Summary Background Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer's disease. By assessing the ...accumulation of Aβ in people at risk of genetic forms of Alzheimer's disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease. Methods Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer's disease Colombian kindred aged 18–60 years were recruited from the Alzheimer's Prevention Initiative's registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer's Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions.was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition. Findings We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively.18 F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3–40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions. Interpretation These findings contribute to the understanding of preclinical familial Alzheimer's disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer's disease. Funding Avid Radiopharmaceuticals, Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.
To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer's disease. In line with this ...need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer's disease, in relation to age and symptom severity.
This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer's Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers.
The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers median, 6.37; interquartile range (IQR), 9.15 had an increased volume of WMH compared to both cognitively unimpaired carriers median, 0.85; IQR, 0.79 and non-carriers median, 1.07; IQR, 0.71. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance.
The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer's disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer's disease that is closely related to the progression of clinical symptoms.
Background
Depressive symptoms are common with aging and Alzheimer’s Disease (AD). Both neurodegenerative and cerebrovascular diseases have been postulated as underlying mechanisms, but it’s unclear ...if they contribute to depressive symptom pathogenesis in preclinical stages of AD. Probing these mechanisms using both central (neuroimaging) and peripheral (plasma) biomarkers is critical to gain insight into the neurobiology of depression and provide opportunities for clinical translation.
Method
Longitudinal data were analyzed from 350 Harvard Aging Brain Study participants, an observational cohort study of older adults who are cognitively unimpaired and have no/minimal depressive symptoms at baseline. Depressive symptoms were assessed annually with the 30‐item Geriatric Depression Scale (GDS) (average follow up = 7.2+/‐3.4yrs). At baseline, all participants underwent blood sampling for a plasma marker of general neurodegeneration, neurofilament light (NfL) and 11 cerebrovascular markers in plasma. Participants also underwent baseline amyloid (PiB) PET‐ wherein a cortical amyloid composite was derived‐ and baseline and subsequent MRI scans every three years‐ to derive slopes of regional cortical thickness and global white matter hyperintensities (WMH). Linear mixed effects models examined relationships between longitudinal GDS scores and predictors: (NfL or cerebrovascular markers)*time, and covariates: age, sex, education. Secondary model examined plasma markers and amyloid as interactive predictors of GDS, and repeated analyses using predictors: regional cortical thickness (neurodegeneration) or global WMH (cerebrovascular injury) slopes.
Result
Higher baseline levels of NfL and of ICAM1, a marker of cerebrovascular injury, predicted increasing GDS scores over time (NfL: β = 0.03+/‐0.01, t = 2.7, p = 0.007; ICAM1: β = 0.02+/‐0.01, t = 2.2, p = 0.03). Each also interacted with amyloid in predicting GDS scores: (NfL X PiB: β = ‐0.03+/‐0.01, t = ‐2.42, p = 0.02; ICAM1 X PiB: β = 0.023+/‐0.01, t = 2.44, p = 0.02). Regarding neuroimaging correlates, medialorbitofrontal cortical thickness slope (β = ‐0.03+/‐0.01, t = ‐2.94, p = 0.004), but not global WMH slope, predicted increasing GDS over time. None of the other cerebrovascular markers interacted with amyloid in predicting GDS.
Conclusion
Findings suggest that cerebrovascular injury, and peripheral and central biomarkers of regional neurodegeneration, alone and in synergy with amyloid burden, are associated with depressive symptoms in cognitively unimpaired older adults. Future studies incorporating additional measures of peripheral and central neurodegeneration, tauopathy, and cerebrovascular injury are needed to guide AD prevention efforts targeting depressive symptoms.
Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical ...symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD.
Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers.
Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers.
Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.
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