Network anatomy in logopenic variant of primary progressive aphasia

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis

Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer's disease

Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD +/- 8.5) years versus 54.8 (SD +/- 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-epsilon 4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD +/- 39.3) pg/ml dominantly inherited versus 296 (SD +/- 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles;sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design

Narratives bridge the divide between distant events in episodic memory

These data supplement the manuscript of the same title

Comparison of plasma and CSF biomarkers across ethnoracial groups in the ADNI.

IntroductionEthnoracial differences in cerebrospinal fluid (CSF; amyloid beta 42 [Aβ42], total tau [t-tau], phosphorylated tau 181 [p-tau181], and plasma (p-tau181, neurofilament light [NfL]) biomarkers of Alzheimer's disease (AD) are incompletely understood.MethodsWe performed cross-sectional analyses with and without adjustment for covariates comparing baseline CSF (Aβ42, t-tau, p-tau181) and plasma (p-tau181, NfL) values in 47 African Americans (AAs) matched to 141 non-Hispanic Whites (NHWs) and 43 Latinos (LAs) matched to 129 NHWs from the Alzheimer's Disease Neuroimaging Initiative (ADNI).ResultsUnadjusted comparisons revealed no significant differences in plasma or CSF biomarkers between AAs and NHWs. A trend toward a lower CSF t-tau and p-tau181 in LAs compared to NHWs was observed, without significant differences in plasma biomarkers. After adjusting for covariates, there were no significant differences in CSF or plasma biomarkers between AAs and NHWs or between LAs and NHWs.DiscussionPlasma and CSF AD biomarkers may perform similarly across diverse populations but future studies in large, diverse cohorts are needed

Narratives bridge the divide between distant events in episodic memory

Many studies suggest that information about past experience, or episodic memory, is divided into discrete units called "events." Yet we can often remember experiences that span multiple events. Events that occur in close succession might simply be linked because of their proximity to one another, but we can also build links between events that occur farther apart in time. Intuitively, some kind of organizing principle should enable temporally distant events to become bridged in memory. We tested the hypothesis that episodic memory exhibits a narrative-level organization, enabling temporally distant events to be better remembered if they form a coherent narrative. Furthermore, we tested whether post-encoding memory consolidation is necessary to integrate temporally distant events. In three experiments, participants learned and subsequently recalled events from fictional stories, in which pairs of temporally distant events involving side characters ("sideplots") either formed one coherent narrative or two unrelated narratives. Across participants, we varied whether recall was assessed immediately after learning, or after a delay: 24 hours, 12 hours between morning and evening ("wake"), or 12 hours between evening and morning ("sleep"). Participants recalled more information about coherent than unrelated narrative events, in most delay conditions, including immediate recall and wake conditions, suggesting that post-encoding consolidation was not necessary to integrate temporally distant events into a larger narrative. Furthermore, post hoc modeling across experiments suggested that narrative coherence facilitated recall over and above any effects of sentence-level semantic similarity. This reliable memory benefit for coherent narrative events supports theoretical accounts which propose that narratives provide a high-level architecture for episodic memory

Head-to-head comparison between plasma p-tau217 and flortaucipir-PET in amyloid-positive patients with cognitive impairment.

BACKGROUND: Plasma phosphorylated tau (p-tau) has emerged as a promising biomarker for Alzheimers disease (AD). Studies have reported strong associations between p-tau and tau-PET that are mainly driven by differences between amyloid-positive and amyloid-negative patients. However, the relationship between p-tau and tau-PET is less characterized within cognitively impaired patients with a biomarker-supported diagnosis of AD. We conducted a head-to-head comparison between plasma p-tau217 and tau-PET in patients at the clinical stage of AD and further assessed their relationships with demographic, clinical, and biomarker variables. METHODS: We retrospectively included 87 amyloid-positive patients diagnosed with MCI or dementia due to AD who underwent structural MRI, amyloid-PET (11C-PIB), tau-PET (18F-flortaucipir, FTP), and blood draw assessments within 1&nbsp;year (age = 66 ± 10, 48% female). Amyloid-PET was quantified in Centiloids (CL) while cortical tau-PET binding was measured using standardized uptake value ratios (SUVRs) referenced against inferior cerebellar cortex. Plasma p-tau217 concentrations were measured using an electrochemiluminescence-based assay on the Meso Scale Discovery platform. MRI-derived cortical volume was quantified with FreeSurfer. Mini-Mental State Examination (MMSE) scores were available at baseline (n = 85) and follow-up visits (n = 28; 1.5 ± 0.7&nbsp;years). RESULTS: Plasma p-tau217 and cortical FTP-SUVR were correlated (r = 0.61, p &lt; .001), especially in temporo-parietal and dorsolateral frontal cortices. Both higher p-tau217 and FTP-SUVR values were associated with younger age, female sex, and lower cortical volume, but not with APOE-ε4 carriership. PIB-PET Centiloids were weakly correlated with FTP-SUVR (r = 0.26, p = 0.02), but not with p-tau217 (r = 0.10, p = 0.36). Regional PET-plasma associations varied with amyloid burden, with p-tau217 being more strongly associated with tau-PET in temporal cortex among patients with moderate amyloid-PET burden, and with tau-PET in primary cortices among patients with high amyloid-PET burden. Higher p-tau217 and FTP-SUVR values were independently associated with lower MMSE scores cross-sectionally, while only baseline FTP-SUVR predicted longitudinal MMSE decline when both biomarkers were included in the same model. CONCLUSION: Plasma p-tau217 and tau-PET are strongly correlated in amyloid-PET-positive patients with MCI or dementia due to AD, and they exhibited comparable patterns of associations with demographic variables and with markers of downstream neurodegeneration

Quantitative analysis of 6,150 real-world amyloid Positron Emission Tomography (PET) scans from the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study

BackgroundAmyloid-PET had been widely used and validated in research settings, using highly selected samples, harmonized acquisition protocols, co-registration with MRI, and central interpretation by highly experienced experts. In contrast, in clinical settings, more heterogeneous acquisition, reconstruction, and interpretation may compromise the accuracy of the imaging. We quantitatively analyzed real-world amyloid-PET scans to assess their validity.MethodIDEAS acquired 18,295 amyloid PET scans at 343 PET facilities in patients with MCI or dementia using 18F-florbetapir, 18F-florbetaben, or 18F-flutemetamol. Scans were visually interpreted at each site as either negative or positive for cortical tracer retention. Scans from consenting patients were archived. As of December 1, 2021, amyloid-PET scans from 6,263 unique participants were available for analysis. Exclusion for lack of valid images or clinical data and failure of quality checks resulted in 6,150 (98.2%) valid scans. We analyzed the scans using a recently validated PET-only processing pipeline designed to process heterogeneous amyloid-PET scans (Iaccarino et al, 2022) and quantified cortical uptake in Centiloid (CL) units. A previously established neuropathology-based threshold of 24.4 CL was used to define amyloid-PET positivity independent of visual reads.ResultMean CL was higher in dementia (mean±SD = 53±51) than in MCI (40±48) (mean difference: 13; 95%CI: 10-15). Mean CL of visually negative scans (3±27) was very close to 0, as expected for patients without amyloid accumulation, and significantly lower than visually positive scans (72±41) (mean difference: 69; 95%CI: 67-70) (table 1). High concordance was found between local visual reads and CL-based positivity (86.5%, Cohen’s κ=0.72, figure 1). CL exhibited a bimodal distribution, with most scans clearly positive or negative, and a minority of visual-quantitative discordant scans surrounding the positivity threshold (figure 2). CL negatively correlated with MMSE (r=-0.19, p<.001, figure 3). CL further correlated with the level of confidence in the diagnosis of Alzheimer’s Disease (AD), as was indicated by clinicians before the performance of PET (r=0.13, p<.001, figure 4).ConclusionA large heterogeneous dataset of real-world amyloid-PET scans analyzed quantitatively, shows high concordance with visual reads, and expected relationships with clinical and neuropsychological measures of AD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175496/1/alz066217.pd