bluuebunny/crossref_metadata_2025 huggingface dataset:
The Bay Area Verbal Learning Test (BAVLT)
Authors: Williams Garrett , Hall Kathleen , Geraci Kristin , Blank Michael , Baldo Juliana , Schendel Krista , Chok Jas M. , Lwi Sandy J. , Herron Tim , Wyma‐Hughes John , Woods David L.
Published: December 2022

Background

Verbal learning tests are sensitive measures of memory decline in pre‐clinical Alzheimer’s Disease with recall scores correlating with amyloid and tau burden (Bejanin et al., 2017). Here we describe a digital version of the Bay Area Verbal Learn‐ing Test (BAVLT) (Woods et al., 2017)— a brief (8.5 minute), fully automated verbal learning test administered from participants’ homes.

Method

The BAVLT was administered to 399 healthy adults (41.5% female, Age = 64.4 years, ±15.0) from their homes using a tablet‐based testing interface (Figure 1). Participants underwent two test sessions on successive days and were remotely monitored via the test interface’s remote proctoring function.

Participants were instructed to remember two lists — each with 12 words in four semantic categories. List A was presented three times with immediate recall after each presentation, followed by a single presentation and recall of distractor List B, then an uncued recall of List A. Thirty minutes later, participants completed a List A delayed recall, followed by a 2‐choice List A recognition test (Figure 2).

Result

The BAVLT showed excellent test‐retest reliability (r = 0.86 total, r = 0.73 delayed). Multiple regression analysis of total recall scores revealed significant effects of age (p< 10–13) (Figure 2), gender (p< 10–11), vocabulary (p<10‐15), and education (p<0.03), with these four variables aggregately accounting for 37.4% of variance. Total recall scores improved over list presentations and increased by 0.97 standard deviations on repeat testing (p<10‐15) (Figure 3).

Conclusion

At‐home administration of the BAVLT demonstrated excellent psychometric properties that are similar to those of well‐established verbal learning tests such as the CVLT (Delis et al., 1987).
Differential impact of APOE on associations between phosphorylated tau 181 and multi‐domain cognitive outcomes using cerebrospinal fluid and plasma markers
Authors: Weigand Alexandra J. , Ortiz Gema , Walker Kayla S. , Galasko Douglas R. , Bondi Mark W. , Thomas Kelsey R.
Published: December 2022

Background

Biomarkers of phosphorylated tau have previously been linked to cognitive function in prodromal Alzheimer’s disease (AD). However, the differential dynamics of various biomarker methods used as indicators of tau accumulation remain under investigation, particularly with respect to their associations with cognitive function and the moderating influence of APOE.

Method

Data for 741 participants from the Alzheimer’s Disease Neuroimaging Initiative with concurrent plasma, cerebrospinal fluid (CSF), and neuropsychological data were included. T‐tests assessed for cognitive classification (cognitively unimpaired [CU] vs mild cognitive impairment [MCI]) and APOE ε4 [carrier vs. non‐carrier] differences in levels of tau phosphorylated at threonine 181 (p‐tau181) measured in plasma and CSF. Multiple linear regression assessed for a main effect of plasma and CSF p‐tau181 on domains of memory, language, and executive function, as well as the moderating effect of APOE ε4 status, adjusting for age, sex, education, and cognitive classification. Sensitivity analyses included CSF amyloid‐beta 1‐42 as a covariate and stratified by cognitive classification.

Result

Results indicated that both the MCI group and the APOE ε4 carrier group had significantly higher levels of plasma (cognitive group t=5.84, p<.001; APOE group t=4.89, p<.001) and CSF p‐tau181 (cognitive group t=5.14, p<.001; APOE group t=10.18, p<.001). For plasma p‐tau181, a main effect was observed only for memory (t=‐2.20, p=.03), whereas APOE ε4 interactions were observed only for language (t=‐2.65, p=.01) and executive function (t=‐2.19, p=.03) with ε4 carriers exhibiting a stronger negative association. For CSF p‐tau181, both a main effect (t=‐5.04, p<.001) and APOE ε4 interaction (t=‐2.10, p=.04) were observed only for memory. Sensitivity analyses revealed that these findings were driven by the MCI group and were largely unchanged when including amyloid‐beta 1‐42 as a covariate.

Conclusion

Plasma and CSF p‐tau181 are both elevated in the context of increased AD risk and both are associated with poorer memory. However, different patterns for plasma p‐tau181 emerge across other cognitive domains (i.e., language, executive function) when APOE ε4 carrier status is considered. However, future research (particularly in more representative samples) is needed given prior research demonstrating increased sensitivity of CSF relative to plasma.
Association between plasma Alzheimer’s disease markers and MRI markers of cerebral small vessel disease and neurodegeneration: the SMART‐MR Study
Authors: Twait Emma L. , Gerritsen Lotte , Moonen Justine E. , Verberk Inge M.W. , Teunissen Charlotte E. , Visser Pieter Jelle , van der Flier Wiesje M. , Geerlings Mirjam I. ,   the NCDC Consortium
Published: December 2022

Background

Biomarkers for Alzheimer’s disease (AD), including amyloid‐beta (Abeta) and phosphorylated‐tau have recently been accurately detected in blood. Non‐specific biomarkers such as neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) have been added as complementary biomarkers to fully investigate AD etiology in vivo. This has increased the possibility to examine relationships with other pathways to AD, such as white matter hyperintensities (WMH) and brain atrophy on MRI. Our aim was to explore the relationship between plasma AD biomarkers and MRI markers of cerebral small vessel disease and neurodegeneration in mid‐ and late life.

Method

Data from 594 individuals (mean (SD) age: 64 (8) years; 17% female) were included from the SMART‐MR Study, a prospective cohort study of non‐demented individuals with a history of vascular disease from the UMC Utrecht in the Netherlands. MRI markers of CSVD included WMH, presence of infarcts, total brain volume (TBV), and hippocampal volume (HV) assessed on 1.5T MRI. AD plasma markers (Abeta1‐40, Abeta1‐42, pTau‐181, NFL, and GFAP) were assessed using Single Molecular Array (Simoa; Quanterix) assays. Linear regressions were performed for each plasma marker, as well as Abeta1‐42/Abeta1‐40 ratio, with age, sex, education, and intracranial volume, with WMH volume, TBV, and HV. Additionally, logistic regressions were performed for the presence of infarcts, including lacunar infarcts and cortical infarcts, corrected for age, sex, and education. Plasma AD levels were converted to z‐scores. P < 0.01 was considered statistically significant.

Result

Higher NFL and pTau‐181 were associated with larger WMH volume (B NFL=0.17, 95% CI=0.06;0.29, p=0.003; B pTau‐181=0.16, 95% CI=0.06;0.26, p=0.001). Higher Abeta1‐40 (B=‐0.11, 95% CI=‐0.17;‐0.05, p<0.001) levels were associated with lower HV. Higher NFL (B=‐5.63, 95% CI=‐8.95;‐2.31, p<0.001) and Abeta1‐42 (B=‐3.61, 95% CI=‐6.26;‐0.96, p=0.008) were associated with lower TBV. Regarding infarcts, higher NFL was associated with any infarct (OR=1.42, 95% CI=1.13;1.78, p=0.003). Higher GFAP was marginally associated only with cortical infarcts (OR=1.45, 95% CI=1.09;1.92, p=0.01).

Conclusion

Within non‐demented adults with a history vascular disease, plasma AD markers differentially mapped to MRI markers. NFL and pTau‐181 were associated with markers reflecting vascular damage, whereas amyloid markers were associated with atrophy in the TBV and HV.
Subjective Cognitive Decline Interacts with Sex and Education on CSF β‐Amyloid.
Authors: Bolton Corey J , Zetterberg Henrik , Blennow Kaj , Jefferson Angela L. , Hohman Timothy J. , Gifford Katherine A.
Published: December 2022

Background

Subjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer’s disease (AD) biomarkers in non‐demented older adults.

Method

Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n = 129, 73±7 years, 33% mild cognitive impairment, 28% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test 3rd edition Reading subtest to assess reading level at baseline. Cerebrospinal fluid (CSF) biomarkers for AD (β‐amyloid42 (Aβ42), Aβ42/40 ratio, phosphorylated tau, tau, neurofilament light) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)‐e4 status, cognitive diagnosis, and Geriatric Depression Scale scores (minus points for cognition). Follow‐up models assessed SCD x reading level, SCD x education, and SCD x sex interactions on AD biomarkers.

Result

In main effect models, higher SCD was associated with lower Aβ42 and Aβ42/40 ratio (p‐values<0.005) but not associated with tau, p‐tau, or NfL levels (p‐values>0.38). SCD score interacted with education on Aβ42 and Aβ42/40 ratio (p‐values<0.005), such that associations were stronger in individuals with higher education. In stratified models, no significant associations were observed in any individual educational tertile (p‐values>0.07). SCD score interacted with sex on Aβ42/40 ratio (p = 0.03). In stratified models, higher SCD was associated with lower Aβ42/40 ratio in men (p = 0.002) but not in women (p = 0.89). Reading level did not interact with SCD score on any biomarker (p‐values>0.19), though significant associations between SCD score and Aβ42 and Aβ42/40 ratio were observed in the higher reading level (p‐values<0.005), but not the lower reading level group (p‐values>0.11).

Conclusion

Among community‐dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD may be most useful in detecting early AD pathology in individuals of higher education and men. SCD was not associated with CSF markers of tau or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.
Mechanisms of Protection in Early and Mid‐Stage Alzheimer’s Disease by Treatment with NAD+ Preserving Compound
Authors: Chaubey Kalyani , Vázquez‐Rosa Edwin , Shin Min‐Kyoo , Dhar Matasha , Franke Kathryn , Cintrón‐Pérez Coral , Koh Yeojung , Yu Youngmin , Barker Sarah , Miller Emiko , Rose Sophia , Bud Zea , Fujioka Hisashi , Sridharan Preethy , Pieper Andrew A.
Published: December 2022

Background

Alzheimer’s disease (AD) currently affects around 6 million Americans and is growing exponentially with our aging population. Impaired homeostasis of nicotinamide adenine dinucleotide (NAD+) impacts several neurodegenerative diseases, including AD. Aging and traumatic brain injury, two of the principle causes of AD, are also associated with impaired NAD+ homeostasis.

Method

We measured NAD+ levels in brain tissue from two different cohorts of patients with AD, along with matched controls, as well in 5xFAD mice and WT littermates. We also evaluated the efficacy of treating 5xFAD mice with the NAD+ stabilizing compound P7C3‐A20, at various stages throughout disease progression. Outcome measures included neurobehavioral assay and immunohistochemical and biochemical assessment of pathology, as well as brain NAD+ levels.

Result

We detected significantly decreased NAD+ levels in the brains of human patients with AD, relative to matched control brain tissue. We also detected significantly decreased NAD+ in the brains of 5xFAD mice, relative to WT littermates, throughout the disease process across young, mid, and old age. Treatment of 5xFAD mice with P7C3‐A20 restored NAD+ levels in the brain of 5xFAD mice at the same time points, and also protected from cognitive decline and depression‐like behavior. Treatment with P7C3‐A20 also decreased Aβ plaque load, neuroinflammation, axonal degeneration, and blood‐brain barrier deterioration, in both male and female 5xFAD mice.

Conclusion

Disruption in NAD+ homeostasis is a hallmark of AD, and we demonstrate here that treatment with the NAD+‐stabilizing molecule P7C3‐A20 prevents and reverses AD‐like behavior and pathology in 5xFAD mice. This provides proof of principle for a potential new approach to treating patients with AD.
Grip Strength as a Potential Biomarker for Insoluble Tau Accumulation
Authors: Alava Bryan , Esser Karyn , Abisambra Jose F. F
Published: December 2022

Background

The risk of Alzheimer’s Disease (AD) is associated with muscle weakness, but the molecular basis of this association is unknown. Beyond motor function, skeletal muscle is a highly metabolic endocrine organ, and it crosstalks with other systems. Therefore, disruptions in skeletal muscle health may influence whole‐body homeostasis with AD progression. Accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD. Neurodegeneration could negatively impact muscle function; likewise, dysfunctional skeletal muscle can also deleteriously impact the environment of whole‐body processes, including tau pathogenesis. Therefore, measuring temporal changes in muscle function relative to insoluble tau accumulation would offer insight into whether skeletal muscle contributes to the progression of tau pathology.

Methods

Male and female inducible muscle specific Bmal1 knockout (iMSBmal1KO) mice were used to model muscle weakness. Intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (n= 15) and yellow fluorescent protein (YFP) (n=18) were done at postnatal day 0. Grip strength, rotarod, and body composition were measured at 16 weeks. At 18 weeks, intraperitoneal injections were performed with either tamoxifen (n=8 tau, 11 YFP) or corn oil (n=7 tau, 7 YFP) to delete the core clock gene Bmal1 exclusively in skeletal muscle. Brains were harvested at 24 weeks. Soluble and insoluble tau were biochemically measured after a sarkosyl extraction protocol. Immunohistochemistry was performed. An additional cohort of wildtype C57BL/6 mice were intracerebroventricularly injected with AAV‐P301L human tau (n= 11) and the empty AAV construct (n= 10). Grip strength was measured at 10 and 12 weeks.

Results

Grip strength was reduced at 16 weeks in the mutant tau treated iMSBmal1KO mice, two weeks before induced muscle weakness, and 10 weeks before NFTs are reported in this tauopathy model. Insoluble tau was detected biochemically at 24 weeks. Grip strength was reduced in tau treated wildtype mice at 10 and 12 weeks.

Conclusions

Changes in grip strength preceded NFT formation in this tauopathy model in both iMSBmal1 transgenic and wildtype mice. This suggests that a) muscle weakness may serve as a biomarker and b) that disrupted skeletal muscle health may be capable of contributing to tauopathy progression.
[18F]PI‐2620 PET in four‐repeat tauopathies: a preliminary study
Authors: Soleimani‐Meigooni David N. , Thomas Wesley P. , Brendel Matthias , Vento Stephanie , Heuer Hilary W. , Ljubenkov Peter A. , Rojas Julio C. , Chen Miranda , Iaccarino Leonardo , La Joie Renaud , Mundada Nidhi S. , Boeve Bradley F. , Grossman Murray , Dickerson Bradford C. , Irwin David J. , Litvan Irene , Pantelyat Alex , Tartaglia Carmela , Rabinovici Gil D. , Baker Suzanne L. , Boxer Adam L.
Published: December 2022

Background

There is a critical need for tau PET radiotracers that accurately detect non‐Alzheimer’s disease (AD) tau pathology. We aim to evaluate [18F]PI‐2620 PET tracer retention in patients with non‐AD, 4R tau‐related clinical syndromes, including progressive supranuclear palsy (PSP) with Richardson’s syndrome (PSP‐RS) and with predominant parkinsonism (PSP‐P), corticobasal syndrome (CBS), and nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA).

Method

38 participants underwent amyloid and [18F]PI‐2620 PET (Table 1). 5 mCi ± 10% of [18F]PI‐2620 was administered. [18F]PI‐2620 PET SUVR images were generated using an inferior cerebellar gray matter reference from PET data acquired 30‐60 minutes post‐injection. Mean SUVR values were extracted from each participant in neuroanatomical structures that have elevated tau burden in PSP and CBS due to corticobasal degeneration (regions of interest in Table 2). Comparison between each diagnostic group and healthy controls (HCs) was performed using a one‐tailed, independent‐samples t‐test. Spearman correlation was used to evaluate the relationship between tracer binding (SUVR) and disease severity (PSP rating scale) in patients with PSP‐RS.

Result

Patients with PSP‐RS had increased tracer retention in the left globus pallidus internus and externus, left subthalamic nucleus, and left dorsolateral prefrontal cortex compared to HCs (all p < 0.05). CBS and nfvPPA patients did not have increased tracer retention at any ROIs compared to HCs, but there were low numbers of patients in these groups (Table 2, Figures 1‐3). PSP rating scale values did not correlate with tracer binding in PSP‐RS (no correlations in any regions, rs < 0.44, p > 0.05 uncorrected).

Conclusion

[18F]PI‐2620 PET 30‐60 minute SUVR images may have limited ability to distinguish PSP from HCs, especially on visual read, and tracer uptake did not correlate with PSP disease severity. Other post‐injection PET acquisition windows (e.g., 30‐40 minute SUVR, 0‐60 minute DVR) will be evaluated to determine if they can maximize differences between PSP and HCs. A limitation of this preliminary study is the modest number of patients and controls, with most controls provided from a different study. Additional participants are being scanned in the multicenter 4RTNI study to understand the utility of this tracer as a neuroimaging biomarker for 4R tauopathies.
Longitudinal changes in the expression of Alzheimer’s disease‐related pattern and default mode network
Authors: Perovnik Matej , Tang Chris C , Šalamon Sandi , Eidelberg David ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2022

Background

The Alzheimer’s disease‐related pattern (ADRP) is an imaging biomarker of AD, for which expression levels correlate with cognitive impairment in individual patients. The default mode network (DMN) is a dominant metabolic network expressed in healthy individuals. Longitudinal changes in ADRP and DMN expression levels have not been comprehensively studied in patients with AD or mild cognitive impairment (MCI), or in cognitively normal (CN) subjects.

Method

We obtained longitudinal data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database of participants who were CN (n=59), or who had MCI (n=128) at baseline and underwent 3 or more FDG PET scans (nscans
=704) and had CSF amyloid and APOE information available. Groups were divided based on the conversion status, i.e., if they developed MCI/dementia at follow‐up. There were 36 stable and 23 converting CN participants and 73 stable (sMCI) and 55 converting (cMCI) participants. Amyloid positivity was defined as CSF Aβ42 < 880 pg/mL and APOE positivity as presence of one or more APOE4 allele. We used an automated algorithm to calculate standardized ADRP and DMN expression levels for each scan. Repeated measurements ANOVA (RMANOVA) was used to evaluate longitudinal changes in network expression in each group, as well as network interactions with conversion status, amyloid and APOE positivity.

Results

ADRP expression increased over time, but at with different rates in the CN, sMCI and cMCI groups (p<0.001). The interaction effect was significant between CN and cMCI (p<0.001) and sMCI and cMCI (p=0.009), but not between CN and sMCI (p=0.51). There was no significant interaction between group and time on DMN expression (p=0.60). Analysis of each group separately revealed no significant interaction between APOE4 status and time on ADRP or DMN expression levels (all p>0.10). There was a significant interaction between conversion status and time on ADRP and DMN in CN group (p<0.04). There was also a significant main effect of time on ADRP and DMN in cMCI group (p<0.04) and a significant interaction between amyloid and time on DMN expression (p=0.03).

Conclusion

ADRP progression was faster in cMCI compared to CN and sMCI. The longitudinal changes in DMN were not significantly different across groups.
Assessing the Unmet Needs of Spanish Speaking Family Caregivers of Persons Living with Dementia in the Greater Boston Area
Authors: Ramirez‐Gomez Liliana A. , Madarasmi Saira , Paulina Gutierrez Ramirez A , Ceciliana Aldarondo A , Mischoulon David , Pederson Aderonke B , Quiroz Yakeel T. , Ritchie Christine S , Jain Felipe A
Published: December 2022

Background

Spanish‐speaking family caregivers of persons living with dementia (PLD) have limited resources in Spanish to aid in psychological coping with caregiver burden. They often have difficulty attending in‐person training due to barriers such as transportation costs, identifying substitute care, and ongoing COVID‐19 pandemic containment measures. There are few studies identifying Spanish language caregiver unique needs and preferences regarding desired caregiving skills and stress‐reduction interventions. In this study, we sought to identify the unmet needs of Spanish‐speaking family caregivers of PLD in the greater Boston area, as well as their preferences for virtual intervention frequency and duration.

Methods

We conducted two virtual focus groups with twelve Spanish language family caregivers of PLD (ages 37 to 87 years) recruited from the greater Boston area. Participants were asked semi‐structured questions regarding their unmet needs for caregiver skills training and stress reduction. We employed an inductive and deductive driven mixed method analytic approach. A taxonomy was created to organize results based on participant responses.

Results

Three major thematic clusters emerged. First, caregivers noted a desire to develop skills for managing stress, emotional reactivity, frustration, and grief. Second, there was an expressed need for education regarding disease‐specific knowledge such as stages of dementia, common manifestations, management of challenging symptoms and communication strategies with the PLD; how to navigate the health care system; and finding additional resources for care in the community. Third, there was an interest in learning about interventions for the PLD, such as specific activities to help keep them engaged and active. A particular interest was expressed in any interventions that might slow disease progression. Regarding frequency and duration for virtual intervention, caregivers most commonly preferred weekly sessions for 6‐10 weeks.

Conclusions

Unmet needs of Spanish language family caregivers of PLD in the greater Boston area include education regarding disease‐specific symptoms and their management, and resources to enhance well‐being both in the caregiver and the PLD. Based on these results, we will develop a comprehensive virtual therapeutic intervention incorporating stress reduction techniques to facilitate emotion regulation, caregiver skills training, psychoeducation regarding dementia and caregiver resources, and healthful activities for the PLD.
TRIAD multi‐dimensional biobank for biomarker discovery
Authors: Stevenson Jenna , Rahmouni Nesrine , Chamoun Mira , Benedet Andréa Lessa , Stevenson Alyssa , Pallen Vanessa , Therriault Joseph , Lussier Firoza Z , Tissot Cécile , Bezgin Gleb , Pascoal Tharick A , Vitali Paolo , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2022

Background

The Translational Biomarkers in Aging and Dementia (TRIAD) is a longitudinal, biomarker‐based cohort designed to study interactions between the pathophysiological processes driving to dementia. Currently, 50 million people worldwide have dementia [1]. PET and MRI imaging have been widely used to assess disease stage, though expensive and not readily accessible [2]. More recently though, breakthroughs in blood‐based biomarkers have proven a useful, available, and more cost‐effective way of evaluating amyloid and tau positivity. The TRIAD Biobank provides a unique framework to study disease stage using blood‐based biomarkers in conjunction with PET and CSF studies. Our cohort allows for validation of novel biomarkers as we simultaneously acquire gold standard second generation imaging acquisitions with full spectrum fluid biomarkers (CSF, saliva, plasma, urine). Importantly, the data acquired is integrated in a database compliant to multi‐dimensional biomarker analysis.

Method

Figure 1 depicts the cohort's banked fluids by diagnostic group. Figure 2 depicts the cohort's banked fluids by sex grouping.

Result

The TRIAD Biobank stores 1,034 blood samples from 655 participants, 658 of these being follow‐up collections. Additionally, cerebrospinal fluid has been collected from 381 individuals accounting for 520 collections in the bank, 812 urine collections from 662 individuals and 591 saliva samples from 432 individuals.

Additionally, the cohort has collected 761 tau PET scans using [18F]MK6240, 644 amyloid PET scans using [18F]AZD4694 and 804 MRI using 3 Tesla.

Conclusion

With dementia being one of the leading, most costly causes of death, the need for early detection, more affordable, less invasive, and more readily available ways to determine disease stage is apparent [2]. The TRIAD multi‐dimensional biobank provides a wealth of resources to discover affordable biomarkers needed for early diagnosis and Alzheimer’s disease prevention.

[1] Patterson, C. 2018. World Alzheimer Report 2018: The state of the art of dementia research, new frontiers. London, England: Alzheimer's Disease International.

[2] Gauthier S, Rosa‐Neto P, Morais JA, & Webster C. 2021. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London, England: Alzheimer’s Disease International.
Lower synaptic density and higher neurofibrillary tau are associated with worse cognitive performance
Authors: DiFilippo Alexandra H , Xin Yangchun , Jonaitis Erin M. , Kohli Akshay , Ennis Gilda E. , McVea Andrew K , McLachlan Max , Pasquesi Mary‐Elizabeth , Davenport Nancy J , Betthauser Tobey J , Barnhart Todd E , Engle Jonathan W , Johnson Sterling C. , Bendlin Barbara B. , Christian Bradley T
Published: December 2022

Background

Synaptic loss is a major feature of symptomatic Alzheimer’s disease (AD). PET radioligands for synaptic vesicle glycoprotein 2A (SV2A) provide an index for synaptic density in the brain. While development of these tracers is a major advance for the field of AD, little is yet known about regional synapse loss in AD or the extent to which synapse loss accounts for cognitive dysfunction in vivo. Here we tested whether regional synaptic density measured with [11C]UCB‐J is associated with cognition. Secondarily, we examined the association between tau, measured using [18F]MK‐6420 PET, and cognitive dysfunction.

Method

Participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study (Table 1). Cognitive functioning was measured using the Preclinical Alzheimer Cognitive Composite (PACC)(Donohue et al, 2014). Neurofibrillary tau in the entorhinal cortex (ERC) was detected using [18F]MK‐6420 SUVR. A global measure of synaptic density was calculated using volume‐averaged DVRs in the medial temporal lobe (hippocampus, entorhinal cortex, parahippocampus, and perirhinal cortex), superior and inferior parietal cortices, and the frontal lobe. Pearson’s correlations assessed the following relationships: PACC : ERC tau, PACC : global synaptic density, and PACC : regional synaptic density.

Result

ERC tau and PACC score showed a significant inverse relationship: r = ‐0.51, P = 0.004. While global synaptic density and PACC score were not significantly related, when individual regions were tested, hippocampal synaptic density showed a significant positive relationship with the PACC score (P = 0.05) (Figure 1A).

Conclusion

ERC tau PET SUVR was robustly associated with poorer cognitive performance. While synapse loss has been observed among multiple regions in AD, our preliminary results suggest that synapse loss in the hippocampus is most closely associated with cognitive dysfunction. This preliminary work suggests that ERC tau is more strongly associated with Alzheimer’s‐related cognitive decline than global or hippocampal synaptic density in participants who are mostly cognitively unimpaired. Future work will include group comparisons between participants with and without significant amyloid and tau pathology, as well as exploratory analyses into which regions are most significantly affected by Alzheimer’s‐associated synaptic loss.
Baseline Reliability and Six‐Month Stability of a Remotely Administered Battery of Smartphone Cognitive Tests
Authors: Taylor Jack C , Clark Annie L , Heuer Hilary W. , Wise Amy B , Manoochehri Masood , Forsberg Leah K. , Mester Carly T. , Rao Meghana , Brushaber Danielle , Kramer Joel H. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. , Staffaroni Adam M.
Published: December 2022

Background

Frontotemporal dementia (FTD) is a collection of neurodegenerative diseases affecting behavior, cognition, and motor functions. FTD treatment trials will benefit from sensitive assessments capable of detecting and longitudinally tracking cognitive changes. Remote smartphone cognitive tests may improve the sensitivity to detect and monitor cognitive decline via novel methods of data capture and more frequent assessments within ecologically valid environments, while simultaneously reducing patient burden. The first step in determining the utility of these measures is establishing their reliability. We previously reported baseline reliability estimates for the ALLFTD Mobile App cognitive tests in a small pilot sample. Here we extend these results using a larger sample and evaluate six‐month stability.

Method

We enrolled a diagnostically mixed sample of 128 participants (CDR®+NACC‐FTLD = 0 [n = 84]; CDR®+NACC‐FTLD = 0.5 [n = 21]; CDR®+NACC‐FTLD≥1 [n = 23]) from ongoing studies of healthy aging (Hillblom Network) and frontotemporal dementia (ALLFTD). Participants self‐administered five cognitive tests from the ALLFTD Mobile App on their own smartphone; they were asked to complete each test three times within two weeks. Tests included gamified versions of N‐back, Stroop, Flanker, and Go/No‐Go paradigms, and an adaptive short‐term memory test. We evaluated the internal consistency of each test’s first occurrence using Spearman‐Brown split‐half reliability (100 simulations). Test‐retest reliability over the first three baseline replicates (as available) was evaluated by calculating intraclass correlations (ICC). In a preliminary analysis, we tested the six‐month stability of test performance in nine functionally intact participants who completed baseline and follow‐up Flanker, N‐Back, and adaptive memory assessments by calculating Spearman’s rho.

Result

Split‐half reliability estimates were in the good to excellent range (r’s: 0.81–0.97). Test‐retest reliability estimates were in the adequate to excellent range (ICCs: 0.72–0.96). ICC estimates were comparable for participants with and without clinical impairment (CDR®+NACC‐FTLD = 0 (0.74–0.95) and CDR®+NACC‐FTLD >0 (0.67–0.95). Among functionally intact individuals, baseline and 6‐months scores were highly correlated (r’s: 0.76–0.93, p’s<.05).

Conclusion

Our findings of adequate to excellent internal consistency, test‐retest reliability, and 6‐month stability support the feasibility of remote, smartphone‐based cognitive testing among a diagnostically mixed sample typical of healthy aging and frontotemporal dementia research studies.
Examination of associations between female natural reproductive span and dementia risk
Authors: Saelzler Ursula G , Sundermann Erin E. , Karlsson Ida , Gatz Margaret , Pedersen Nancy L. , Panizzon Matthew S.
Published: December 2022

Background

Despite substantial evidence for a greater prevalence of Alzheimer’s disease and related dementias (ADRD) among women, there is a limited understanding of sex‐specific mechanisms which may modify risk. Greater lifetime estrogen exposure (often approximated by the length of the reproductive span) is hypothesized to be protective, however, previous investigations into the relationship between the female reproductive span and ADRD have been mixed.

Method

A series of Cox proportional hazards models were applied to data from 6,351 naturally post‐menopausal, exogenous hormone‐naive women from the Swedish Twin Registry. The age of dementia diagnosis (determined by clinical interview or approximated by an adjusted appearance of diagnostic codes in national health registries) was used as the event time, while the time of death or data aggregation were used as the time of censoring. Covarying for birth year, children, and education, stratifying by smoking history, and adjusting for the reduced sensitivity of dementia detection in health registries, the fit of three models, including either a linear, a quadratic, or a cut‐point reproductive span term, was compared and the reproductive span coefficients examined.

Result

There was a progressive improvement in model fit across the linear, quadratic, and cut‐point models. The linear term from the linear model was not significant (HR = 0.002, p = 0.752), while the linear and quadratic terms from the quadratic model were small, but significant predictors of ADRD hazard (HR = 1.016, p = 0.035 and HR = 1.004, p < 0.005, respectively). The optimal cut‐point model indicated that the length of the reproductive span is not predictive of ADRD hazard, until the span exceeds 44 years, at which point each 1‐year increase in reproductive span is associated with an 8.22% increase in ADRD hazard (below cut point term: HR = 0.988 p = 0.120; above cut‐point term: HR = 1.0822, p < 0.005).

Conclusion

In contrast to the anticipated protective role of lifetime estrogen exposure, exceptionally long reproductive spans (i.e., those 1.77 SD or greater than the mean) are associated with increased ADRD hazard. The non‐linear nature of the relationship may contribute to the mixed findings in the literature.
Similar lysosomal abnormalities in cortex of patients with sporadic FTLD‐TDP type A and patients with FTD‐GRN
Authors: Davis Skylar E. , Cook Anna K. , Voskobiynyk Yuliya , Carullo Nancy VN , Hakim Ahmad R. , Anderson Kristian M. , Hobdy Kierra P. , Pugh Derian A , Murchison Charles F , McMeekin Laura J. , Simmons Micah S. , Cowell Rita M. , Li Alissa Nana , Spina Salvatore , Grinberg Lea Tenenholz , Miller Bruce L. , Seeley William W. , Arrant Andrew E.
Published: December 2022

Background

Loss‐of‐function mutations in progranulin (GRN) are an autosomal dominant cause of frontotemporal dementia (FTD). Progranulin is critical for maintenance of lysosomal function. Patients with FTD due to GRN mutations (FTD‐GRN) exhibit signs of lysosomal dysfunction, which may contribute to FTD‐GRN pathogenesis. To assess the potential involvement of lysosomal dysfunction in FTD of sporadic origin, we investigated whether the lysosomal abnormalities of FTD‐GRN are also present in patients with sporadic frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) type A, the same FTLD subtype found in patients with FTD‐GRN.

Method

We used enzyme activity assays, western blot, immunostaining, and Nanostring analysis to assess changes in lysosomal protein and gene expression in orbital and occipital cortex of patients with FTD‐GRN, sporadic FTLD‐TDP type A, or controls. We measured lipofuscin using autofluorescence and staining with Sudan Black B. In follow‐up studies, we assessed these lysosomal markers in a transgenic mouse line expressing wild‐type human TDP‐43 under the Thy1 promoter.

Result

We found similar lysosomal abnormalities in orbital cortex of patients with FTD‐GRN or sporadic FTLD‐TDP type A. Both FTD patient groups exhibited elevated levels of lysosomal enzymes and membrane proteins, higher expression of many lysosomal genes, and greater lipofuscin accumulation than controls. These changes were largely absent in occipital cortex from both groups. Analysis of frontal cortex from a transgenic mouse model of TDP‐opathy also revealed elevated levels of some lysosomal proteins and elevated lipofuscin levels.

Conclusion

These studies indicate that the lysosomal abnormalities of patients with FTD‐GRN may be more closely associated with TDP‐opathy or neurodegeneration than with progranulin insufficiency. Orbital cortex, an affected brain region in FTD‐GRN, exhibited elevated lysosomal protein levels and lipofuscin accumulation, which were also found in patients with sporadic FTLD‐TDP type A. In contrast, the occipital cortex, a relatively spared brain region in FTD‐GRN, exhibited much milder lysosomal abnormalities. Future studies will assess signs of lysosomal dysfunction in patients with other classes of FTLD pathology to determine whether these changes are limited to patients with FTLD‐TDP or may be found throughout the FTLD spectrum.
Genetically diverse mouse models of Alzheimer’s Disease reveal an association between amyloid deposition and glycan metabolism in the brain
Authors: Uyar Asli , Elk Kevin J , Garceau Dylan , Bednarczyk Daria , Sasner Michael , Carter Gregory W , Howell Gareth R
Published: December 2022

Background

Varying degrees of cerebral amyloid angiopathy (CAA) co‐occur with parenchymal amyloid deposition in majority of Alzheimer’s Disease (AD) cases. However, common mouse models of familial AD generated on a single inbred strain do not recapitulate the spectrum of parenchymal and vascular amyloid pathogenesis in the brain. To better represent phenotypic diversity in AD, we generated a panel of genetically diverse Collaborative Cross (CC) mouse strains harboring APOE4 allele and amyloidogenic mutations.

Method

Five CC strains (CC002, CC006, CC013, CC037 and CC041) were selected for maximal genetic and transcriptional variation in AD‐relevant genes. Selected CC strains were crossed to C57BL/6J (B6J) mice homozygous for humanized APOE4 allele and carrying mutant APP and PS1 alleles (APPswe
, PS1de9
). Cohorts of male and female B6JCCnF1.APOE4.APP/PS1 mice and controls were aged to 8 months, and brain hemispheres were processed for RNA‐Seq transcriptomics and neuropathological assessment. Weighted Gene Co‐Expression Networks Analysis (WGCNA) and gene set enrichment analysis were performed to identify gene modules and biological pathways associated with plaque deposition and CAA in CC strains.

Result

Neuropathological assessment revealed significant strain and sex‐dependent differences in both parenchymal and vascular amyloid pathology. Highest levels of plaque deposition in cortex and hippocampus was observed in female CC002 mice. Female mice had higher plaque load compared to male mice in all strains, whereas CAA score was higher in males and in CC037 strain. CC006 represented lowest levels of plaque deposition and CAA at comparable levels with B6J mice. RNA‐Seq data revealed a common microglia/neuroinflammation related transcriptional response observed in all strains and both sexes. On the other hand, gene expression signatures associated with varying levels of plaque deposition and CAA revealed alterations in metabolic pathways, in particular glucose, lipid and glycan metabolisms.

Conclusion

Our results suggest that major genetic diversity modulates distinctive parenchymal and vascular amyloid phenotypes, and differentially impacts transcriptomic signatures in the mouse brain. Overall, CC lines mouse models better represent the spectrum of neuropathological and molecular phenotypes associated with AD.
The Alzheimer’s Disease Sequencing Project Follow Up Study (ADSP‐FUS): increasing ethnic diversity in Alzheimer’s disease (AD) genetics research.
Authors: Mena Pedro Ramon , Kunkle Brian W. , Faber Kelley M. , Adams Larry D. , Inciute Jovita D. , Whitehead Patrice L. , Foroud Tatiana M. , Reyes‐Dumeyer Dolly , Kuzma Amanda B , Leung Yuk Yee , Naj Adam C. , Martin Eden R. , Dalgard Clifton L. , Schellenberg Gerard D. , Wang Li‐San , Mayeux Richard , Vardarajan Badri N. , Vance Jeffery M. , Cuccaro Michael L. , Pericak‐Vance Margaret A.
Published: December 2022

Background

The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP Discovery and Discovery Extension cohorts beyond non‐Hispanic Whites of European Ancestry (NHW‐EA). Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to sequence existing ethnically diverse and unique cohorts. The upcoming phase for ADSP‐FUS, ADSP‐ FUS 2.0: The Diverse Population Initiative, focuses on Hispanic/Latino (HL), non‐Hispanic Black with African Ancestry (NHB‐AA), and Asian populations (e.g., the Asian cohort for Alzheimer’s disease). The ADSP‐FUS enables the utility of new discoveries for individuals from all populations.

Method

ADSP‐FUS cohorts consist of studies of AD, dementia, and age‐related conditions. Clinical classifications (AD, dementia, and cognitively intact) are assigned based on standard criteria and derived from clinical measures and history. Data dictionaries are curated for each cohort by the FUS clinical staff. The ADSP‐FUS initiatives intend to sequence over 100,000 individuals from diverse ancestries.

Biospecimens are processed and DNA is prepared and allocated for whole genome sequencing (WGS) at designated NIA sequencing centers. All raw sequence data is transferred to the Genome Center for Alzheimer’s Disease (GCAD) for processing and harmonization following QC analysis at the University of Pennsylvania and University of Miami, resulting in analysis‐ready genotype and sequence data. All clinical, genotype and sequence data are housed at the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS), which stores, manages, and distributes ASDP‐FUS data to AD researchers.

Results

Over 50,152 samples have been ascertained with ancestry groupings as follows: 10,166 NHB‐AA; 10,531 HL; 22,002 NHW‐EA (including 1,400 EOAD and 3,745 autopsy); 89 Amerindian; and 7,364 Asian (Korean and Indian) individuals. Currently, we have sequenced up to a total of 31,990 individuals.

Conclusion

The ADSP‐FUS continues to identify shared and novel genetic risk factors for AD among diverse populations. This genomic resource is crucial to expanding our knowledge of potential genetic risk and protective variants for AD across all populations with the hope of developing new treatments for everyone.
Different criteria modify Alzheimer’s disease diagnosis and prognosis
Authors: Bieger Andrei , Brum Wagner S. , De Bastiani Marco Antônio , Benedet Andréa Lessa , Moreira Amanda Gressler , Borelli Wyllians Vendramini , Pascoal Tharick A , Schumacher‐Schuh Artur Francisco , Castilhos Raphael Machado , Rosa‐Neto Pedro , Souza Diogo O. , Schilling Lucas Porcello , Zimmer Eduardo R
Published: December 2022

Background

Alzheimer’s disease (AD) has recently been reconceptualized into a dual entity, a biological disease, and a clinical syndrome. Following these advances, the National Institute on Aging – Alzheimer’s Association (NIA‐AA) and the International Working Group (IWG) released four updated diagnostic guidelines for AD diagnosis: NIA‐AA 2011, IWG 2016, NIA‐AA 2018, and IWG 2021. Although many studies still rely solely on a clinical diagnosis of AD, and a consensus on diagnostic criteria is still lacking. Here, we aim to elucidate how the aforementioned AD guidelines affect the individuals’ diagnostic label.

Method

Clinical, demographic and biomarker data were extracted from ADNI (n = 1215), and used to build classification algorithms according to diagnostic criteria from NIA‐AA 2011, IWG 2016, NIA‐AA 2018, and IWG 2021. Subjects then were labeled as Not AD (NA), At Risk of Developing AD (AR), or AD. Results were compared according to cognitive stage, cognitively unimpaired (CU) or cognitively impaired (CI), and to AD biomarkers profile. Kaplan‐Meier curves were used to evaluate conversion to CI in CU individuals using each diagnostic guideline. All analyses were performed in R (v 4.0.3).

Result

Individuals were diagnosed using criteria from the NIA‐AA 2011 [NA = 36.8%, AR = 23.2%, AD = 40%], IWG 2016 [NA = 37.9%, AR = 28.8%, AD = 33.3%], NIA‐AA 2018 [NA = 40.5%, AR = 11.1%, AD = 48.4%], and the IWG 2021 [NA = 51.3%, AR = 8.7%, AD = 40%] (Figure 1). Diagnoses were discordant between criteria in 39.8% of the individuals, with 69.4% of those being in the A+T‐ or A‐T+ biomarker groups. Conversion to CI of CU individuals AR compared to NA were calculated for the NIA‐AA 2011 [log‐rank 0,001], IWG 2016 [log‐rank 0,000], NIA‐AA 2018 [log‐rank 0,24], and IWG 2021 [log‐rank 0,000].

Conclusion

Our findings indicated that almost 40% of the studied population presented discordant diagnoses using different AD criteria. Most of these had only one positive biomarker (amyloid or tau). All guidelines except for the NIA‐AA 2018 managed to differentiate asymptomatic individuals at risk of developing cognitive impairment. Our findings have important implications in clinical practice and the design of future clinical trials.
Two year cognitive and biomarker change in a racially diverse, middle‐aged, cohort at risk for Alzheimer’s disease
Authors: Butts Brittany , Hu William T. , Huang Hanfeng , Kehoe Patrick G , Miners Scott , Verble Danielle D , Zetterberg Henrik , Zhao Liping , Wharton Whitney
Published: December 2022

Background

Alzheimer’s disease (AD) incidence among Black/African Americans (B/AA) is 64% higher than non‐Hispanic Whites (NHW). Studies show CSF total and phosphorylated tau are lower in cognitively unimpaired middle‐aged B/AAs compared to NHWs. Cognitive changes in B/AA adults are associated with smaller increases in CSF tau. We examined rate of cognitive and CSF AD biomarker change, over two years, in a cognitively unimpaired, racially diverse, middle‐aged cohort with a parental history of AD.

Method

Cognitive tests (MOCA, Trails B, Digit Span, Benson Delay, Buschke Delay, and MINT) were collected at baseline (BL), 1 year (Y1), and 2 years (Y2). CSF was collected at BL and Y2 for AD biomarkers (Aβ and tau) and sPDGFRβ, an index of blood brain barrier damage. Analyses controlled for age, sex, race, education, and APOE4.

Result

Participants (N=80) were mostly female (69%), highly educated (81% ≥college), and 34% B/AA. B/AAs exhibited lower levels of p‐tau, t‐tau, and sPDGFRβ at BL and Y2 compared to NHWs (p≤0.02). P‐tau increased from BL to Y2 for all participants (p<0.01). NHWs outperformed B/AAs in 7/7 cognitive tests at baseline and 6/7 at Y2. Digit Span improved from BL to Y2 (p=0.014) for all participants. Analyses by race demonstrated improvements for MOCA and Buschke Delay among B/AAs, and improvements for Trails B and Benson Delay among NHWs. There was a difference in rate of change over time by race in Benson Delay (F=8.22, p=0.0055). Linear models showed positive associations between Trails B and p‐tau and sPDGFRβ (p≤0.05). Negative associations were found between Benson Delay and p‐tau and t‐tau (p≤0.04), between MINT and sPDGFRβ, p‐tau, and t‐tau (p=0.04), and between Bushcke Delay and sPDGFRβ (p=0.03).

Conclusion

While cognitive scores changed over time, group analyses showed improvements among B/AA participants in verbal memory and global cognition, while NHW participants improved in tests of processing speed and visuospatial memory. CSF p‐tau increased over 2 years. As CSF AD biomarkers were predictive of cognitive function scores, AD pathologic processes may begin earlier in at‐risk adults. Further study of race‐associated differences in AD biomarkers is needed, as these differences may contribute to AD‐related health disparities.