bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of reduced injected dose on the quantification of [18F]RO948 and [18F]Flortaucipir PET for in vivo tau pathology
Authors: Young Peter , Thomas Wesley P. , Axelsson Jan , Himmelmann Jakob , Dominguez Pablo Aguilar , Ohlsson Tomas , Hansson Oskar , Lubberink Mark , Bohorquez Sandra Sanabria , Rieckmann Anna , Baker Suzanne L. , Schöll Michael
Published: February 2022

Background

Previous research has demonstrated that the injected dose in PET examinations can be reduced without substantial effects on quantitative outcomes. These reductions can lead to lower radiation burden for subjects, reduced costs for institutions and potential for additional research scans of the same subject. Here, we investigated the effect of reduced injected doses of [18F]RO948 and [18F]Flortaucipir (FTP) on standardised uptake value ratios (SUVRs) and associated outcomes.

Method

Images were manipulated from list‐mode data to simulate injected doses of 70%, 50%, 25% and 12.5% of the true injected dose. Initial analyses were scan time reduction for RO948 and dose reduction for FTP with future harmonisation of processing intended. Inferior cerebellum‐grey was used to compute SUVRs in regions‐of‐interest (ROIs) corresponding to the in vivo Braak regions of tau spread. Differences between true and reduced injected doses (given as a percentage) were calculated in individual regions as the mean of [SUVRreduced – SUVRtrue] over the means of SUVRreduced and SUVRtrue values across subjects.

Result

Previously reported test‐retest variability for RO948 and FTP are 2‐6% (±6%) and 1.5‐3.3% (±3%) respectively. Regionally, RO948 remained below this TRT variability at 25% injected dose, with an average SUVR difference of 2.3% (±8%) (figure 2), whereas FTP remained below TRT variability only at 70% injected dose with an average SUVR difference of 2.9% (±3%). However, differences were above TRT variability for FTP at lower injected doses. FTP average SUVR differences were observed to be higher in CN compared to AD patients at reduced injected doses but with greater variability in AD than CN. There were no differences observed between Ab+ and Ab‐ controls.

Conclusion

Preliminary findings suggest that lower injected tracer‐doses for RO948 and FTP yield robust SUVRs. However, the degree to which injected doses can be reduced must be investigated further for different demographics and for different tracers. Ongoing work aims to harmonise the simulation list‐mode processing, add MCI/AD RO948 subjects, and evaluate dose reduction in [18F]GTP1 data. Further validation will be performed against demographic and clinical variables, as well as for longitudinal data.
Association of AD biomarker levels with functional connectivity within and between large‐scale brain networks among cognitively normal individuals
Authors: Soldan Anja , Pettigrew Corinne , Bilgel Murat , Kutten Kwame , Miller Michael I. , Hou Xirui , Lu Hangzhang , Albert Marilyn S.
Published: February 2022

Background

It is well documented that amyloid pathology accumulates many years prior to the emergence of clinical symptoms of Alzheimer’s disease (AD), when individuals are cognitively normal. Few prior studies have investigated the impact of AD pathology on brain connectivity among cognitively normal individuals. We investigated the impact of AD biomarkers on functional connectivity within and between large‐scale brain networks important for cognitive function.

Method

Analyses included 123 cognitively normal participants (mean age=69 years) from the BIOCARD Study who completed clinical and cognitive assessments, resting state functional magnetic resonance imaging (rs‐fMRI) scans, and cerebrospinal fluid (CSF) measures of AD biomarkers [abeta1‐42 (AB42), abeta1‐40 (AB40), total tau (ttau), and phosphorylated tau 181 (ptau)] during their annual visit. Among these, 106 participants also had 11C‐PiB PET imaging to assess amyloid burden. Functional connectivity within 7 large‐scale, non‐overlapping networks was measured and averaged to compute global within‐network connectivity. Between‐network connectivity was measured using graph theory‐based metrics of modularity and segregation. Linear regressions (covarying age, sex, education, whole brain volume, and vascular risks) tested the associations between the connectivity measures and the CSF and PET AD biomarkers.

Result

Older age was associated with reduced global connectivity within networks and reduced network modularity and segregation (all p’s <0.05), indicating reduced functional specialization with older age, consistent with prior studies. Amyloid positivity on PET, as well as lower AB42/AB40 and higher ttau/AB42 and ptau/AB42 ratios were associated with higher network modularity and segregation (all p’s <=0.01). When AB42/40, ttau, and ptau were simultaneously entered in the regressions, only AB42/AB40 remained significantly associated with modularity and segregation (p’s<0.01). There were no associations between the CSF or PET biomarkers and global within‐network connectivity.

Conclusion

Among older individuals with normal cognition, more abnormal AD biomarker levels were related to greater network modularity and segregation. Given that higher modularity and segregation are important for maintaining cognitive function with age, these results suggest that the associations with rs‐fMRI connectivity may reflect a compensatory response of the brain to accumulating pathology. These findings are consistent with autopsy studies showing compensatory increases in neuronal size (neuronal hypertrophy) among asymptomatic individuals with AD pathology.
Courage in care planning: Advanced care planning readiness in caregivers of individuals living with dementia
Authors: Brandt Katherine , Quimby Megan , Wong Bonnie , Quintiliani Lisa M , Marchesano Amy , Howe Inola , Paasche‐Orlow Michael K , Krahn Erin , Krivensky Samantha , O’Chander Raseeka , Dickerson Brad C , Volandes Angelo
Published: February 2022

Background

Family caregivers of individuals living with dementia due to Alzheimer’s Disease, Frontotemporal Dementia and related diseases must make medical decisions and develop care plans for current and future needs of care recipients, often without a comprehensive understanding of those needs. Educational tools are available to help caregivers but little guidance is offered to healthcare providers about when and how to raise the topic of advanced care planning and present educational tools.

Method

As part of a larger study about the utility of video decision aids for advanced care planning in dementia, we conducted 16 focus groups, interviewing 28 caregivers of individuals living with dementia, separated into those with mild, moderate, or severe dementia. During each group, video decision aids about specific caregiving topics were shown. After each video, participants answered six questions about acceptability and then responded to open‐ended questions to explain their ratings. We coded the focus group transcripts using a qualitative content analysis method; similar codes were grouped into themes.

Result

The qualitative data support the following major themes, which did not differ across dementia severity stages. Caregivers like learning through videos even when serious illness topics are presented, and would like this opportunity at early stages and in an ongoing way. Caregivers would like to engage in care planning with loved ones who have dementia early in the process so that they may have a voice in planning.

Conclusion

The evidence from this qualitative study revealed that caregivers of individuals with dementia like learning about advanced care planning topics through videos—including serious illness topics—and that access to such information at an early stage and in an ongoing way is desirable. We plan to evaluate whether empowering caregivers with information about anticipated medical decisions at an earlier stage promotes earlier care planning. We also plan to evaluate whether earlier care planning allows some individuals living with dementia to engage with caregivers in the process, and whether that increases caregiver confidence in planning for healthcare decisions. We believe that early dyadic engagement in care planning promotes dignity and person‐centered care planning for individuals living with dementia.
The relationship between flutriciclamide PET uptake and grey matter atrophy in mild cognitive impairment and Alzheimer’s disease
Authors: Raza Sanara , Calsolaro Valeria , Buckley Christopher , Gentleman Steve , Brooks David J. , Edison Paul
Published: February 2022

Background

Microglial activation plays a significant role in neuroinflammation in the neurodegenerative process. Microglial activation is characterised by the over‐expression of a mitochondrial protein (TSPO), that can be targeted by PET Tracers. This study aims to evaluate the relationship between [18F]GE180 PET uptake and grey matter atrophy.

Method

In this PET study, we evaluated microglial activation in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) using the novel TSPO ligand flutriciclamide ([18F]GE180). Forty‐eight participants have been assesed with [18F]GE180 PET using arterial input. Spectral analysis was used to generate parametric maps of the impulse response function at 90 minutes. Additionally, hippocampal volume analysis was performed on structural magnetic resonance images (MRIs).

Result

In a group‐wise analysis a significant reduction in hippocampal volume was found between the AD and healthy controls cohorts. Hippocampal volume significantly negatively correlated with the IRF90 in the temporal lobe and occipital lobes as well as and composite region in AD patients compared to healthy controls.

Conclusion

In this [18F]GE180 PET imaging study in AD/MCI cohort, we have demonstrated that there is hippocampal atrophy when [18F]GE180 PET goes up in AD patients. The results indicate that regional [18F]GE180 PET uptake has a close association with neurodegeneration of key memories processing centre.
Tau pathology progression across PET‐based stages of regional amyloid deposition
Authors: Moscoso Alexis , Grothe Michel J. , Schöll Michael
Published: February 2022

Background

Previous research has consistently reported widespread tau aggregation in the presence of global amyloid‐β (Aβ) pathology, but the association of Aβ pathology severity with tau accumulation remains unclear. Here, we studied cross‐sectional and longitudinal tau aggregation in relation to progressive stages of regional Aβ deposition as determined by a recently established Aβ PET‐based staging approach.

Method

We examined 244 cognitively unimpaired (CU) and 180 impaired (CI) subjects from the Alzheimer’s Disease Neuroimaging Initiative with concurrent T1 MRI, 18F‐Florbetapir‐PET (FBP), and 18F‐Flortaucipir‐PET (FTP) scans. A subset of 153 individuals had at least one follow‐up FTP scan. An Aβ PET‐based staging method for FBP was used to stratify participants into four progressive stages of Aβ deposition. Linear regressions adjusted for age and sex were used to assess regional FTP uptake across Aβ stages in CU and CI individuals (additionally controlled for clinical diagnosis ‐ MCI/AD). Longitudinal tau accumulation was assessed in the pooled CU and CI sample, using linear mixed effects models adjusted for age, sex, and clinical diagnosis. Finally, we assessed cross‐sectional tau‐related markers (p‐tau181 and p‐tau181/Aβ1‐42) in cerebrospinal fluid (CSF) across Aβ stages in another subset of participants (n=227).

Result

Cross‐sectionally, FTP uptake in Braak I/II regions increased gradually from Aβ stages 1 through 4, though only Aβ stage 4 in CU and stages 3 and 4 in CI yielded widespread neocortical tau deposition compared to stage 0 (Fig. 1). Similarly, faster longitudinal FTP increases in Braak I/II regions were observed from Aβ stage 2 onwards, but only Aβ stages 3 and 4 showed faster tau accumulation in regions exceeding Braak I/II (Fig. 2). Corroborating the PET findings, cross‐sectional levels of p‐tau181 and p‐tau181/Aβ1‐42 in CSF showed gradual increases across Aβ stages 2‐4 (Fig. 3).

Conclusion

Early stages of Aβ pathology selectively affect medial temporal lobe tau deposition, but more severe and widespread tau pathology does not occur before more advanced stages of Aβ deposition. Since these only cover a subpopulation of Aβ‐positive individuals as conventionally defined, specifically recruiting individuals at advanced Aβ stages might represent an effective strategy for clinical trials in which longitudinal tau PET is used as an outcome measure.
Correlates of neuroimaging measures with pathological scales of cerebrovascular disease
Authors: Vemuri Prashanthi , Kouri Naomi , Przybelski Scott A. , Labuzan Sydney A. , Lesnick Timothy G. , Reid Robert I. , Reichard Ross R. , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Mielke Michelle M. , Dickson Dennis W. , Graff‐Radford Jonathan , Murray Melissa E.
Published: February 2022

Background

Summarizing the multiplicity and heterogeneity of cerebrovascular disease (CVD) features into a single measure has been difficult in both pathology and imaging studies. The objective of this work was to evaluate the association between neuroimaging surrogates of CVD and two available neuropathologic CVD scales in those with both antemortem imaging CVD measures and post‐mortem CVD evaluation. We used (1) Strozyk scale (Strozyk et. al. NBA 2010) which is based on presence and number of three macroscopic lesions (large infarctions, lacunar infarctions, and leukoencephalopathy) and (2) Kalaria scale (Deramecourt et. al. Neurology 2012) which summarizes detailed evaluation of vessel wall modifications (arteriolosclerosis, amyloid angiopathy), perivascular spaces, myelin loss, microinfarctions, and large infarctions.

Method

We identified n=51 individuals in Mayo Clinic Study of Aging (mean age of 83.8 years, 37% female) with MRI scans within 5 years of death. We computed CVD measures from DTI (fractional anisotropy of the genu of the corpus callosum [FAGCC] and fractional anisotropy of cingulum adjoining the hippocampus [FACGH]), FLAIR (white matter hyperintensities [WMH] and total number of infarctions), and T2* GRE (total number of microbleeds). We also computed our recently developed imaging CVD composite score which summarizes the variability in all individual CVD imaging measures described above. We computed the Strozyk and Kalaria scales on postmortem tissue. We used weighted linear regression models with adjustments for MRI scan time to death to evaluate the associations between the antemortem neuroimaging measures and pathology scales in those who had scans within 3 years of death (N=31) and 5 years of death (N=51) (tables 1 and 2).

Result

Of all the neuroimaging measures, DTI measures were the best predictors of the Strozyk and Kalaria Scales (p<0.05). In sensitivity analyses of data in Table 1, FAGCC explained 44% and FACGH predicted only 5.5% variability in white matter sub‐component of the Strozyk scale. The CVD composite score was a poor surrogate of the composite pathological scales.

Conclusion

Microstructural white matter injury measurement using DTI may be a good surrogate of pathological CVD scales and possibly captures diffuse (and early) changes to white matter and secondary neurodegeneration due to lesions.
Factors associated with disclosing a diagnosis of dementia to one’s social network: A systematic review
Authors: Kohl Gianna , Ulate Mauricio Molinari , Bhatt Jem , Scior Katrina , Charlesworth Georgina
Published: February 2022

Background

Dementia, to a certain degree in the early stages, can be a concealable condition. People with dementia often feel stigmatized and choose not to disclose their diagnosis to others. While concealing the diagnosis can prevent further stigmatization, it can also contribute to psychological consequences and limited social support, and prevent access to services and resources. The decision to disclose a concealable diagnosis is personal and complex, and a nuanced understanding of this decision is of great relevance to practitioners and researchers. This review examines factors influencing the decision to disclose or conceal a diagnosis of dementia to or from others, including individuals’ attitudes and experiences regarding disclosure or concealment.

Method

The protocol of this review has been registered on PROSPERO (CRD42020192495). A systematic literature search was conducted in the MEDLINE, PsycINFO, Embase, Emcare, CINAHL and Scopus databases. Search terms related to ‘disclosure’ or ‘concealment’, and ‘dementia’. Any research design was included and no date or language restrictions were applied. The methodological quality of included studies was assessed using the Mixed Methods Appraisal Tool (MMAT). Data was analyzed by means of thematic synthesis.

Result

A total of sixteen studies published between 2000 and 2020 were included in the systematic review. Factors associated with disclosure and concealment were regrouped into codes and themes related to stigma, interpersonal relationships, personal identity, sense of control, privacy, symptom visibility, and advocacy and awareness. People with dementia may anticipate negative responses from others when they disclose their diagnosis to them, but reactions are often positive.

Conclusion

Results of this review suggest that the decision to disclose or conceal a diagnosis of dementia to or from one’s social network is highly individual and complex. People with dementia may often want to disclose, but do not know how. Raising awareness in the general public may support individuals in making optimal decisions about disclosure. Findings of this review will inform an empowerment intervention supporting disclosure decision‐making in people with dementia.
Differences in functional connectivity amongst older adults with mild cognitive impairment, subjective cognitive decline or normal cognition
Authors: Srikanthanathan Arunan , Vandermorris Susan , Verhoeff Nicolaas Paul L.G. , Chen Jean , Herrmann Nathan , Mah Linda
Published: February 2022

Background

Subjective cognitive decline (SCD), hypothesized as a preclinical stage of Alzheimer’s disease (AD), describes individuals with subjective cognitive concerns despite normal performance on cognitive tests (Jessen et al., 2014). The reduced ability of the salience network (SN) to control switching between the central executive network (CEN) and the default mode network (DMN) has been linked to deterioration of cognitive functioning in normal aging, mild cognitive impairment (MCI) and AD dementia (He et al., 2014). Since alterations in functional connectivity between these networks have been implicated in MCI and AD, we compared connectivity of the SN with CEN and DMN amongst SCD, MCI and older adults who were cognitively unimpaired (CU). We predicted that SCD would show reduced SN connectivity between CEN and DMN networks compared to CU, but greater connectivity compared to MCI.

Method

Participants were 72 older adults [39 females, mean age=71.5] who were classified as either CU (n=26), SCD (n=29), or MCI (n=17). CU reported no memory concerns and performed within normal limits on neuropsychological (NP) assessments. SCD was established by affirmative responses to “Do you feel like your memory is becoming worse?” “If so, are you worried?” and normal NP test performance. MCI was based on the presence of subjective cognitive concerns and impairment on ≥ 2 NP measures within a cognitive domain, and functional independence. Participants underwent resting state functional magnetic resonance imaging (rs‐fMRI) for 6 minutes in an awake state with their eyes closed using gradient‐echo EPI BOLD at 3T (TR=2000ms, TE=30ms). Imaging data were processed using CONN toolbox. Seed‐based analysis using left and right frontoinsular cortices as seeds, which are key nodes in the SN network (MNI coordinates: ‐34,24‐,6 and 38,16,6, respectively), was conducted to measure connectivity between SN and the other two networks, CEN and DMN, within each group.

Result

Groups did not differ in age, years of education, or sex distribution [F(2,69)=0.415, p=0.66;F(2,69)=2.20, p=0.12;X2(2, N=72)=1.89, p=0.39, respectively]. Results from imaging data analyses will be presented.

Conclusion

Examination of functional connectivity in SCD can be conducted using rs‐fMRI and may provide a window to the neurobiology of SCD.
"Let's Connect": Implementing a tablet‐based intervention for people with dementia and caregivers
Authors: Dove Erica , Shearer Teresa , Cotnam Karen , Gural Paul , Chamoun Elicia , Astell Arlene J
Published: February 2022

Background

Let’s Connect training to use tablets and accessible apps with people living with dementia was implemented with staff, volunteers and family caregivers to evaluate the program impact.

Method

Eighty‐six staff and volunteers (18‐88 years of age) in 14 adult day programs and long‐term care homes in Ontario, Canada received training to deliver Let’s Connect groups as part of their daily or weekly programming. They were supported to deliver Let’s Connect group program for an initial eight sessions program with 118 people with dementia (56‐98 years of age). Staff and volunteers completed the Dementia Attitudes Scale (DAS) before and after the eight sessions and an exit interview, which was also completed by family caregivers who received training to support Let's Connect at home. People with dementia completed the QoL‐AD and SPS‐10 measure of social connectedness plus exit interviews.

Result

There was an improvement in staff and volunteer’s DAS score, while the people with dementia attending the adult day programs maintained their relatively high levels of social connectedness. Thematic analysis identified social interaction as a key benefit for staff, volunteers, caregivers and people with dementia. Further benefits and potential barriers were also identified.

Conclusion

Let’s Connect was well‐received, directly improved attitudes towards dementia and enhanced social activity. All of the sites that received training continued with the Let’s Connect group program after the research project ended. We will share our training strategy that can be applied to other tablet‐based activities.
Associations between biomarker status (amyloid, tau) and risk for progression to MCI/Dementia in the Harvard Aging Brain Study
Authors: Papp Kate V. , Rentz Dorene M. , Winskill Carolyn , Betensky Rebecca A. , Amariglio Rebecca E. , Schultz Aaron P. , Johnson Keith A. , Sperling Reisa A.
Published: February 2022

Background

Previous reports have shown that elevated AD biomarkers among clinically normal (CN) older adults confer heightened risk for a subsequent diagnosis of cognitive impairment using CSF and amyloid imaging. Here, we examine the impact of biomarker status on neuroimaging for both amyloid(A+/A‐) and tau(T+/T‐) on risk for clinical progression.

Method

Participants were CN at enrollment and underwent PET with 11CPiB to characterize global amyloid‐β(A) burden and F18Flortaucipir (FTP) to quantify inferior temporal tau(T). Participants were dichotomized as A+/A‐ and T+/T‐ using previously described mixture model distribution cut‐points. Because FTP only became available mid‐study, we undertook two analytical approaches: 1) cox regression analysis with first PiB scan as time origin (n=342, follow‐up=6.10 years;range=1‐9) with tau treated as a time‐varying covariate (setting it to T‐ prior to the first FTP scan if T‐ and setting it to missing prior to first scan if T+) and 2) first FTP scan as time origin with tau treated as fixed at that time (n=242, follow‐up=5.12 years;range=1‐7). Participants were diagnosed annually by biomarker‐blinded case conference. Covariates included Demographics and E4(+/‐).

Result

In the larger sample (31 individuals diagnosed with MCI/dementia), A+ was associated with increased diagnostic risk (HR=12.43, 95%CI=4.89‐31.57). In a model that included T as time‐varying (but not A), T+ was associated with increased risk for diagnosis (HR=4.46, 95% CI=0.99,20.11, p=0.051). Including A in the model, A+ was associated with increased diagnostic risk (HR=5.30, 95%CI=1.29,21.72) and T+ additionally appeared to confer higher risk, though not statistically significant (HR=2.89, 95%CI=0.12,67.73). An interaction term was not significant (HR for A+T+ versus A+T‐=4.65,95%CI=0.28,77.79). In the smaller sample with tau (19 individuals diagnosed), T+ was also associated with greater risk for diagnosis (HR=3.61, 95%CI=1.38‐9.40). Older age (HR=1.09, 95%CI=1.02‐1.18) and E4+ (HR=5.40, 95%CI=1.96‐14.89) were contributory. Both A+ (HR=13.83, 95%CI=2.82‐67.81) and T+ (HR=2.75, 95%CI=1.05‐7.24) are associated with higher diagnostic risk when included in the same model. A+T+ was associated with higher risk(HR=2.59, 95%CI=0.98‐6.83,p=0.055) compared with A+T‐.

Conclusion

A+ in combination with T+, is a significant risk factor for clinical progression. These findings provide further encouragement that interrupting A among CN older adults may mitigate risk for clinical progression.
Association of mitochondrial DNA copy number with brain MRI and cognitive function in the TOPMed Program
Authors: Zhang Yuankai , Liu Xue , Wiggins Kerri L. , Sofer Tamar , Guo Xiuqing , DeCarli Charles S. , Glahn David C. , González Hector M. , Levy Daniel , Nyquist Paul , Pitsillides Achilleas N. , Psaty Bruce M. , Rodrigue Amanda L. , Rotter Jerome I. , Smith Jennifer A. , Yanek Lisa R. , Seshadri Sudha , Bis Josh C. , Heckbert Susan , Fitzpatrick Annette L. , Fornage Myriam , Liu Chunyu , Satizabal Claudia L.
Published: February 2022

Background

Mitochondria are the main energy source for normal neuronal functions. Mitochondrial DNA (mtDNA) copy number (CN), a measure of mtDNA levels in the cell, correlates with cellular energy generating capacity and metabolic status. Previous studies have observed a significant decrease of circulating cell‐free mtDNA content in the cerebrospinal fluid of patients with Alzheimer's disease (AD). However, it is unknown whether mtDNA CN circulating in the blood is related to AD endophenotypes. We aimed to investigate the cross‐sectional association of mtDNA CN with MRI markers of abnormal brain aging and cognitive function.

Method

We included dementia‐free, multiethnic participants from seven population‐based cohorts with whole‐genome sequencing as part of the Trans‐Omics for Precision Medicine (TOPMed) program. The average mtDNA CN in whole blood was estimated as twice the ratio of the average coverage of mtDNA to the average coverage of the nuclear DNA using fastMitoCalc from mitoAnalyzer. Brain MRI markers included total brain volume, hippocampal volume, and white matter hyperintensities. General cognitive function was derived from at least three distinct cognitive domains using principal component analysis. We related mtDNA CN to AD endophenotypes assessed within 5 years of blood draw per cohort and further performed random‐effects or sample size‐weighted meta‐analyses. Models were adjusted for demographics and vascular risk factors.

Result

Higher mtDNA CN was significantly associated with better general cognitive function (P‐values<0.05) in four cohorts after adjusting for age, sex, batch effect, self‐reported race/ethnicity, the time between blood draw and MRI/Cognitive evaluation, cohort‐specific variables, and education (Figure 1). Meta‐analysis across all cohorts confirmed and strengthened the significant association between mtDNA CN and general cognitive function (n=11,021, Beta=0.046, SE=0.01, P‐value=0.0002). Additional adjustment for diabetes, hypertension, hyperlipidemia, and obesity led to similar results (Beta=0.043, SE=0.01, P‐value=0.002). We observed no significant associations between mtDNA CN and brain MRI markers.

Conclusion

This study suggests that higher mtDNA CN is cross‐sectionally associated with better general cognitive function in a large sample from diverse communities across the US, providing novel findings that support the role of mtDNA in healthy brain aging. Additional analyses are underway to relate mtDNA CN to AD endophenotypes prospectively and to incident dementia.
Associations between MRI‐assessed locus coeruleus integrity and restriction spectrum imaging of cortical gray matter microstructure
Authors: Elman Jeremy A. , Puckett Olivia K. , Hagler Donald J. , Pearce Rahul C. , Fennema‐Notestine Christine , Hatton Sean N. , Dale Anders M. , Panizzon Matthew S. , Lyons Michael J. , Franz Carol E. , Kremen William S.
Published: February 2022

Background

The locus coeruleus (LC) serves as the primary source of norepinephrine for the brain. Findings that the LC is one of the earliest sites of tau pathology make it a key structure in the early stages of Alzheimer’s disease (AD) progression. An important question is whether measures of LC integrity are associated with indexes of brain structure that may suggest broader patterns of neurodegeneration, particularly if such patterns are detectable prior to substantial macrostructural change. We therefore examined whether LC structural integrity was associated with differences in cortical gray matter microstructure among adults in early old age.

Method

Participants were 435 men (mean age=67.5; range=62‐71.7) from the Vietnam Era Twin Study of Aging (VETSA). Rostral LC structural integrity was indexed by contrast‐to‐noise ratio (LCCNR) from a neuromelanin‐sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi‐shell diffusion technique, was used to characterize cortical microstructure, modeling diffusion in restricted, hindered, and free water compartments. Associations between LCCNR and isotropic diffusion within each compartment were examined for bilateral averages of 34 cortical ROIs defined by the Desikan‐Killiany parcellation. As a sensitivity analysis, we also examined whether LCCNR was associated with mean diffusivity (MD), a conventional diffusion tensor imaging (DTI) metric, or cortical thickness in the same regions.

Result

After correction for multiple comparisons, higher LCCNR (greater structural integrity) was significantly associated with higher hindered isotropic diffusion and lower free water diffusion across multiple brain regions. In contrast, LCCNR was only associated with lower MD in one brain region and there were no associations with cortical thickness after correction.

Conclusion

These results provide evidence that lower MRI‐assessed LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cellular membranes due to broader neurodegenerative processes. Individual differences in LC integrity were only detected with more advanced measures of microstructure that may be more sensitive to early changes than conventional diffusion imaging or macrostructural measures. These results highlight the potential utility for MRI of the LC and cortical microstructure in early identification of AD risk.
18F‐Flortaucipir PET imaging compared with autopsy in a clinically and pathologically heterogeneous group of patients with neurodegenerative dementias
Authors: McGinnis Scott M. , Touroutoglou Alexandra , Eckbo Ryan , Brickhouse Michael , Quimby Megan , Wong Bonnie , Frosch Matthew P. , Gomperts Stephen , Johnson Keith A. , Dickerson Brad C.
Published: February 2022

Background

We aimed to investigate the utility of qualitative visual rating of 18F‐flortaucipir tau (FTP) PET to predict the neuropathologic diagnosis in patients with a diverse array of clinical syndromes who were followed to autopsy.

Method

FTP PET, PiB PET, and high resolution T1 MRI scans were rated independently by visual inspection by two raters blinded to clinical diagnosis in n=22 subjects, including patients with a clinical syndrome of amnesic dementia (n=1), posterior cortical atrophy (n=2), logopenic primary progressive aphasia (n=1), nonfluent PPA (n=4), semantic PPA (n=3), corticobasal syndrome (n=1), behavioral variant frontotemporal dementia with a MAPT mutation (n=3) or GRN mutation or C9orf72 expansion (n=2), progressive supranuclear palsy (n=4), or dementia with Lewy bodies (DLB; n=1). FTP scans were classified using a two‐tiered system. First‐tier classification distinguished scans as either “abnormal‐>high‐confidence AD,” “abnormal‐>mildly‐elevated uptake,” or “normal.” Among scans classified as “abnormal‐>high‐confidence AD,” second‐tier classification distinguished “typical AD,” “atypical AD,” or “late‐stage AD.” Among scans classified as “abnormal‐>mildly‐elevated uptake,” second‐tier classification distinguished “possible early‐stage AD,” “possible FTLD,” or “indeterminate.”

Result

All individuals with ADNC as the primary pathology were classified as abnormal‐>high confidence AD. All individuals with FTLD as the primary pathology were classified as abnormal‐>mildly‐elevated uptake‐>possible FTLD, but cases with FTLD‐TDP43 pathology were not distinguishable based on FTP from those with FTLD‐tau, supporting prior observations. Additional details will be reported on these and the other cases.

Conclusion

In a clinically and pathologically diverse sample of patients with neurodegenerative dementias, visual rating of FTP PET accurately differentiates AD from FTLD. FTP PET is not useful for the discrimination of FTLD‐tau vs. FTLD‐TDP43.
Quantifying acute tau inoculations in living rats using PET
Authors: Kunach Peter
Published: February 2022

Background

Monitoring tau propagation in the living brain has important pathophysiological and therapeutic implications. As tau imaging agents are dependent on tau conformations, we aimed to determine the tau species amenable to in vivo imaging. Previously we demonstrated that ex vivo tau preparations may be used to image tau seeds in living murine systems, as opposed to recombinant preparations. As such, the goal of this work is to examine the dose‐dependent relationship of patient derived AD‐tau fibrils on PET imaging outcomes.

Method

A total of two 15‐month‐old (2 wild‐type, one male and one female) rats were used. All animal had a baseline scan with [18F] MK6240 before the stereotaxic injections. We tested tau PHFs from AD brains using ultracentrifugation of sarkosyl‐insoluble brain fractions. AD‐tau preparations were stereotaxically injected in the dorsal hippocampus. We tested injection volumes of 1 and 3 uL of equal concentrations (80 ng/uL). Contralateral hemispheres were injected with equivalent amounts of PBS, the solvent for tau preparations. All PET images were coregistered to the Waxholm Space Atlas of the Sprague Dawley Rat Brain sMRI using a linear transformation. The non‐displaceable binding potential (BPND) images were generated using cerebellar grey as a reference region based on Simplified Reference Tissue Method (SRTM).

Result

Injection of sarkosyl‐insoluble brain fractions from AD patients displayed positive BPnd outcome in both volumes tested. Control hemispheres injected with PBS showed potential off‐target binding. Reliability of this outcome was investigated using peak normalized TACs. Hemispheres receiving AD‐tau injections showed visible divergence in retention, as compared to baseline. The hemisphere that was inoculated with 3uL of AD‐tau showed separation during washout. A similar effect was seen in the control hemisphere.

Conclusion

These results continue to suggest ex vivo tau preparations may be used to image tau seeds in living murine systems. The reliability of PET and kinetic outcomes are dependent on the volume injected. Further investigation will aim to evaluate AD‐tau concentration as the dosage variable instead of injection volume. Cerebellar tissue from patients used to extract AD‐tau species should be as a control injection to account for the reagents used for protein extraction, instead of PBS alone.
Efficacy of a timed activity intervention in improving sleep and well–being: Findings from the Healthy Patterns trial
Authors: Hodgson Nancy A , Talwar Sonia , Aryal Subhash
Published: February 2022

Background

Irregular sleep‐wake patterns are common in persons living with dementia, pose a great burden to caregivers, and are the principal causes of distress and institutionalization. A growing body of research supports the importance of activity‐based interventions to reduce the frequency and intensity of sleep wake disruption, enhance personhood and dignity, and improve quality of life (QOL).

Method

A two‐arm RCT was conducted with 170 dyads of persons living at home with dementia and with symptoms of sleep‐wake disruption, and their family caregiver. Specific components of the Healthy Patterns intervention include: 1) assessing health/functional status and preferences/interests; 2) educating caregivers on environmental cues to promote activity and sleep; and 3) training caregivers in using timed morning, afternoon, and evening activities based on circadian needs. Outcomes included: QOL, function, neuropsychiatric symptoms, and actigraphic and proxy‐reported measures of sleep‐wake patterns.

Result

At 4 weeks, the intervention group showed significantly greater improvement than the control group in QOL (p=.01) and sleep efficiency (p=.04).

Conclusion

Results provide new fundamental knowledge regarding the nature and timing of activities for persons with dementia. It has the potential to change how and when activities for persons with dementia are provided.
Cortical gray matter volume and working memory in a NHP model of AD‐like neuropathology
Authors: Frye Brett M. , Craft Suzanne , Register Thomas C. , Kim Jeongchul , Whitlow Christopher T. , Barcus Richard A. , Lockhart Samuel N. , Solingapuram Sai Kiran K. , Shively Carol A.
Published: February 2022

Background

Age‐related neurodegeneration characteristic of late‐onset Alzheimer’s disease (LOAD) begins in middle age, well before symptoms. Therefore, translational models to identify modifiable risk factors in middle‐age are needed to understand the etiology and identify early therapeutic targets for intervention. Vervet monkeys (Chlorocebus aethiops sabaeus), like humans, have complex central nervous systems and naturally develop several risk factors for LOAD with age, including obesity, prediabetes, hypertension and decline in physical function. Furthermore, aged vervets also recapitulate many of the characteristics of early AD that are associated with reduced brain volumes, including human‐like Aβ accumulation in the brain, greater Aβ plaque burden, and reduced CSF Aβ. Thus, these NHPs are ideal models for studying healthy versus neuropathological aging.

Method

Using structural magnetic resonance imaging and cognitive assessments, we examined the relationships between age, working memory, and neuroanatomy by measuring the thicknesses and volumes of AD‐signature cortical regions of interest (“meta‐ROIs”) in 46 middle‐aged to elderly female vervets (8‐29 years of age).

Result

Using linear mixed effects models with age as a fixed effect and individual as a random effect, we found that cortical gray matter volume significantly decreased with increasing age (β=‐51.94, SE=14.37; t=‐3.61; p<0.001). The thickness of the AD‐signature meta‐ROIs was not affected by age (β<0.01, SE<0.01; t=‐0.19; p=0.85), however, the volumetric meta‐ROI tended to decline with age in older animals (β=‐6.95, SE= 4.20; t=‐1.65; p= 0.098). In the precuneus, a component region of the meta‐ROI that has been shown to be reduced in preclinical AD, volume decreased with increasing age (β=‐1.69, SE=0.72; t=‐2.36; p= 0.023). In addition to these age‐related effects, the volume of the AD‐signature meta‐ROI was positively correlated with performance on the delayed response test of working memory (R= 0.235; p=0.026).

Conclusion

Taken together, these findings demonstrate that cortical gray matter diminishes with age in vervet monkeys in regions relevant to AD risk, and is associated with cognitive impairment. This study provides important insights about the relationships between age, neuroanatomy, and memory in vervets, and lays the groundwork for future investigations to identify at‐risk phenotypes such that therapeutic interventions may be tested in this nonhuman primate model.
Locus coeruleus integrity as a proxy of initial tau burden: in vivo versus ex vivo observations
Authors: Jacobs Heidi I.L. , Becker Alex , Kwong Kenneth , Engels Nina , Prokopiou Prokopis C. , Papp Kate V. , Properzi Michael J , Hampton Olivia L. , Sanchez Justin S. , Rentz Dorene M. , Fakhri Georges El , Normandin Marc D. , Bennett David A. , Sperling Reisa A. , Johnson Keith A.
Published: February 2022

Background

Autopsy studies reported the locus coeruleus (LC) as one of the initial regions in the brain harboring hyperphosphorylated tau pathology. MR signal intensity in the LC has been proposed as a measure of LC integrity, but the contribution of tau pathology, commonly found in LC, to this signal intensity is not currently measurable in vivo. We related in‐vivo LC MR signal intensity to Alzheimer’s disease (AD) phenotype and PET measures and used ROSMAP autopsy data to guide interpretation of the MR LC measure as tau‐related or cellular integrity‐related.

Method

One‐hundred seventy‐two participants from the Harvard Aging Brain Study (HABS) underwent 3T LC‐MRI imaging, FTP and PiB‐PET imaging (median age: 75 years, 58% female, n=22 with CDR=0.5/1). In 160 individuals from ROSMAP, LC tangle density and neuronal density were quantified at autopsy (median age at death: 89 years, 67% female, 66 control, 53 mild cognitively impaired, 41 AD patients; Figure 1). Groups were compared using ANCOVA. LC measures were related to Mini‐Mental State Examination (MMSE) scores using Spearman correlations (age‐adjusted). In HABS, LC integrity was vertex‐wise regressed on tau‐PET. In ROSMAP, Spearman correlations related LC tangle or neuronal density to cortical tangle density or Braak staging.

Result

LC measures correlated with measures of disease progression: in HABS, LC integrity was lower in impaired individuals compared to controls, and correlated positively with MMSE score. In ROSMAP, LC tangle density was higher in MCI/AD patients compared to controls; and correlated negatively with MMSE scores. No associations were found for LC neuronal density (Figure 2). Furthermore, lower LC integrity correlated with higher tau in medial‐lateral temporal regions in HABS, mirroring the consecutive Braak‐staging. Similarly, In ROSMAP, higher LC tangle density, but not LC neuronal density, correlated positively with cortical tangle burden and Braak staging (Figure 3).

Conclusion

The comparable associations of MRI‐LC integrity or LC tangle density with disease progression and tau suggest that MRI‐measures of LC integrity may be a proxy for tau pathology, rather than neuronal density. Future verification using head‐to‐head comparison is warranted, but our results indicate that LC integrity holds promise as marker for detection of initial AD‐related processes.
The logistical landscape of lay dementia care
Authors: Reilly Shannon , Manning Carol A
Published: February 2022

Background

In 2018, more than 16 million unpaid caregivers (CG) provided care for people with dementia (PWD), care that is associated with increased caregiver depression, poor health and caregiver burden (Alzheimer’s Association, 2019). This observational, cross‐sectional study examined CGs’ relationships to PWDs, how CGs allot their caregiving time, how caregiving affects their work, and CGs’ mental health. We hypothesized that CGs would be primarily spouses or children of the PWD, that they would provide the majority of unpaid care without an extensive support system and with a significant amount of time spent on caregiving, that would disrupt their employment, and be accompanied by relatively high levels of mental health symptoms.

Method

At the initiation of a dementia care coordination program, CGs (N = 96) were surveyed regarding their personal characteristics, the PWDs they care for (N = 96), and CG perceptions of caregiving. Descriptive information about the landscape of their caregiving at baseline is presented (Table 1).

Result

Most CGs were women, whereas PWD gender was more evenly split. Most CGs were spouses or children of PWDs, and over 70% lived with the PWD. Only about half were the PWD’s power of attorney. The majority of CGs provided over 80% of care to the PWD, often unpaid and without other help. On average, CGs spent the equivalent of a full‐time job supervising and assisting with complex activities of daily living (ADLs) and the equivalent of a part‐time job assisting with basic ADLs. Of employed CGs (<50%), over 85% were not paid for caregiving, and caregiving disrupted their work. CGs on average had a clinical degree of depression, minimal anxiety, and mild to moderate caregiver burden.

Conclusion

This sample of CGs is generally consistent with our expectations and national U.S. statistics on CGs (e.g., Alzheimer’s Association, 2019). Importantly, CGs spend large amounts of time providing unpaid caregiving with significant financial consequences and little support from others. CGs are a vulnerable group in terms relatively high levels of depression and CG burden. Innovations in provision of caregiver support are needed to help this vulnerable but growing population.
Lower regional cerebrovascular reactivity relates to worse episodic memory among older adults
Authors: Robb W. Hudson , Ahmed Humza A. , Kim Darcie S. , Landman Bennett A. , Pechman Kimberly R. , Gifford Katherine A. , Donahue Manus J. , Hohman Timothy J. , Jefferson Angela L.
Published: February 2022

Background

Cerebrovascular reactivity (CVR) measures the ability of the cerebrovasculature to respond to vasoactive stimuli. Decreased CVR in the default mode network (DMN) has been associated with increased vascular risk factor burden. DMN connectivity is fundamentally dependent on vascular compliance, which can be altered in MCI, and may impact episodic memory consolidation. This study cross‐sectionally evaluated whether the topography of CVR is associated with episodic memory performance.

Method

Vanderbilt Memory & Aging Project participants free of stroke were included (n=117, 76.0±7.3 years, 46% female). Participants underwent neuropsychological assessment and multimodal 3T brain MRI, including T1‐weighted imaging and T2*‐weighted blood‐oxygenation level‐dependent (BOLD‐fMRI) for quantifying CVR. During the BOLD‐fMRI acquisition, a hypercapnic normoxic respiratory challenge was administered by alternating normocapnic normoxia and hypercapnic normoxia (5% CO2/95%‐air) in 90s blocks. BOLD‐fMRI data were time‐delay processed, yielding whole‐brain mapping of the maximum correlation with the gas stimulus (CVRMAX) and time‐to‐max CVR (CVRDELAY). Mean CVR metrics were calculated in atlas‐derived DMN regions. Ordinary least squares regression models related DMN‐CVR to episodic memory performance adjusting for demographics, Framingham Stroke Risk Profile, and apolipoprotein E‐e4 status. Clusters were corrected using family‐wise‐error rate p<0.05.

Result

DMN‐CVRMAX was related to episodic memory performance (b=1.0x10‐3, p=0.03) but DMN‐CVRDELAY was not (p=0.09). In voxelwise analysis relating CVRMAX to memory, seven clusters surviving correction were identified, all suggesting lower CVRMAX related to worse memory performance. The peak value of the top cluster was located in the middle temporal gyrus. In voxelwise analysis relating CVRDELAY to memory, 11 clusters surviving correction were identified, all indicating longer CVRDELAY related to worse memory performance. The peak value of the top cluster was located in postcentral gyrus.

Conclusion

Among older adults, lower DMN‐CVRMAX is associated with worse episodic memory performance and this association is not confined to the DMN. Associations between regionally reduced vascular compliance and episodic memory may result from vascular impairment of large‐scale brain networks such as the DMN, though these associations should be further explored. T32‐AG058524, IIRG‐08‐88733, R01‐AG034962, R01‐NS100980, K24‐AG046373, P20‐AG068082