Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequen... more Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. We investigated the relationships of TDP-43 proteinopathy and hippocampal sclerosis with APOE ε4. We used data from two community-based cohort studies of ageing and dementia: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). A battery of cognitive tests examining multiple cognitive domains is given to ROS-MAP participants each year, and a measure of annual global cognitive function for each participant is derived by averaging Z scores of these tests. The final clinical diagnosis is assigned after death by a neurologist using all available clinical data without access to post-mortem pathol...
There is a need to find cognitive markers that can help identify individuals at risk for Alzheime... more There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). The three-factor...
Alzheimer's disease (AD) patients exhibit temporally graded memory loss with remote memories ... more Alzheimer's disease (AD) patients exhibit temporally graded memory loss with remote memories remaining more intact than recent memories. It is unclear whether this temporal pattern is observable in clinically normal adults with amyloid pathology (i.e. preclinical AD). Participants were asked to recall the names of famous figures most prominent recently (famous after 1990) and remotely (famous from 1960-1980) and were provided with a phonemic cue to ensure that memory failure was not purely due to verbal retrieval weaknesses. In addition, participants identified line drawings of objects. Clinically normal older adults (n = 125) were identified as amyloid β positive or negative (Aβ+/-) using Pittsburgh compound B positron emission tomography. The relationship between Aβ+/- and recall of remote and recent famous face-names and objects was examined using repeated measures analyses and general linear models controlling for demographics and media usage. When provided with a phonemic c...
The journal of prevention of Alzheimer's disease, 2017
Impairment in activities of daily living is a major burden to both patients and caregivers. Mild ... more Impairment in activities of daily living is a major burden to both patients and caregivers. Mild impairment in instrumental activities of daily living is often seen at the stage of mild cognitive impairment. The field of Alzheimer's disease is moving toward earlier diagnosis and intervention and more sensitive and ecologically valid assessments of instrumental or complex activities of daily living are needed. The Harvard Automated Phone Task, a novel performance-based activities of daily living instrument, has the potential to fill this gap. To further validate the Harvard Automated Phone Task by assessing its longitudinal relationship to global cognition and specific cognitive domains in clinically normal elderly and individuals with mild cognitive impairment. In a longitudinal study, the Harvard Automated Phone Task was associated with cognitive measures using mixed effects models. The Harvard Automated Phone Task's ability to discriminate across diagnostic groups at basel...
Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitat... more Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cin...
Cerebral cortex (New York, N.Y. : 1991), Jan 7, 2018
White matter degradation has been proposed as one possible explanation for age-related cognitive ... more White matter degradation has been proposed as one possible explanation for age-related cognitive decline. In the present study, we examined 2 main questions: 1) Do diffusion characteristics predict longitudinal change in cognition independently or synergistically with amyloid status? 2) Are the effects of diffusion characteristics on longitudinal cognitive change tract-specific or global in nature? Cognitive domains of executive function, episodic memory, and processing speed were measured annually (mean follow-up = 3.93 ± 1.25 years). Diffusion tensor imaging and Pittsburgh Compound-B positron emission tomography were performed at baseline in 265 clinically normal older adults (aged 63-90). Tract-specific diffusion was measured as the mean fractional anisotropy (FA) for 9 major white matter tracts. Global diffusion was measured as the mean FA across the 9 white matter tracts. Linear mixed models demonstrated independent, rather than synergistic, effects of global FA and amyloid sta...
On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target... more On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography. We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition. FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residua...
It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as... more It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpai...
Objective:To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alz... more Objective:To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD).Methods:We examined self-reported and study partner–based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried thePSEN-1E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing.Results:Self-reported SMC were greater in carriers than noncarriers (p= 0.02). Study partner–based SMC did not differ between groups (p= 0.21), but in carriers increased with age (r= 0.66,p< 0.001) and decreased with hippocampal volume (r= −0.35,p= 0.08).Conclusions:Cognitively unimpairedPSEN-1carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset.
Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimer... more Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimer's disease (AD). Previous findings in AD dementia patients suggest that anosognosia is due to both functional metabolic changes within cortical midline structures involved in self-referential processes, as well as functional disconnection between these regions. The present study aims to extend these findings by investigating the neural correlates of anosognosia in the prodromal stage of AD. Here, we used regional brain metabolism (resting state 18-F fluorodeoxyglucose positron emission tomography (FDG-PET)) to unravel the metabolic correlates of anosognosia in subjects with amnestic mild cognitive impairment (aMCI) and subsequently resting state functional magnetic resonance imaging (rs-fMRI) to investigate the intrinsic connectivity disruption between brain regions. Thirty-one subjects (mean age: 74.1; Clinical Dementia Rating (CDR) global score: 0.5) with aMCI, and 251 cognitively ...
Age-related memory decline has been well-documented; however, some individuals reach their 8th-10... more Age-related memory decline has been well-documented; however, some individuals reach their 8th-10th decade while maintaining strong memory performance. To determine which demographic and biomarker factors differentiated top memory performers (aged 75+, top 20% for memory) from their peers and whether top memory performance was maintained over 3 years. Clinically normal adults (n=125, CDR=0; age: 79.5±3.57 years) from the Harvard Aging Brain Study underwent cognitive testing and neuroimaging (amyloid PET, MRI) at baseline and 3-year follow-up. Participants were grouped into Optimal (n=25) vs. Typical (n=100) performers using performance on 3 challenging memory measures. Non-parametric tests were used to compare groups. There were no differences in age, sex, or education between Optimal vs. Typical performers. The Optimal group performed better in Processing Speed (p=0.016) and Executive Functioning (p<0.001). Optimal performers had larger hippocampal volumes at baseline compared w...
While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's ... more While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the preclinical and prodromal stages of the disease. Paradoxically, very early in the Alzheimer's disease process, individuals may experience heightened awareness of memory changes before any objective cognitive deficits can be detected, here referred to as hypernosognosia. In contrast, awareness of memory dysfunction shown by individuals with mild cognitive impairment (MCI) is very variable, ranging from marked concern to severe lack of insight. This study aims at improving our mechanistic understanding of how alterations in memory self-awareness are related to pathological changes in clinically normal (CN) adults and MCI patients. 297 CN and MCI patients underwent PiB-PET (Positron Emission Tomography using Pittsburgh Compound B) in vivo amyloid imaging. Amyloid burden w...
logical battery, participants completed the California Verbal Learning Test (CVLT-II), Brief Visu... more logical battery, participants completed the California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R), and Benton Facial Recognition Test (BFRT). A mixed ANOVAwas used to analyze behavioural responses as a function of valence and group. Results:No group differences on the BFRTwere found. On the VALENCE task, sd-aMCI rated faces more positively compared to DEP (p1⁄4.019). Further, neutral faces were rated more positively by sd-aMCI relative to CN and DEP (F[2, 64]1⁄47.3, p1⁄4.001). On the LABEL task, a group x valence interaction revealed that sd-aMCI were more accurate in labelling neutral faces compared to DEP (F[2, 63]1⁄45.4, p1⁄4.007), who incorrectly misattributed neutral as sad. In sd-aMCI, better delayed recall on BVMT-R was associated with decreased accuracy in labelling fearful expressions, and more positive ratings of happy faces (Spearman’s rho1⁄4-.55, p1⁄4.026; rho1⁄4-.51, p1⁄4.04 respectively), with a similar inverse association between the latter and CVLT-II delayed recall (rho1⁄4-.59, p1⁄4.017). Conclusions: Intact perception of facial features and recognition of emotional expressions, together with more positive valence judgements of neutral faces, suggest that sd-aMCI is associated with a positive bias in interpretation of facial expressions. The inverse associations betweenmemory and the positivity bias support the hypothesis that preclinical Alzheimer’s disease is characterized by a positive bias in early processing of emotional information, which may attenuate with disease progression.
Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations... more Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD. To determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults. Cross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B-positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for ...
Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomark... more Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomarker evidence of Alzheimer's disease (AD) prior to objective clinical impairment. However, the sensitivity of SCC reports in early AD may be biased by demographic factors. Here, we sought to investigate whether age, education, and sex influence the relationship between SCC and amyloid (Aβ) burden. In this cross-sectional study, we examined 252 clinically normal (CN) individuals (57.7% females) enrolled in the Harvard Aging Brain Study, ages 63-90 years (mean 73.7±6) with 6-20 years of education (mean 15.8±3). SCC was assessed as a composite score comprising three questionnaires. Cortical Aβ burden was assessed with Pittsburgh compound B positron emission tomography imaging. A series of linear regression models assessed the potential modifying role of demographic variables with respect to Aβ burden and SCC. A post-hoc mediation model was implemented to further understand the relationshi...
The journal of prevention of Alzheimer's disease, 2016
Technological advances now make it feasible to administer cognitive assessments at-home on mobile... more Technological advances now make it feasible to administer cognitive assessments at-home on mobile and touch-screen devices such as an iPad or tablet computer. Validation of these techniques is necessary to assess their utility in clinical trials. We used a Computerized Cognitive Composite for Preclinical Alzheimer's Disease (C3-PAD) developed for iPad 1) to determine the feasibility of performing the C3-PAD at home by older individuals without the presence of a trained psychometrician; 2) to explore the reliability of in-clinic compared to at-home C3-PAD performance and 3) to examine the comparability of C3-PAD performance to standardized neuropsychological tests. Forty-nine cognitively normal older individuals (mean age, 71.467.7 years; 20% non-Caucasian) were recruited from research centers at the Massachusetts General Hospital and Brigham and Women's Hospital. Participants made two in-clinic visits one-week apart and took five 30-minute alternate versions of the C3-PAD at...
A cross-sectional group study of the effects of aging on brain metabolism as measured with (18)F-... more A cross-sectional group study of the effects of aging on brain metabolism as measured with (18)F-FDG-PET was performed using several different partial volume correction (PVC) methods: no correction (NoPVC), Meltzer (MZ), Müller-Gärtner (MG), and the symmetric geometric transfer matrix (SGTM) using 99 subjects aged 65-87years from the Harvard Aging Brain study. Sensitivity to parameter selection was tested for MZ and MG. The various methods and parameter settings resulted in an extremely wide range of conclusions as to the effects of age on metabolism, from almost no changes to virtually all of cortical regions showing a decrease with age. Simulations showed that NoPVC had significant bias that made the age effect on metabolism appear to be much larger and more significant than it is. MZ was found to be the same as NoPVC for liberal brain masks; for conservative brain masks, MZ showed few areas correlated with age. MG and SGTM were found to be similar; however, MG was sensitive to a ...
Family history of dementia (FH) is a major risk factor for Alzheimer's disease (AD), particularly... more Family history of dementia (FH) is a major risk factor for Alzheimer's disease (AD), particularly when the FH is maternal and when the age of dementia onset (AO) is younger. This study tested whether brain amyloid-beta (Aβ) deposition, measured in vivo with 11 C-Pittsburgh compound B (PiB), was associated with parental dementia and/or younger parental AO. Detailed FH and positron emission tomography (PiB-PET) data were acquired in 147 non-demented aging individuals (mean age 75±8). No participant had both positive maternal and paternal FH. A series of analyses revealed that those with maternal, but not paternal, FH had greater levels of PiB retention in a global cortical region than those without FH. PiB retention in maternal FH was not significantly greater than paternal FH. Younger maternal dementia AO was related to greater PiB retention in offspring, while younger paternal dementia AO was not. Overall, results suggest that not only is Aβ burden greater in individuals with maternal FH, but also that the burden is greater in association with younger maternal AO.
Aging-related differences in white matter integrity, the presence of amyloid plaques, and density... more Aging-related differences in white matter integrity, the presence of amyloid plaques, and density of biomarkers indicative of dopamine functions can be detected and quantified with in vivo human imaging. The primary aim of the present study was to investigate whether these imaging-based measures constitute independent imaging biomarkers in older adults, which would speak to the hypothesis that the aging brain is characterized by multiple independent neurobiological cascades. We assessed MRI-based markers of white matter integrity and PET-based marker of dopamine transporter density and amyloid deposition in the same set of 53 clinically normal individuals (age 65-87). A multiple regression analysis demonstrated that dopamine transporter availability is predicted by white matter integrity, which was detectable even after controlling for chronological age. Further post-hoc exploration revealed that dopamine transporter availability was further associated with systolic blood pressure, ...
We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer di... more We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer disease biomarkers. In a cross-sectional study, we evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with mean age of 74 ± 6 years. Using backward elimination general linear models, we tested the hypotheses that greater cognitive or physical activity would be associated with lower Pittsburgh compound B-PET retention, greater (18)F-fluorodeoxyglucose-PET metabolism, and larger hippocampal volume, as well as better cognitive performance on neuropsychological testing. Linear regression demonstrated that history of greater cognitive activity was correlated with greater estimated IQ and education, as well as better neuropsychological testing performance. Self-reported recent physical activity was related to objective exercise monitoring. However, c...
Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequen... more Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. We investigated the relationships of TDP-43 proteinopathy and hippocampal sclerosis with APOE ε4. We used data from two community-based cohort studies of ageing and dementia: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). A battery of cognitive tests examining multiple cognitive domains is given to ROS-MAP participants each year, and a measure of annual global cognitive function for each participant is derived by averaging Z scores of these tests. The final clinical diagnosis is assigned after death by a neurologist using all available clinical data without access to post-mortem pathol...
There is a need to find cognitive markers that can help identify individuals at risk for Alzheime... more There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). The three-factor...
Alzheimer's disease (AD) patients exhibit temporally graded memory loss with remote memories ... more Alzheimer's disease (AD) patients exhibit temporally graded memory loss with remote memories remaining more intact than recent memories. It is unclear whether this temporal pattern is observable in clinically normal adults with amyloid pathology (i.e. preclinical AD). Participants were asked to recall the names of famous figures most prominent recently (famous after 1990) and remotely (famous from 1960-1980) and were provided with a phonemic cue to ensure that memory failure was not purely due to verbal retrieval weaknesses. In addition, participants identified line drawings of objects. Clinically normal older adults (n = 125) were identified as amyloid β positive or negative (Aβ+/-) using Pittsburgh compound B positron emission tomography. The relationship between Aβ+/- and recall of remote and recent famous face-names and objects was examined using repeated measures analyses and general linear models controlling for demographics and media usage. When provided with a phonemic c...
The journal of prevention of Alzheimer's disease, 2017
Impairment in activities of daily living is a major burden to both patients and caregivers. Mild ... more Impairment in activities of daily living is a major burden to both patients and caregivers. Mild impairment in instrumental activities of daily living is often seen at the stage of mild cognitive impairment. The field of Alzheimer's disease is moving toward earlier diagnosis and intervention and more sensitive and ecologically valid assessments of instrumental or complex activities of daily living are needed. The Harvard Automated Phone Task, a novel performance-based activities of daily living instrument, has the potential to fill this gap. To further validate the Harvard Automated Phone Task by assessing its longitudinal relationship to global cognition and specific cognitive domains in clinically normal elderly and individuals with mild cognitive impairment. In a longitudinal study, the Harvard Automated Phone Task was associated with cognitive measures using mixed effects models. The Harvard Automated Phone Task's ability to discriminate across diagnostic groups at basel...
Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitat... more Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cin...
Cerebral cortex (New York, N.Y. : 1991), Jan 7, 2018
White matter degradation has been proposed as one possible explanation for age-related cognitive ... more White matter degradation has been proposed as one possible explanation for age-related cognitive decline. In the present study, we examined 2 main questions: 1) Do diffusion characteristics predict longitudinal change in cognition independently or synergistically with amyloid status? 2) Are the effects of diffusion characteristics on longitudinal cognitive change tract-specific or global in nature? Cognitive domains of executive function, episodic memory, and processing speed were measured annually (mean follow-up = 3.93 ± 1.25 years). Diffusion tensor imaging and Pittsburgh Compound-B positron emission tomography were performed at baseline in 265 clinically normal older adults (aged 63-90). Tract-specific diffusion was measured as the mean fractional anisotropy (FA) for 9 major white matter tracts. Global diffusion was measured as the mean FA across the 9 white matter tracts. Linear mixed models demonstrated independent, rather than synergistic, effects of global FA and amyloid sta...
On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target... more On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography. We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition. FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residua...
It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as... more It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpai...
Objective:To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alz... more Objective:To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD).Methods:We examined self-reported and study partner–based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried thePSEN-1E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing.Results:Self-reported SMC were greater in carriers than noncarriers (p= 0.02). Study partner–based SMC did not differ between groups (p= 0.21), but in carriers increased with age (r= 0.66,p< 0.001) and decreased with hippocampal volume (r= −0.35,p= 0.08).Conclusions:Cognitively unimpairedPSEN-1carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset.
Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimer... more Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimer's disease (AD). Previous findings in AD dementia patients suggest that anosognosia is due to both functional metabolic changes within cortical midline structures involved in self-referential processes, as well as functional disconnection between these regions. The present study aims to extend these findings by investigating the neural correlates of anosognosia in the prodromal stage of AD. Here, we used regional brain metabolism (resting state 18-F fluorodeoxyglucose positron emission tomography (FDG-PET)) to unravel the metabolic correlates of anosognosia in subjects with amnestic mild cognitive impairment (aMCI) and subsequently resting state functional magnetic resonance imaging (rs-fMRI) to investigate the intrinsic connectivity disruption between brain regions. Thirty-one subjects (mean age: 74.1; Clinical Dementia Rating (CDR) global score: 0.5) with aMCI, and 251 cognitively ...
Age-related memory decline has been well-documented; however, some individuals reach their 8th-10... more Age-related memory decline has been well-documented; however, some individuals reach their 8th-10th decade while maintaining strong memory performance. To determine which demographic and biomarker factors differentiated top memory performers (aged 75+, top 20% for memory) from their peers and whether top memory performance was maintained over 3 years. Clinically normal adults (n=125, CDR=0; age: 79.5±3.57 years) from the Harvard Aging Brain Study underwent cognitive testing and neuroimaging (amyloid PET, MRI) at baseline and 3-year follow-up. Participants were grouped into Optimal (n=25) vs. Typical (n=100) performers using performance on 3 challenging memory measures. Non-parametric tests were used to compare groups. There were no differences in age, sex, or education between Optimal vs. Typical performers. The Optimal group performed better in Processing Speed (p=0.016) and Executive Functioning (p<0.001). Optimal performers had larger hippocampal volumes at baseline compared w...
While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's ... more While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the preclinical and prodromal stages of the disease. Paradoxically, very early in the Alzheimer's disease process, individuals may experience heightened awareness of memory changes before any objective cognitive deficits can be detected, here referred to as hypernosognosia. In contrast, awareness of memory dysfunction shown by individuals with mild cognitive impairment (MCI) is very variable, ranging from marked concern to severe lack of insight. This study aims at improving our mechanistic understanding of how alterations in memory self-awareness are related to pathological changes in clinically normal (CN) adults and MCI patients. 297 CN and MCI patients underwent PiB-PET (Positron Emission Tomography using Pittsburgh Compound B) in vivo amyloid imaging. Amyloid burden w...
logical battery, participants completed the California Verbal Learning Test (CVLT-II), Brief Visu... more logical battery, participants completed the California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R), and Benton Facial Recognition Test (BFRT). A mixed ANOVAwas used to analyze behavioural responses as a function of valence and group. Results:No group differences on the BFRTwere found. On the VALENCE task, sd-aMCI rated faces more positively compared to DEP (p1⁄4.019). Further, neutral faces were rated more positively by sd-aMCI relative to CN and DEP (F[2, 64]1⁄47.3, p1⁄4.001). On the LABEL task, a group x valence interaction revealed that sd-aMCI were more accurate in labelling neutral faces compared to DEP (F[2, 63]1⁄45.4, p1⁄4.007), who incorrectly misattributed neutral as sad. In sd-aMCI, better delayed recall on BVMT-R was associated with decreased accuracy in labelling fearful expressions, and more positive ratings of happy faces (Spearman’s rho1⁄4-.55, p1⁄4.026; rho1⁄4-.51, p1⁄4.04 respectively), with a similar inverse association between the latter and CVLT-II delayed recall (rho1⁄4-.59, p1⁄4.017). Conclusions: Intact perception of facial features and recognition of emotional expressions, together with more positive valence judgements of neutral faces, suggest that sd-aMCI is associated with a positive bias in interpretation of facial expressions. The inverse associations betweenmemory and the positivity bias support the hypothesis that preclinical Alzheimer’s disease is characterized by a positive bias in early processing of emotional information, which may attenuate with disease progression.
Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations... more Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD. To determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults. Cross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B-positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for ...
Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomark... more Converging evidence suggests that subjective cognitive concerns (SCC) are associated with biomarker evidence of Alzheimer's disease (AD) prior to objective clinical impairment. However, the sensitivity of SCC reports in early AD may be biased by demographic factors. Here, we sought to investigate whether age, education, and sex influence the relationship between SCC and amyloid (Aβ) burden. In this cross-sectional study, we examined 252 clinically normal (CN) individuals (57.7% females) enrolled in the Harvard Aging Brain Study, ages 63-90 years (mean 73.7±6) with 6-20 years of education (mean 15.8±3). SCC was assessed as a composite score comprising three questionnaires. Cortical Aβ burden was assessed with Pittsburgh compound B positron emission tomography imaging. A series of linear regression models assessed the potential modifying role of demographic variables with respect to Aβ burden and SCC. A post-hoc mediation model was implemented to further understand the relationshi...
The journal of prevention of Alzheimer's disease, 2016
Technological advances now make it feasible to administer cognitive assessments at-home on mobile... more Technological advances now make it feasible to administer cognitive assessments at-home on mobile and touch-screen devices such as an iPad or tablet computer. Validation of these techniques is necessary to assess their utility in clinical trials. We used a Computerized Cognitive Composite for Preclinical Alzheimer's Disease (C3-PAD) developed for iPad 1) to determine the feasibility of performing the C3-PAD at home by older individuals without the presence of a trained psychometrician; 2) to explore the reliability of in-clinic compared to at-home C3-PAD performance and 3) to examine the comparability of C3-PAD performance to standardized neuropsychological tests. Forty-nine cognitively normal older individuals (mean age, 71.467.7 years; 20% non-Caucasian) were recruited from research centers at the Massachusetts General Hospital and Brigham and Women's Hospital. Participants made two in-clinic visits one-week apart and took five 30-minute alternate versions of the C3-PAD at...
A cross-sectional group study of the effects of aging on brain metabolism as measured with (18)F-... more A cross-sectional group study of the effects of aging on brain metabolism as measured with (18)F-FDG-PET was performed using several different partial volume correction (PVC) methods: no correction (NoPVC), Meltzer (MZ), Müller-Gärtner (MG), and the symmetric geometric transfer matrix (SGTM) using 99 subjects aged 65-87years from the Harvard Aging Brain study. Sensitivity to parameter selection was tested for MZ and MG. The various methods and parameter settings resulted in an extremely wide range of conclusions as to the effects of age on metabolism, from almost no changes to virtually all of cortical regions showing a decrease with age. Simulations showed that NoPVC had significant bias that made the age effect on metabolism appear to be much larger and more significant than it is. MZ was found to be the same as NoPVC for liberal brain masks; for conservative brain masks, MZ showed few areas correlated with age. MG and SGTM were found to be similar; however, MG was sensitive to a ...
Family history of dementia (FH) is a major risk factor for Alzheimer's disease (AD), particularly... more Family history of dementia (FH) is a major risk factor for Alzheimer's disease (AD), particularly when the FH is maternal and when the age of dementia onset (AO) is younger. This study tested whether brain amyloid-beta (Aβ) deposition, measured in vivo with 11 C-Pittsburgh compound B (PiB), was associated with parental dementia and/or younger parental AO. Detailed FH and positron emission tomography (PiB-PET) data were acquired in 147 non-demented aging individuals (mean age 75±8). No participant had both positive maternal and paternal FH. A series of analyses revealed that those with maternal, but not paternal, FH had greater levels of PiB retention in a global cortical region than those without FH. PiB retention in maternal FH was not significantly greater than paternal FH. Younger maternal dementia AO was related to greater PiB retention in offspring, while younger paternal dementia AO was not. Overall, results suggest that not only is Aβ burden greater in individuals with maternal FH, but also that the burden is greater in association with younger maternal AO.
Aging-related differences in white matter integrity, the presence of amyloid plaques, and density... more Aging-related differences in white matter integrity, the presence of amyloid plaques, and density of biomarkers indicative of dopamine functions can be detected and quantified with in vivo human imaging. The primary aim of the present study was to investigate whether these imaging-based measures constitute independent imaging biomarkers in older adults, which would speak to the hypothesis that the aging brain is characterized by multiple independent neurobiological cascades. We assessed MRI-based markers of white matter integrity and PET-based marker of dopamine transporter density and amyloid deposition in the same set of 53 clinically normal individuals (age 65-87). A multiple regression analysis demonstrated that dopamine transporter availability is predicted by white matter integrity, which was detectable even after controlling for chronological age. Further post-hoc exploration revealed that dopamine transporter availability was further associated with systolic blood pressure, ...
We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer di... more We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer disease biomarkers. In a cross-sectional study, we evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with mean age of 74 ± 6 years. Using backward elimination general linear models, we tested the hypotheses that greater cognitive or physical activity would be associated with lower Pittsburgh compound B-PET retention, greater (18)F-fluorodeoxyglucose-PET metabolism, and larger hippocampal volume, as well as better cognitive performance on neuropsychological testing. Linear regression demonstrated that history of greater cognitive activity was correlated with greater estimated IQ and education, as well as better neuropsychological testing performance. Self-reported recent physical activity was related to objective exercise monitoring. However, c...
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Papers by Reisa Sperling