSE), Auditory Verbal Learning Test(AVLT), the Clinical Dementia Rating scale(CDR), Functional Activity Questionnaire(FAQ), the Modified Hachinski Ischemic Scale(M-HIS), Center for Epidemiologic Studies(CES-DC)to evaluate neuropsychological characteristics. Results AMCI versus VMCI group showed that the total scores of MoCA were(9.63±5.17 vs.9.98±6.02), total scores of MMSE were(16.90±4.84 vs.16.90±6.19), AVLT immediate memory was(2.35±1.39 vs.2.91±1.84), AVLT delayed recall was(2.23±2.09 vs.2.47±2.20), AVLT delayed recognition was(7.33±3.98 vs.6.85±4.02)and total scores of CDR(0.5 vs.0.5), with no differences between the 2 groups(all P>0.05). Based on MoCA survey, AMCI versus VMCI group showed statistically significant differences(all P<0.05)in parameters of visual space and execution(0.71±1.02 vs.0.92±1.26), language function(0.34±0.56 vs.0.50±0.80)and abstract thinking(0.25±0.49 vs.0.15±0.43), but based on MMSE survey, no difference was found in the various cognitive domains between the two groups.The AMCI versus VMCI group showed statistically significant differences(all P<0.05)in parameters of CES-DC scale(1.75±4.27 vs.2.76±6.72), FAQ scale(4.42±4.66 vs.8.71±7.03), M-HIS scale(0.40±0.64 vs.7.59±3.53). Conclusions There is no significant difference in general cognitive impairment between AMCI and VMCI, but the visual space and execution, language function are more impaired in AMCI than VMCI, and the abstract thinking, social function are more impaired with more depressive symptoms in VMCI than in AMCI. Key words: Cognition disorders; Neuropsychological tests; Amnesia; Blood vessels

Regional cortical atrophy in depression and neurocognitive disorders.

This study aimed to explore the potential of whole brain white matter patterns as novel neuroimaging biomarkers for assessing cognitive impairment and disability in older adults. We conducted an in-depth analysis of magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) scans in 454 participants, focusing on white matter patterns and white matter inter-subject variability (WM-ISV). The white matter pattern ensemble model, combining MRI and amyloid PET, demonstrated a significantly higher classification performance for cognitive impairment and disability. Participants with Alzheimer's disease (AD) exhibited higher WM-ISV than participants with subjective cognitive decline, mild cognitive impairment, and vascular dementia. Furthermore, WM-ISV correlated significantly with blood-based biomarkers (such as glial fibrillary acidic protein and phosphorylated tau-217 [p-tau217]), and cognitive function and disability scores. Our results suggest that white matter pattern analysis has significant potential as an adjunct neuroimaging biomarker for clinical decision-making and determining cognitive impairment and disability. The ensemble model combined both magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) and demonstrated a significantly higher classification performance for cognitive impairment and disability. Alzheimer's disease (AD) revealed a notably higher heterogeneity compared to that in subjective cognitive decline, mild cognitive impairment, or vascular dementia. White matter inter-subject variability (WM-ISV) was significantly correlated with blood-based biomarkers (glial fibrillary acidic protein and phosphorylated tau-217 [p-tau217]) and with the polygenic risk score for AD. White matter pattern analysis has significant potential as an adjunct neuroimaging biomarker for clinical decision-making processes and determining cognitive impairment and disability.

Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model – neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-β PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.

Subjective cognitive decline (SCD) is an established predictor of neurocognitive disorders (NCD) (i.e. mild cognitive impairment and dementia). Yet, its construct remains contentious. Many individuals with SCD do not progress to NCD, leading to an alternative term in the literature - 'functional cognitive disorders' - to describe the SCD experience in these individuals. This study examined the distinct differences in trajectories of subjective cognitive decline (SCD), between those who did and did not eventually develop NCD. This case-control study included 5,167 participants aged ≥50 years, followed-up near-annually to evaluate for SCD and NCD (median follow-up=8.1 years; range=1.0-18.0). Cases were defined as those who developed incident NCD during follow-up; controls completed ≥10 years of follow-up and had normal cognition throughout follow-up period. SCD trajectories were modelled with mixed-effect logistic regression, using a backward timescale. Those who developed NCD (cases) had new onset of SCD within past 20 years, which became particularly noticeable 13-14 years before diagnosis, and became even more prominent in the last 4 years. Those who did not develop NCD (controls) reported SCD since younger age, with the probability of SCD remaining constant over time. The distinctive trajectories were consistent across Alzheimer's & non-Alzheimer's disease, and among those with higher baseline rates of SCD due to psychiatric conditions. SCD has distinctive trajectories among those who do and do not progress to NCD. The distinctive trajectories can inform NCD risk for early interventions, and guide public health messaging to distinguish high-risk SCD from normal ageing. Future SCD scales may possibly need to evaluate for symptom changes over a longer, 20-year horizon to better capture new onset of SCD within this longer timeframe.

BackgroundEfficient identification of older adults with Mild Cognitive Impairment (MCI), including MCI due to AD, is a pressing challenge. Remote methods to accurately identify older adults with MCI are a promising approach. Subjective cognitive decline (SCD), reported by individuals and their study partners, can be efficiently collected remotely.MethodsIn 1286 older adults in the Brain Health Registry (BHR, Table 1), using logistic regression, we determined the accuracy of online self‐report mood (Geriatric Depression Scale Short Form, GDS), family history of AD, Everyday Cognition Scale (ECog) as a measure of SCD, and Cogstate Brief Battery one card learning (OCL) accuray to distinguish (1) Cognitively‐unimpaired (CU) from MCI, and (2) CU from b‐amyloid (Ab)+ MCI. In a subset of 289 participants with enrolled study partners, we measured the contribution of study partner‐report SCD to predicting diagnostic category, and the correlation between self‐ and study partner‐report SCD. Models covaried for age, gender, and education level.ResultsSelf‐ and study partner‐report SCD scores were moderately correlated (r=0.44); associations between the two measures were significantly lower in participants with higher GDS scores, indicating more depressive symptoms (p=0.03). Models including self‐ and study partner‐report SCD and Cogstate OCL scores had the highest accuracy for distinguishing CU from all MCI, as well as CU from Ab+ MCI (AUC=0.90 for CU vs MCI; AUC=0.93 for CU vs Ab+ MCI). Models excluding study partner‐report SCD had moderate accuracy at diagnostic classification (AUC=0.81 for CU vs MCI; AUC=0.83 for CU vs Ab+ MCI). Models excluding all SCD measures, and instead relying on OCL accuracy scores, had lower accuracy (AUC=0.73 for CU vs MCI; AUC=0.76 for CU vs Ab+ MCI). Model outputs are summarized in Table 2.ConclusionsRemotely‐collected self‐ and study partner‐report SCD accurately distinguish CU from MCI, as well as CU from biomarker positive MCI. SCD measures perform well in identifying MCI, even in the absence of objective cognitive measures. Results support utilization of remote SCD measures to identify older adults for prodromal AD clinical trials, and who are suitable candidates to receive future anti‐amyloid therapeutics.

Fluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease. To characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET). Between 2010 and 2019, 322 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent CSF and PET assessments of tau pathology. Data-driven, clinically relevant thresholds for CSF phosphorylated tau (P-tau) (≥26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio ≥1.37) indicated participants' tau status as CSF-/PET-, CSF+/PET-, CSF-/PET+, and CSF+/PET+. Of 1659 ADNI participants with a CSF or flortaucipir assessment, 588 had both measures (1071 were excluded). Among these, 266 were further excluded because they did not have flortaucipir and CSF testing within less than 25 months, leaving 322 for analysis. Of these, 213 were cognitively unimpaired (CU); 98 had mild cognitive impairment (MCI); and 11 had AD dementia. We compared tau-positive vs tau-negative groups as indicated by either modality or demographic and clinical variables, amyloid β-PET burden, and flortaucipir-PET binding across Braak stage-related ROIs. We also compared 5-year rates of CSF P-tau accumulation and cognitive decline prior to flortaucipir-PET scanning. Among the 322 study participants, 180 were women (56%), and the mean (SD) age was 73.08 (7.37) years. Two hundred ten participants were CSF-/PET- (65%); 63 were CSF+/PET- (19.5%); 15 were CSF-/PET+ (4.6%); and 34 were CSF+/PET+ (10.5%). Most CSF-/PET+ participants had measures near CSF or PET tau thresholds. The CSF+/PET- participants showed faster 5-year accrual of P-tau and increased flortaucipir-PET binding in early Braak ROIs but similar memory decline compared with CSF-/PET- participants. Tau-positive individuals by either measure showed increased amyloid β-PET burden. All CSF+/PET+ individuals were amyloid-positive, and 26 had MCI or AD dementia (76%). Compared with the CSF-/PET- group, CSF+/PET+ individuals had experienced faster 5-year accrual of CSF P-tau and decline in memory and executive function, resulting in reduced cognitive abilities at the time of flortaucipir-PET assessment. Suprathreshold CSF P-tau without flortaucipir-PET abnormality may indicate a stage of AD development characterized by early tau abnormality without measurable loss in cognitive performance. Persons with both tau CSF and PET abnormality appear to have reduced cognitive capacities resulting from faster antecedent cognitive decline. Elevation of CSF P-tau appears to precede flortaucipir-PET positivity in the progression of AD pathogenesis and related cognitive decline.

The Case Against Heavy PETing

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.