Background
Hypometabolism is observed in early Alzheimer’s disease (AD), though its relation to underlying pathology remains uncertain. We first examined the relationships between glucose metabolism, ...β‐amyloid (Aβ), and tau in Presenilin‐1 (PSEN1) E280A mutation carriers and non‐carriers from the Massachusetts General Hospital Colombia‐Boston (COLBOS) Biomarker Study. We then examined the associations between glucose metabolism and episodic memory and depressive symptoms, two cognitive‐behavioral domains affected in early AD.
Method
Fludeoxyglucose (18F‐fludeoxyglucose;FDG) positron emission tomography (PET) images and neuropsychological assessments were analyzed from 31 PSEN1 E280A carriers (20F; mean age = 39 years; 21 cognitively unimpaired/10 cognitively impaired) and 33 age‐matched non‐carrier family members (20F, mean age = 39 years). Measures of Aβ (11C‐Pittsburgh compound‐B) and tau (18F‐flortaucipir) PET were available in a subset of this sample (22 carriers, 26 non‐carriers), collected on average 1.36 years prior to FDG‐PET. Entorhinal cortex, inferior temporal cortex, and precuneus were FDG‐ and tau‐PET regions of interest (ROIs). Group differences in FDG were tested followed by post‐hoc pairwise comparisons (non‐carriers/unimpaired carriers/impaired carriers). Linear regression was used to assess (1) age‐related trajectories of FDG as function of group (carrier/non‐carrier); and (2) whether cortical Aβ and regional tau predict FDG in carriers. FDG associations with memory (CERAD Word List Delayed Recall) and depression (Geriatric Depression Scale) were tested using Spearman correlation within carriers.
Result
Impaired carriers had lower metabolism in all ROIs compared to unimpaired carriers (ps<.006) and non‐carriers (ps<.031); unimpaired carriers and non‐carriers did not differ (ps>.116). Age was more negatively associated with precuneus (p = .030) and inferior temporal (p = .006) metabolism in carriers than non‐carriers. Age‐related trajectories of entorhinal metabolism did not differ by group (p = .107). In carriers, higher cortical Aβ and regional tau were associated with lower metabolism in all ROIs (ps<.013); only the relationship between precuneus tau and FDG survived adjustment for age (p = .05). Higher recall was associated with lower metabolism in all ROIs (ps<.017). Higher depressive symptoms were associated with lower inferior temporal metabolism (p = .014).
Conclusion
Glucose hypometabolism is evident in prodromal autosomal dominant AD and may reflect both Aβ and tau pathology. Hypometabolism is associated with increased cognitive‐behavioral symptoms. Future studies should consider longitudinal associations between these measures.
Background
Awareness of memory was previously found to be reduced in the pre‐dementia stages, reaching unawareness/anosognosia 6‐years before dementia onset in individuals who carry the PSEN1 E280A ...mutation for autosomal dominant Alzheimer’s disease (Vannini et al.,2021). Whether there are potential differences in awareness for specific types of situations involving memory as well as their association with molecular markers of AD disease progression in preclinical AD is unknown. Here, we investigated memory awareness on an item‐level basis as well as its relationship to neocortical amyloid and regional tau levels in non‐demented mutation carriers and non‐carrier family members.
Method
A total of 119 Colombian kindred members, 56 carriers (7 mildly impaired) and 63 non‐carriers were included (Table.1). Awareness indexes were calculated using participant and study‐partner discrepancy scores for each of the 15 questions of the Memory Complaint Scale (Spanish version). A score of ≥0 indicates that the participant is aware and <0 unaware. A subset of 67 kindred members (N = 31 carriers, 1 impaired) underwent amyloid (PiB) and tau (FTP) scans. For each question, odds ratio and Fisher’s exact test were used to evaluate prevalence of awareness/unawareness in carriers and non‐carriers. Pearson correlations, corrected for multiple comparisons, were used to assess the associations between awareness and pathology in the mutation carriers.
Result
Mutation carriers had significantly decreased overall awareness (p = 0.03), increased mean cortical amyloid (p<0.001) and inferior temporal tau (p = 0.001), compared to non‐carriers. Two questions (items 10 and 15), showed significantly lower awareness in the carriers than non‐carriers (both p = 0.002, Table.2). These results remained significant after removing impaired carriers. In carriers, decreased awareness was related to increased tau for 5/15 (33%) questions (Table.3 and Figure.1). No significant associations were found between awareness and amyloid.
Conclusion
Our results support previous findings that awareness is decreased in pre‐dementia stages of AD and related to tau, and not to amyloid pathology (Gagliardi et al.,2021). Importantly, we found that loss of awareness of specific memory items could differentiate carriers from non‐carriers. These findings support the usefulness of study‐partner‐reported cognitive decline. Individuals who become unaware of cognitive changes may represent a specific risk group to harbor pathology and develop AD dementia.
Background
Long‐term forgetting (LTF) over days or weeks may be a sensitive early marker of Alzheimer’s disease (AD), useful for preclinical AD trials. We examined associations between LTF and ...markers of brain pathology in individuals from the world’s largest kindred with autosomal dominant AD due to the Presenilin‐1 (PSEN1) E280A mutation.
Methods
A total of 14 cognitively unimpaired PSEN1 mutation carriers (mean age: 35.9 years) and 16 matched non‐carriers (mean age: 32.8 years) from the Colombia‐Boston Biomarker Study of autosomal dominant AD were included. Participants underwent amyloid (11‐C Pittsburgh compound B) and tau (Flortaucipir) PET imaging, and memory tasks (NEUROPSI word list, stories and semi‐complex figure). We examined performance on learning and delayed recall after a 20‐min, 1‐day and 7‐day interval. LTF was calculated for the three tasks as the proportion of material retained at 20 min that was recalled 7 days later. Mann‐Whitney tests were conducted to compare memory performance and LTF between PSEN1 mutation carriers and non‐carriers. Spearman’s correlations were used to examine the association between LTF and brain pathology markers of amyloid burden and regional tau (entorhinal and inferior temporal cortices). Fisher’s exact tests were used to compare correlation coefficients between groups.
Results
Learning did not differ between carriers and non‐carriers. Compared to non‐carriers, carriers had lower 20‐min recall in all three tasks (p<0.05), and lower 1‐day and 7‐day recall of word list and stories. There were no group differences in word list, stories or figure LTF. Further, no group differences were observed in the association of amyloid burden and LTF on any of the tasks. Lower word list LTF was associated with greater entorhinal burden among carriers, and the strength of this association was significantly different between carriers and non‐carriers (p = 0.046; carriers: r = 0.73, p = 0.003; non‐carriers: r = 0.43, p = 0.094).
Conclusions
Our preliminary findings show that, while rates of LTF over 7 days did not differ between PSEN1 carriers and non‐carriers, carriers had lower verbal memory recall over 1 and 7 days. Further, LTF was associated with early tau accumulation, suggesting that longer recall intervals may be more sensitive to detect subtle memory changes in cognitively unimpaired individuals at risk for AD.
Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although ...apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.
Primary Systems and Candidate Ideology Rogowski, Jon C.; Langella, Stephanie
American politics research,
09/2015, Letnik:
43, Številka:
5
Journal Article
Recenzirano
The nomination of ideologically extreme candidates in party primaries has led many scholars and observers to speculate about the role played by different kinds of primary systems. Models of candidate ...competition that account for the two-stage nature of the electoral process suggest that more restrictive primary systems produce more ideologically extreme candidates. In contrast with previous research that examines the relationship between primaries and legislative ideology, we focus on how primary systems affect the ideological extremity of candidates’ campaign platforms. Using data on more than 85,000 major party candidates for Congress and state legislatures from 1980-2012, we find no evidence that the restrictiveness of primary participation rules is systematically associated with candidate ideology.
Background
Previous work has shown that neuropsychiatric symptoms (NPS) such as depression in older adults are associated with cognitive decline and brain pathology related to Alzheimer’s disease ...(AD), but the constellation of NPS driving these associations is unclear. Traditionally, depressive symptoms have been assessed with the Geriatric Depression Scale (GDS), but newer NPS assessments, such as the Mild Behavioral Impairment‐Checklist (MBI‐C), have shown promise for identification of specific early features of symptomology. Here we examined the two affective domains of the MBI‐C in cognitively unimpaired older adults with moderate‐to‐severe depressive symptoms and non‐depressed older adults, and the association between these domains and neuroimaging biomarkers of AD.
Method
21 clinically normal (CN) older adults who met DSM5 criteria for major depression (MDD) (73.0±4.3 y.o., 62% female) and 25 non‐depressed older adults from related observational studies at our site (70.8±3.7 y.o., 64% female) underwent a clinical battery that included the GDS and MBI‐C self‐report domains focused on decreased interest‐motivation‐drive and increased dysphoria‐anhedonia‐anxiety (Range for each domain: 0–18). Participants completed neuroimaging consisting of MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET. We focused analyses on neocortical amyloid and regional tau and atrophy in the amygdala and hippocampus. A Pearson correlation was used to assess the association between GDS total score and MBI‐C component scores. Linear regressions adjusted for age were used to investigate relationships between MBI‐C domains and ATN biomarkers.
Result
GDS total score was correlated with both MBI‐C domains across all participants (Fig.1, p<0.01). In participants with MDD, the MBI‐C decreased interest‐motivation‐drive domain was associated with elevated FTP in the amygdala and hippocampus, while the increased dysphoria‐anhedonia‐anxiety domain was not significantly related to PET signal (Table 2, Fig.2). MBI‐C domains were not related to PET signal or atrophy in non‐depressed control participants.
Conclusion
Preliminary findings with the MBI‐C suggest that the decreased interest‐motivation‐drive domain may be associated with tau pathology in older adults with moderate‐to‐severe depression. Additional work needs to be done in a larger depressed cohort to further understand the associations between specific depressive phenotypes and AD pathology.
Background
Carriers of the Presenilin‐1 (PSEN1) E280A mutation are virtually determined to develop Alzheimer’s disease (AD) dementia by midlife. Tau pathology accumulates in the amygdala of PSEN1 ...carriers prior to clinical onset. Amygdala dysfunction, particularly in basolateral regions, may contribute to early neuropsychiatric symptoms in sporadic AD and other dementias. We aimed to examine the cognitive‐behavioral associations of subregional amygdala tau pathology in preclinical PSEN1 carriers, focusing on episodic memory and neuropsychiatric symptoms.
Methods
Participants included 25 unimpaired PSEN1 carriers and 37 non‐carriers from the Colombia‐Boston (COLBOS) Biomarker Study, matched in age, sex, and education (Table 1). In vivo regional tau pathology was measured using PET (Flortaucipir), with lateral and basal (aggregate region comprised of basal and accessory basal nuclei) amygdala as primary regions of interest (automatic segmentation using FreeSurfer v7). Memory was measured using the CERAD Word List Delayed Recall. Neuropsychiatric symptoms were measured using the Geriatric Anxiety Scale (GAI) and Geriatric Depression Scale (GDS). Associations with tau were tested using Spearman correlation. Group differences on cognitive‐behavioral measures were tested using independent samples t‐tests.
Results
Carriers and non‐carriers did not differ in overall depression or anxiety symptoms, but carriers had lower memory recall scores (Table 1). In carriers, lower recall was associated with greater tau accumulation in lateral (r = ‐.422, p = .036) but not basal (r = ‐.291, p = .158) amygdala. Higher depressive symptoms in carriers were associated with greater tau in both lateral (r = .530, p = .007) and basal (r = .467, p = .019) amygdala. Anxiety symptoms were not associated with amygdala tau in carriers (ps > .309). No significant associations were observed in non‐carriers.
Conclusions
Amygdala tau pathology is associated with depressive symptoms and lower memory recall in cognitively unimpaired PSEN1 carriers, particularly in lateral amygdala. These results suggest that lateral amygdala tauopathy may be an early indicator of disease progression and may underlie cognitive and neuropsychiatric changes associated with early AD. Future longitudinal studies with larger samples and additional regional tau measures are needed to clarify the effects of subregional amygdala tau pathology on clinical onset and progression of AD.
INTRODUCTION
Plasma tau phosphorylated at threonine 217 (P‐tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer's disease (AD) pathology. Few studies have examined the role of ...sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD.
METHODS
We examined the effects of sex and age on plasma P‐tau217 and NfL, and their association with cognitive performance in a cross‐sectional study of 621 Presenilin‐1 E280A mutation carriers (PSEN1) and non‐carriers.
RESULTS
As plasma P‐tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non‐carriers.
DISCUSSION
Our findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance.
HIGHLIGHTS
We examined sex differences in plasma P‐tau217 and NfL in Presenilin‐1 E280A (PSEN1) mutation carriers and non‐carriers.
Female carriers had a greater plasma NfL increase, but not P‐tau217, than male carriers.
As plasma P‐tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers.
The interaction effect of sex by plasma NfL levels did not predict cognition among carriers.
INTRODUCTION
Depressive symptoms are among early behavioral changes in Alzheimer's disease (AD); however, the relationship between neurodegeneration and depressive symptoms remains inconclusive. To ...better understand this relationship in preclinical AD, we examined hippocampal volume and depressive symptoms in cognitively unimpaired carriers of the presenilin‐1 (PSEN1) E280A mutation for autosomal dominant AD.
METHODS
A total of 27 PSEN1 mutation carriers and 26 non‐carrier family members were included. Linear regression was used to test the relationship between hippocampal volume and 15‐item Geriatric Depression Scale.
RESULTS
Carriers and non‐carriers did not differ in depressive symptoms or hippocampal volume. Within carriers, lower hippocampal volume was associated with greater depressive symptoms, which remained significant after adjusting for age and cognition. This relationship was not significant in non‐carriers.
DISCUSSION
Hippocampal neurodegeneration may underlie depressive symptoms in preclinical autosomal dominant AD. These findings provide support for the utility of targeting depressive symptoms in AD prevention.
Highlights
We compared unimpaired autosomal dominant Alzheimer's disease (AD) mutation carriers and non‐carriers.
Carriers and non‐carriers did not differ in severity of depressive symptoms.
In carriers, hippocampal volume was inversely associated with depressive symptoms.
Depressive symptoms may be a useful target in AD prevention.
