Longitudinal Trajectories of Memory Performance in Patients with Early-Stage Breast Cancer.

Background: While breast cancer and its treatments may affect cognition, the longitudinal trajectories of cognition among those receiving differing cancer treatment types remain poorly understood. Prior research suggests hippocampal-prefrontal cortex network integrity may influence cognition, although how this network predicts performance over time remains unclear. Methods: We conducted a prospective trial including 69 patients with early-stage breast cancer receiving adjuvant therapy and 12 controls. Longitudinal cognitive testing was conducted at four visits: pretreatment-baseline, 6-7 months, 14-15 months, and 23-24 months. Cognitive composite scores of episodic memory, executive functioning, and processing speed were assessed at each timepoint. Baseline structural MRI was obtained in a subset of these participants, and hippocampal and prefrontal cortex regional volumes were extracted. Results: Longitudinal linear mixed modeling revealed significant group by time interactions on memory performance, controlling for age and education. Post hoc analyses revealed this effect was driven by patients treated with chemotherapy or chemotherapy plus hormone therapy, who demonstrated the least improvement in memory scores over time. Treatment group did not significantly influence the relationship between time and processing speed or executive functioning. Neither pretreatment hippocampal nor prefrontal volume differed between groups, and there were no significant group by time by baseline regional volume effects on cognition. Conclusion: Patients with early-stage breast cancer treated with chemotherapy or chemotherapy plus hormone therapy benefit less from practice effects seen in healthy controls on memory tests. Loss of longitudinal practice effect may be a new and clinically relevant measure for capturing patients' experience of cognitive difficulties after treatment.

Characteristics of subjective cognitive decline associated with amyloid positivity.

INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.

Age, vascular disease, and Alzheimer's disease pathologies in amyloid negative elderly adults.

BACKGROUND: We recently reported that CSF phosphorylated tau (p-Tau181) relative to Aß40 (CSF p-Tau/Aß40 ratio) was less noisy and increased associations with Alzheimer's disease (AD) biomarkers compared to CSF p-Tau181 alone. While elevations of CSF p-Tau/Aß40 can occur in amyloid-ß (Aß) negative (Aß-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aß positivity. METHODS: We examined relationships between CSF p-Tau/Aß40, and CSF Aß42/Aß40, Aß PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer's disease (AD) pathway due to negative Aß status on both CSF and PET. Subgroups had 18F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aß40 associations with these measures as well. RESULTS: Elevated CSF p-Tau/Aß40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aß42/Aß40, higher WMH, and hypertension but not age, sex, Aß PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aß40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aß40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements. CONCLUSIONS: These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aß. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aß are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.

Detecting earlier stages of amyloid deposition using PET in cognitively normal elderly adults.

OBJECTIVE: To examine the feasibility of using cross-sectional PET to identify cognitive decliners among ß-amyloid (Aß)-negative cognitively normal (CN) elderly adults. METHODS: We determined the highest Aß-affected region by ranking baseline and accumulation rates of florbetapir-PET regions in 355 CN elderly adults using 18F-florbetapir-PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The banks of the superior temporal sulcus (BANKSSTS) were found as the highest Aß-affected region, and Aß positivity in this region was defined as above the lowest boundary of BANKSSTS standardized uptake value ratio of Aß+ (ADNI-defined COMPOSITE region) CN individuals. The entire CN cohort was divided as follows: stage 0, BANKSSTS-COMPOSITE-; stage 1, BANKSSTS+COMPOSITE-; and stage 2, BANKSSTS+COMPOSITE+. Linear mixed-effect (LME) models investigated subsequent longitudinal cognitive change, and 18F-flortaucipir (FTP)-PET was measured 4.8 ± 1.6 years later to track tau deposition. RESULTS: LME analysis revealed that individuals in stage 1 (n = 64) and stage 2 (n = 99) showed 2.5 (p < 0.05) and 4.8 (p < 0.001) times faster memory decline, respectively, than those in stage 0 (n = 191) over >4 years of mean follow-up. Compared to stage 0, both stage 1 (p < 0.05) and stage 2 (p < 0.001) predicted higher FTP in entorhinal cortex. CONCLUSIONS: Nominally Aß- CN individuals with high Aß in BANKSSTS are at increased risk of cognitive decline, probably showing an earlier stage of Aß deposition. Our findings may help elucidate the association between brain Aß accumulation and cognition in Aß- CN cohorts. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in elderly CN individuals those with high PET-identified superior temporal sulcus Aß burden have an increased risk of cognitive decline.

Analytical and Clinical Performance of Amyloid-Beta Peptides Measurements in CSF of ADNIGO/2 Participants by an LC-MS/MS Reference Method.

BACKGROUND: Cerebrospinal fluid (CSF) amyloid-ß1-42 (Aß42) reliably detects brain amyloidosis based on its high concordance with plaque burden at autopsy and with amyloid positron emission tomography (PET) ligand retention observed in several studies. Low CSF Aß42 concentrations in normal aging and dementia are associated with the presence of fibrillary Aß across brain regions detected by amyloid PET imaging. METHODS: An LC-MS/MS reference method for Aß42, modified by adding Aß40 and Aß38 peptides to calibrators, was used to analyze 1445 CSF samples from ADNIGO/2 participants. Seventy runs were completed using 2 different lots of calibrators. For preparation of Aß42 calibrators and controls spiking solution, reference Aß42 standard with certified concentration was obtained from EC-JRC-IRMM (Belgium). Aß40 and Aß38 standards were purchased from rPeptide. Aß42 calibrators' accuracy was established using CSF-based Aß42 Certified Reference Materials (CRM). RESULTS: CRM-adjusted Aß42 calibrator concentrations were calculated using the regression equation Y (CRM-adjusted) = 0.89X (calibrators) + 32.6. Control samples and CSF pools yielded imprecision ranging from 6.5 to 10.2% (Aß42) and 2.2 to 7.0% (Aß40). None of the CSF pools showed statistically significant differences in Aß42 concentrations across 2 different calibrator lots. Comparison of Aß42 with Aß42/Aß40 showed that the ratio improved concordance with concurrent [18F]-florbetapir PET as a measure of fibrillar Aß (n = 766) from 81 to 88%. CONCLUSIONS: Long-term performance assessment substantiates our modified LC-MS/MS reference method for 3 Aß peptides. The improved diagnostic performance of the CSF ratio Aß42/Aß40 suggests that Aß42 and Aß40 should be measured together and supports the need for an Aß40 CRM.

Fluid and PET biomarkers for amyloid pathology in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by amyloid plaques and tau pathology (neurofibrillary tangles and neuropil threads). Amyloid plaques are primarily composed of aggregated and oligomeric ß-amyloid (Aß) peptides ending at position 42 (Aß42). The development of fluid and PET biomarkers for Alzheimer's disease (AD), has allowed for detection of Aß pathology in vivo and marks a major advancement in understanding the role of Aß in Alzheimer's disease (AD). In the recent National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework, AD is defined by the underlying pathology as measured in patients during life by biomarkers (Jack et al., 2018), while clinical symptoms are used for staging of the disease. Therefore, sensitive, specific and robust biomarkers to identify brain amyloidosis are central in AD research. Here, we discuss fluid and PET biomarkers for Aß and their application.