bluuebunny/crossref_metadata_2025 huggingface dataset:
Choroid plexus volume is associated with levels of CSF proteins predominantly expressed by the choroid plexus in non‐demented individuals with AD pathophysiology.
Authors: Delvenne Aurore , Tijms Betty M. , Gobom Johan , Redolfi Alberto , Barkhof Frederik , Zetterberg Henrik , Visser Pieter Jelle , Vos Stephanie J. B. ,   EMIF‐AD MBD study group
Published: December 2022

Background

The choroid plexus (CP) is a structure located inside the brain ventricles and is responsible for the production of cerebrospinal fluid (CSF), transport of proteins across the epithelium to the CSF and clearance of proteins from the CSF. The CP undergoes changes with aging, which are exacerbated in Alzheimer's disease (AD) and could alter CP functioning. Nonetheless, the relation between CP functioning and AD pathophysiology is still unclear. Here, we investigated the association of CP volume with levels of CSF proteins predominantly expressed by the CP and amyloid positivity in non‐demented individuals.

Method

We included 235 individuals with normal cognition (NC) or mild cognitive impairment (MCI) from the European EMIF‐AD MBD study (49% women, mean age 67.9 (SD 7.9) years). Based on CSF Aβ1‐42 (A, data‐driven cut‐offs) and p‐tau (T, center‐specific cut‐offs), individuals were classified as cognitively normal with normal A and T (controls, n=54). Based on CSF Aβ1‐42, individuals with NC or MCI were classified as amyloid‐positive (CN A+, n=61; MCI A+, n=67). CSF proteomic data were centrally generated using TMT mass spectrometry and 5 CSF proteins with predominant expression in the CP were selected based on the Protein Atlas, Harmonizome and literature (TTR, MFRP, SLC5A5, FOLR1, SOD3). CP and hippocampal volumes on MRI were quantified using FreeSurfer. We used non‐parametric (Spearman) partial correlations corrected for age, gender and total intracranial volume (TIV).

Result

Lower Aβ42 levels were associated with higher CP volume in MCI (Figure 1). Higher levels of CP predominant expressed proteins were generally associated with increased CP volume in persons with amyloid positivity, in both preclinical and prodromal AD (Table 1). Lower Aβ42 levels were associated with lower hippocampal volume in MCI (Figure 2). Lower hippocampal volumes were associated with higher CP volumes in MCI (Figure 3). Nonetheless, hippocampal volume and the levels of CP predominant expressed proteins were generally not correlated (Table 2).

Conclusion

Our findings suggest that CP volume is associated with levels of proteins predominantly expressed by the CP in predementia stages of AD. This would suggest CP dysfunction in early AD. This is important for future research and AD treatment development.
Divergent magnetic resonance imaging atrophy patterns in Alzheimer’s disease and primary age‐related tauopathy
Authors: Quintas‐Neves Miguel , Teylan Merilee A. , Morais‐Ribeiro Rafaela , Almeida Francisco , Mock Charles , Kukull Walter A. , Crary John F. , Oliveira Tiago Gil
Published: December 2022

Background

Primary age‐related tauopathy (PART) is a pathological disorder characterized by the presence of tau‐positive neurofibrillary tangles (NFTs) and no amyloid‐beta (Aβ) deposition (“definite PART”). Currently, the diagnosis of PART is histologically assessed by the presence of tau positive NFT with Braak staging and a Consortium to Establish a Registry for Alzheimer’s disease (CERAD) Aβ stage of 0.

Method

Our study compared brain magnetic resonance imaging (MRI) with neuropathological findings in patients with PART and AD, while assessing the relationship between brain atrophy and clinical impairment. We analysed 233 participants: 32 with no plaques (“definite” PART ‐ CERAD 0), and 201 cases within the AD spectrum, with 25 with sparse (CERAD 1), 76 with moderate (CERAD 2) and 100 with severe (CERAD 3) degree of neuritic plaques.

Result

Upon correcting for age, sex and age difference at MRI and death, there were significantly higher levels of atrophy in CERAD 3 compared to CERAD 1‐2 and a trend compared to CERAD 0. In the anterior temporal region, there was a trend for higher levels of atrophy in CERAD 0 compared to CERAD 1. We then assessed the correlation between regional brain atrophy and CDR‐sum‐of‐boxes score for PART and AD, and found that overall cognition deficits are directly correlated with regional atrophy in the AD continuum, but not in definite PART. We further observed correlation between regional brain atrophy with multiple neuropsychological metrics in AD, while PART showed only specific correlations between language deficits and anterior temporal atrophy.

Conclusion

Overall, these findings support PART as an independent pathologic process from AD.
Enabling Characterisation of the NAD+ Biosynthesis Pathway via in vitro CEST MRI
Authors: Slade Festus , Villano Daisy , Luo Jierong , Longo Dario , Collingwood Joanna F
Published: December 2022

Background

The Chemical Exchange Saturation Transfer (CEST) MRI properties of six metabolites required for synthesis of coenzyme nicotinamide adenine dinucleotide (NAD+) and to evaluate the potential for clinical imaging of altered NAD+ regulation in neurodegenerative disorders

Method

CEST images of metabolites in the NAD+ biosynthesis pathway were acquired at physiological temperature with high‐field MRI (9.4T) running a modified magnetisation transfer (MTR) prepared RARE sequence over a range of saturation powers and frequency ofsets, for pH values 5.5‐7.4. CEST data were fitted using spline interpolation, the exchange rate was calculated, and frequency specific MTR maps were generated using pixelwise analysis.

Result

Tryptophan, nicotinamide, nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) and NADH were evaluated. At pH 7.4, all molecules exhibited CEST contrast between 0.1 and 0.9 ppm, originating from the OH hydroxyl proton. NADH exhibited up to 15% CEST contrast in a B1 field of 2.4µT from its fast‐exchanging amine groups at 2 and 3 ppm, and showed a positive dependence of CEST efciency on pH. Tryptophan exhibited three independent peaks at 0.7, 2.6, and 5.4 ppm corresponding to pH 6.7, 5.5 and 7.4. NMN showed high CEST contrast at 0.7ppm originating from its phosphorous OH enabling higher CEST efciency due to enhanced charge delocalisation (Fig.1).

Conclusion

This in vitro feasibility study demonstrates signal detection and characterization of NAD+ biosynthesis pathway precursor molecules over precise temperature, concentration and physiological pH ranges. All molecules exhibited a peak at 0.7 from the hydroxyl group with NMN showing highest CEST efficiency due to phosphate charge delocalisation. NADH showed a peak at 2 and 3ppm from amine group protons and a dependency on temperature and pH.
Using children’s drawings as implicit measurements in future Alzheimer’s research for the detection and alteration of negative stereotyping
Authors: Bormans Kasper , Zwakhalen Sandra
Published: December 2022

Background

Many children have grandparents with dementia. These direct confrontations with decline are reinforced by one‐sided, negative portrayal in the media making youngsters internalize harmful images about old age and dementia. It is vital for the well‐being of future generations that education and research join forces to clearly map and transform these toxic mental representations in children about old age and dementia.

Method

We developed a novel educational trajectory for children regarding healthy ageing and dementia in Belgium and The Netherlands. Participating youngsters (n = 70) made sketches of the elderly before and after the positive interventions. Our innovative research resulted in materials for artistic expositions of children’s drawings (n = 560). The visual representations provide a unique insight into the hidden mental landscape of children and can thus function as a starting point for conversation in educational trajectories about positive aging. These deliverables are a source of inspiration for teachers, journalists, researchers, health professionals and the broader public.

Result

Children’s drawings are one of the most efficient ways to capture young people’s mental representations about old age and dementia. Children’s drawings are implicit measurements that circumvent social desirability.

Conclusion

Children’s drawings are an underused instrument in Alzheimer’s research to gain insight into the content of destructive stereotyping and the possibilities for change of these mental representations.
Regional neuronal compensation in early and late stages of the Alzheimer’s trajectory
Authors: Nowell Joseph , Livingston Nicholas R , Raza Sanara , Edison Paul
Published: December 2022

Background

Glucose hypermetabolism is suggested to occur as a compensatory response to early neuronal damage[1]. Hypermetabolism has been shown to arise in the prodromal phase of Alzheimer’s disease development as a mechanism to prevent against cognitive deficits or as a compensatory mechanism to maintain the neuronal function amidst of other neurodegenerative process. Here we aimed to evaluate whether there is regional glucose hypermetabolism as a proxy to neuronal function in response to tau deposition in different stages of Alzheimer’s disease.

Method

139 amyloid positive cognitively impaired subjects were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (n = 44 diagnosed with Alzheimer’s disease, n = 95 mild cognitive impairment). All subjects had [18F]AV1451 and [18F]FDG PET imaging and an anatomical T1 weighted MRI scan. PET scans were coregistered to the respective anatomical scan and normalised to MNI space in SPM12. Standard uptake value ratio (SUVr) images were created using cerebellar grey matter and pons uptake as reference region for [18F]AV1451 and [18F]FDG, respectively. Voxel‐wise linear regression was conducted between[18F]AV1451 and [18F]FDG. Pearson’s correlations were conducted between regions displaying a positive association.

Result

Voxel‐wise analysis revealed a correlation between higher glucose metabolism and tau deposition localised to the pre and post‐central gyrus in our cognitively impaired cohort. We found evidence that higher tau deposition and higher glucose metabolism were associated in the left and right post‐central gyrus in Alzheimer’s subjects (n=44, r=0.361 p=0.016 and r=0.327 p=0.030, respectively). A significant correlation was observed in both the left and right pre‐central gyrus (n=95, r=0.418 p<0.001 and r=0.361 p<0.001, respectively) as well as the left (r=0.384 p<0.001)and right post‐central gyrus (r=0.324 p=0.001) in subjects diagnosed with mild cognitive impairment.

Conclusion

This correlation between higher tau and higher glucose metabolism in pre‐and post‐central gyrus implies that there is still neuronal compensation occurring in response to tau deposition both in early and later stages of the disease process (Braak stages V‐VI). This suggests that neuronal compensation occurs on a regional basis throughout the Alzheimer’s disease trajectory and may reflect the ability of neurons to still respond to an effective treatment.
Does glucose metabolism dissociate from tau deposition in Alzheimer’s disease?
Authors: Nowell Joseph , Raza Sanara , Livingston Nicholas R , Edison Paul
Published: December 2022

Background

Alzheimer’s disease progression is characterised by accumulation of tau and reductions in cerebral glucose metabolism. However, the spread of tau could be influenced by the presence of amyloid, while changes in cerebral glucose metabolism could be influenced by microglial activation, atrophy, synaptic dysfunction, along with oxidative stress and inflammation. Hence, the association between these biomarkers at a global cortical level remains unclear. Here we sought the establish the global cortical relationship in a novel single subject design.

Method

380 subjects were recruited from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu) (Table 1). Amyloid status (Aβ+/Aβ‐ ve) and T1‐weghted MRI scans were obtained for all participants. Dynamic PET scans were processed with SPM12 and standard uptake value ratio (SUVR) images were created. Cerebellum grey matter and pons were selected as reference region for [18F]AV1451 and [18F]FDG respectively. Each cognitively impaired SUVR image was compared against the healthy control group using Statistical Parametric Mapping software. We extracted the total number of voxels with increases of [18F]AV1451 and decreases of [18F]FDG compared to the controls; termed ‘global cortical tau load’ and ‘global hypometabolism’ for subsequent analysis.

Result

In this sample of 240 cognitively impaired subjects, in Aβ+ve AD subjects, there was no correlation between global cortical tau load and global hypometabolism. Interestingly, there was minimal correlation in Aβ+ve MCI subjects between global cortical tau and global hypometabolism (r=0.209, p=0.042). There were no significant correlations between global cortical tau load and global hypometabolism in Aβ‐ve cognitively impaired subjects.

Conclusion

Glucose hypometabolism and tau deposition dissociate at a global level in AD subjects; while in early stages there may be minimal association between these two processes. The dissociation between glucose metabolism and tau deposition in the later stages of AD trajectory suggests that other pathological features including microglial activation, inflammation, and oxidative stress all influence the metabolic decline in AD, perhaps explaining our apparent lack of association later in disease progression. As such, we argue changes in glucose metabolism and tau deposition have distinct trajectories in the context of Alzheimer’s disease and future clinical trials should consider separate evaluation.
Mild behavioral impairment and functional connectivity in dementia‐free elderly
Authors: Nathan Santhosh , Ghahremani Maryam , McGirr Alexander , Smith Eric E. , Ismail Zahinoor
Published: December 2022

Background

Mild Behavioral Impairment (MBI), characterized by de novo emergent and persistent neuropsychiatric symptoms in later life, may be used to improve early detection of neurodegenerative disease. While alterations in resting‐state networks have been demonstrated in early‐stage Alzheimer’s disease (AD), few studies have explored these networks in MBI. Here, we assessed activity in the default mode network (DMN) and the salience network (SN), using resting‐state functional magnetic resonance imaging (fMRI), in association with MBI. We hypothesized that the strength of functional connectivity (FC) within the DMN and SN would be reduced in dementia‐free persons with MBI (MBI+), relative to those without (MBI‐).

Methods

Data from dementia‐free participants in three prospective cohort studies were pooled. MBI+ status was determined using the MBI‐checklist. Imaging data were acquired using 3T MRI. Seed‐based connectivity analyses were performed using the CONN toolbox. The DMN included the posterior cingulate cortex (PCC), medial prefrontal cortex (MPFC), and lateral parietal (LP) regions, with the PCC as the seed. The SN included the anterior cingulate cortex (ACC), anterior insula (AI), rostral prefrontal cortex (RPFC), and supramarginal gyrus (SMG), with the ACC as the seed. FC maps of the DMN and SN were computed for each MBI group; difference maps were extracted to identify regions with significantly different connectivity across MBI groups. A threshold of p<0.05 was used with false discovery rate correction for multiple comparisons at the cluster level; a p<0.001 uncorrected for voxel level was used for group comparisons. All analyses were covaried for age, sex, years of education, and Montreal Cognitive Assessment scores.

Results

Of the 95 participants, 32 were MBI+ and 63 MBI‐ (mean age 71.7; 54.7% female). Within the DMN, MBI+ individuals had lower functional connectivity between the PCC and MPFC, compared to MBI‐ (β=‐0.15, p=0.004). Within the SN, MBI+ was associated with lower functional connectivity between the ACC and left AI (β=‐0.12, p=0.028).

Conclusion

Our findings suggest that in dementia‐free individuals, MBI is associated with decreased functional connectivity in networks disrupted in AD. This result lends additional support to MBI as a potential early marker of disease.
Visuoconstruction Errors in pathologically confirmed Alzheimer’s disease versus Alzheimer’s disease with Lewy Body disease patients
Authors: Hernandez Michelle , Soto Elizabeth , Fernandez Kayri K , Johnson Jordan , Azar Martina , Gu Yian , Stern Yaakov , Cosentino Stephanie
Published: December 2022

Background

Clinical differentiation of Alzheimer’s disease (AD) versus Lewy Body Disease (LBD; including mixed AD‐LBD) is challenging, as both diseases overlap in cognitive symptoms. This can lead to misdiagnosis with detrimental consequences to the patient’s health. While autopsy‐based studies reveal that visuoconstruction tends to be more preserved in AD versus LBD and mixed AD‐LBD, it is well established that patients with AD also have visuoconstructional difficulties. To this end, this study examined performance on three visuoconstruction tasks and qualitatively coded errors on overlapping pentagons to characterize the types of constructional difficulties in pathologically confirmed AD versus LBD and mixed AD‐LBD.

Method

Clinical and autopsy data were available for 30 individuals (19 AD; 11 LBD /mixed AD‐LBD). Overlapping pentagons were given a final score of either 0 or 1. Pentagons were then scored across six parameters: presence of two figures, overlapping figures, 5 sides on each figure, the correct overlap of figures (diamond in the middle), presence of overwriting, and closing‐in to stimulus. Copy of a cube and a circle/diamond figure was also scored as 0 or 1. Chi‐square analyses were used to examine the frequency of impairment on each visuoconstruction score among the pure AD versus LBD/mixed AD‐LBD groups.

Result

The combined LBD and mixed AD‐LBD group was more frequently impaired on circle‐diamond (p = .002), pentagons total score (p = .001), and two pentagons sub‐scores, including the presence of 5‐sides on each figure (p = .006) and the correct pentagon overlap (p = .006). The groups were impaired with equal frequency on the remaining pentagons sub‐scores, and on the cube copy (53% of AD and 37% of LBD/mixed AD‐LBD; p = .39).

Conclusion

As expected, the combined LBD and mixed AD‐LBD group was more frequently impaired on several visuoconstruction tasks in comparison to the pure AD group. Specific pentagons errors were most sensitive to group differences. Of note, both groups were impaired with equal frequency on cube copy, suggesting that the three‐dimensional component of the task best captures the visuospatial difficulties characteristic of AD. Qualitative assessment of visuoconstruction may aid in differential diagnosis.
The coarse‐grained plaque is an Aβ plaque‐type in APOE Ɛ4+ Alzheimer’s disease that is associated with astrogliosis and p‐tau burden
Authors: Boon Baayla D.C. , Kouri Naomi , Labuzan Sydney A , Cabrera‐Rodriguez Janisse N , Tranovich Jessica , Frankenhauser Isabelle , Lachner Christian , Ertekin‐Taner Nilufer , Duara Ranjan , Graff‐Radford Neill R. , Dickson Dennis W. , Murray Melissa E.
Published: December 2022

Background

The coarse‐grained plaque (CGP) is a divergent plaque‐type recently described in Alzheimer’s disease (AD)1. In the current study, we studied the CGPs distribution over the brain, and its association with APOE, p‐tau, and neuroinflammation.

Method

The cohort (N = 60) was selected from the Mayo Clinic brain bank in Jacksonville, USA. Brain tissue from the frontal ‐, parietal ‐, temporal cortex, and the hippocampus was immunohistochemically stained for Aβ (6F/3D), p‐tau (AT8), CD68, and GFAP. The CGP and classic cored plaque (CCP) were scored as previously described1. Total plaque burden was expressed as the sum of all cortical regions.

Result

The CGP was predominantly located in the neocortex and present in ∼60% of AD cases, who were younger at onset (p<0.05) and had a lower brain weight (p<0.05) than CGP negative cases. When stratified for APOE Ɛ4+ and Ɛ4‐, CGP burden was only in Ɛ4+ positively correlated with p‐tau, Aβ, and GFAP burden in the frontal and parietal cortex (Table 1). CGP burden was not correlated with CD68. The CCP was negatively correlated with p‐tau, and not with GFAP, Aβ or CD68 (Table 1). In APOE Ɛ4+ cases, the burden of CGPs was negatively correlated with the burden of CCPs (Fig.1).

Conclusion

The neocortical CGP is correlated with increased p‐tau burden and astrogliosis in APOE Ɛ4+. The CGP is inversely correlated with the common CCP, suggesting an opposite effect of Aβ‐induced tau‐toxicity for the CGP versus the CCP.

1Boon et al., Acta Neuropathologica, 2020
Construct Validity of the ALLFTD Mobile App Cognitive Tests: Associations with Gold Standard Clinical Measures and Brain Volume
Authors: Staffaroni Adam M. , Clark Annie L , Taylor Jack C , Heuer Hilary W. , Wise Amy B , Manoochehri Masood , Forsberg Leah K. , Mester Carly T. , Rao Meghana , Brushaber Danielle , Rojas Julio C. , Kramer Joel H. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. , Consortium ALLFTD
Published: December 2022

Background

Remote digital cognitive assessments validated for use in frontotemporal dementia (FTD) and other neurodegenerative diseases would benefit clinical trials and clinical care. The ALLFTD Mobile App includes several smartphone‐based measures of cognition, and prior studies have provided preliminary support for their reliability. Here we evaluate their validity by testing associations with gold standard clinical outcomes and expected neural correlates.

Method

A diagnostically mixed sample of 92 participants (CDR®+NACC‐FTLD = 0 [n = 33]; CDR®+NACC‐FTLD = 0.5 [n = 15]; CDR®+NACC‐FTLD≥1 [n = 16]; unknown [n = 28]) were recruited from a UCSF healthy aging study (Hillblom Network) and a North American FTD study (ALLFTD). Participants were asked to remotely complete four ALLFTD Mobile App tests of executive functioning (EF) and a memory test on their smartphones. Gold standard clinical measures were also collected; outcomes were the UDSv3 EF composite, CVLT‐SF Total Immediate Recall (memory), and CDR®+NACC‐FTLD Box Score (disease severity). Volumetric brain MRI measurements were available for a subset (n = 37). Expected neural correlates were frontoparietal gray matter volume for EF tests and hippocampal volume for the memory test. Linear models were fitted to evaluate the association of app tests with the gold standard outcomes, controlling for education, sex, and total intracranial volume (imaging only).

Result

Smartphone EF measures were strongly and positively associated with the UDS3‐EF composite (ß’s = 0.6–0.8, all p<.001). The memory test was strongly correlated with the CVLT‐SF (ß = 0.7, p<.001). Tests were less strongly associated with divergent cognitive domains (e.g., associations with a visuospatial test were ß’s = 0.1–0.3). Worse performance on all tests was significantly associated with greater disease severity (ß’s = 0.5–0.7, all p<.001). Worse app‐based EF scores were associated with lower frontoparietal volume (ß’s = 0.4–0.6, all p<.015) and worse memory scores with lower hippocampal volume (ß = 0.5, p<.001).

Conclusion

ALLFTD Mobile App scores were strongly associated with gold standard neuropsychological tests of the same cognitive domain (i.e., convergent validity) and less associated with measures of a different domain (i.e., divergent validity). Worse performance on the smartphone tests was associated with increasing disease severity and volume loss in expected brain regions. These results provide preliminary support for the construct validity of the ALLFTD Mobile App cognitive tests.
Cross‐Validation of a Novel Apathy Measurement Model in a Diverse Ambulatory Cohort of Older Adults with Memory Complaints
Authors: Ceide Mirnova E , Cantor Aviva , Ayers Emmeline , Verghese Joe , Lounsbury David
Published: December 2022

Background

Apathy is a psychological syndrome characterized by a loss of motivation, goal‐directed activity, and diminished emotion (Marin, 1990), which may mediate the relationship between depression and cognitive impairment (Funes et al., 2018) and be an early risk factor for dementia that precedes predementia syndromes including non‐amnestic mild cognitive impairment (NA‐MCI) and motoric cognitive risk syndrome (MCR) (Ceïde et al., 2020). While there is no gold standard measure of apathy, assessment tools vary from subscales of depression instruments to apathy specific questionnaires. Our group conducted a confirmatory factor analysis (CFA) of the Geriatric Depression Scale (GDS) in a pooled cohort of community and memory clinic older adults which identified a novel 2‐factor model that distinguishes apathy from depression. The goal of this study was to cross‐validate this novel apathy measurement model in a bilingual urban primary care clinical cohort.

Method

We conducted a CFA in the primary care cohort that was composed of participants from the 5‐Cog Battery for Detecting Cognitive Impairment and Dementia clinical trial. We compared the reliability measures and model fit indices of both the previous 2‐factor model and this novel model. Cohort characteristics were compared as well.

Result

The primary care clinical cohort was significantly different from the community and memory clinic cohorts in all baseline characteristics. The CFA of the primary care cohort yielded depression and apathy factors with good reliability (α = .78 and .63, respectively). Despite the fact that the primary care cohort included Spanish speakers, it performed similarly to the reliability of the depression and apathy factors in the community dwelling and memory clinic pooled cohort (α = .75 and .63, respectively). Both the primary care and memory clinic cohorts had higher depression and apathy scale scores compared to the community dwelling cohort, with the primary care cohort scoring in between the community and memory clinic cohorts in both depression and apathy scale measurements.

Conclusion

Our 2‐factor measurement model demonstrated similar reliability and fit across 3 distinct cohorts (community dwelling, memory clinic and primary care clinic) and 2 languages (English and Spanish), indicating its appropriateness as an apathy measurement model in further clinical trials.
Measuring brain activity associated with subsequent relational memory in typically developing periadolescent children: preliminary data from the PRANK study
Authors: Ramirez Meghan K , Sexton Jennifer N , Phipps Connor J , Behm Lillian , DeCesare Thomas A , Heller Abi M , Maerlender Arthur C. , Phatak Vaishali S , Cramer Justin A. , Blair James , Murman Daniel L , Warren David E
Published: December 2022

Background

The developing brain undergoes significant structural and functional changes that are associated with substantial cognitive changes, and this maturational trajectory continues during the periadolescent epoch. One such change is improvement in relational memory (RM) abilities. Normal RM requires the hippocampus, as demonstrated by the distinct memory deficits of Alzheimer’s disease (AD) associated with AD‐related hippocampal pathology. Lifelong risk factors for late onset AD may affect childhood brain development in ways that affect vulnerability to AD and other memory deficits later in life. This possibility motivates investigation into the brain’s developmental trajectory and correlations with AD‐vulnerable cognitive abilities, especially memory.

Method

Our ongoing NIA‐funded study, the Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study, measures brain structure, function, and cognitive abilities in periadolescent children (age 8–13 years). Here, we report preliminary data using task‐based fMRI and a subsequent memory (SM) paradigm to measure hippocampal‐dependent RM. A periadolescent sample from the PRANK study provided data for the current project (N = 90). MRI data were collected using protocols adapted from the Human Connectome Project. Hippocampal‐dependent RM was tested using a subsequent memory task where participants were asked to study pairs of common objects while fMRI‐BOLD data were collected. A memory test was completed for the studied materials where participants were presented two types of stimuli (studied match pairs or mismatched pairs of studied items).

Result

Successful SM was associated with increased activity consistent with the frontoparietal networks in the lateral prefrontal and lateral parietal regions, increased activity in the dorsal attention network, and decreased activity in the so‐called memory retrieval network. There was evidence of increased anterior hippocampal activity associated with successful SM.

Conclusion

Using task‐based fMRI to study brains of periadolescent children while they studied pairs of items, we observed SM effects that implicated anterior hippocampus and large‐scale functional brain networks (frontoparietal, dorsal attention, and memory retrieval). Findings from this preliminary analysis are novel in this task and in this population but concordant with previous studies of older and younger individuals. Future work will test whether there is an association in the magnitude of SM effects with polygenic risk for AD among PRANK participants.
Sleep associated electrophysiological activity in subjects at different levels of risk of developing Alzheimer’s disease
Authors: García‐Colomo Alejandra , Nebreda Alberto , de Frutos Jaisalmer , Carrasco‐Gómez Martín , Fernández Ricardo Bruña , Maestú Fernando
Published: December 2022

Background

Alzheimer’s disease (AD) is tightly associated with sleep alterations: as the disease progresses, sleep quality worsens. Therefore, the study of sleep patterns in interaction with other variables could constitute an early biomarker of AD. It is widely known that sleep alterations lead to an impaired cognitive functioning and performance, and recent studies evidence a positive feedback between amyloid beta (AB) accumulation and sleep. Consequently, sleep could constitute an interesting target for interventions aimed at altering the course of the disease. In the present study, we studied the relationship between self‐reported measures of sleep quality (i.e. number of hours of sleep) and the electrophysiological activity at resting‐state recorded using magnetoencephalography (MEG).

Method

The sample for this study was composed of healthy adults, with varying risks of developing AD (direct relatives vs non‐relatives, and APOE‐E4 carriers vs non‐carriers). All participants completed the Pittsburgh Sleep Quality Index, underwent a MEG scan, and were genotyped for their APOE carriage.

Result

Preliminary results show different patterns of brain activation in areas classically associated with the development of AD, in relatives and non‐relatives, in relation with the number of hours of sleep. Non‐relatives present a significant cluster that encompases areas such as the precuneus, where a positive correlation is found between the power in the low beta (12‐20Hz) frequency band and the number of hours of sleep. Relatives do not show clusters where relative power and hours of sleep correlate significantly.

Conclusion

Although further research is needed, a possible interpretation of these results could be the following: non‐relatives’ brain functioning in areas of the default‐mode network, typically associated with AD, are more affected by the number of hours of sleep than relatives, who may not benefit as much due to early damage interfering with the protective effect of sleep.
18F‐MK6240 tau in ento‐ and perihinal cortex is related to episodic memory in the earliest stages of Alzheimer’s disease
Authors: Reinartz Mariska , Schaeverbeke Jolien , Van Laere Koen , Sunaert Stefan , Dupont Patrick , Vandenberghe Rik
Published: December 2022

Background

In a previous study, we showed the sensitivity of the Buschke Selective Reminding test Total Retention (BSRT TR) for detecting and predicting 4‐year cognitive change in cognitively intact older adults. Here, we examined how BSRT TR related to tau load.

Method

The study sample consisted of 29 cognitively intact participants of the Flemish Prevent AD cohort KU Leuven (CDR global=0, MMSE=28‐30, mean age=68.5 year) and eight memory‐clinic recruited patients with prodromal AD (CDR global=0.5, MMSE=21‐30, mean age=71 year). All participants underwent neuropsychological testing, MRI and 18F‐MK6240 PET. Structural T1‐weighted MRI images were processed using CAT12. Tau load was quantified as 18F‐MK6240 DVR with the inferior cerebellum used as reference region. The primary analysis was based on voxel‐wise regression analysis between 18F‐MK6240 DVR scans and BSRT TR mean scores, with age as covariate. The second primary endpoint was the correlation between BSRT TR mean scores and tau DVR in an entorhinal and perirhinal volume of interest (VOI) based on the Brainnetome atlas. The secondary analysis was a VOI analysis based on an early metaVOI also containing hippocampus, parahippocampus, fusiform gyrus and inferior temporal cortex. Results were compared to those obtained for other episodic memory scores (BSRT delayed recall (DR), Auditory Verbal Learning Test (AVLT) total learning (TL) and AVLT DR), and an MRI volumetric analysis.

Result

Voxel‐wise regression analysis showed a negative correlation between BSRT TR mean and DVR in ento‐ and perirhinal cortex bilaterally (x=22, y=‐4, z=‐32, extent=612 voxels, cluster level pcorr<0.001) (x=‐30, y=‐22, z=‐20, extent=2910 voxels, cluster level pcorr<0.001) (Figure A). This was confirmed by the analysis of the entorhinal/perirhinal VOI (rho=‐0.44, p=0.0063; Figure B). Significant correlations with ento‐ and perirhinal DVR were also present for BSRT DR (rho=‐0.39, p=0.017) and AVLT TL (rho=‐0.41, p=0.012), but not for AVLT DR (rho=‐0.29, p=0.084). No significant correlation was found with tau in the early metaVOI for any of the verbal episodic memory measures. Voxel‐wise regression analysis between gray matter volume and BSRT TR mean scores did not show significant results.

Conclusion

The earliest measurable tau aggregate levels in ento‐ and perirhinal cortex correlate with classical episodic memory parameters.
Empirically derived “discourse phenotypes” are associated with neuropsychological performance, cognitive status, and global atrophy: A latent profile analysis of connected speech measures
Authors: Mueller Kimberly D , Koscik Rebecca Langhough , Du Lianlian , Hale Madeline R , Chin Nathaniel A. , Christian Bradley T , Betthauser Tobey J , Johnson Sterling C. , Hermann Bruce P
Published: December 2022

Background

Evidence suggests that “connected speech” (i.e., spoken language, as in discourse) is related to early cognitive decline and early Alzheimer’s disease and related dementias (ADRD), yet performance on speech tasks and cognitive performance in ADRD are notably heterogeneous. Here we examined whether unique spoken language phenotypes could be ascertained using latent profile analysis (LPA), and we examined the association of identified clusters to demographic, clinical and cognitive characteristics. In the subsets with amyloid PET and structural MR, we analyzed cluster associations with estimated amyloid DVR and/or global atrophy at or near the speech sample.

Method

1,039 participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) completed comprehensive neuropsychological testing and provided a spoken language digital recording describing the Cookie Theft picture from the Boston Diagnostic Aphasia Examination. Cognitive status was determined by consensus conference. Five speech‐language metrics based on previous literature (Table 1) were automatically extracted from transcriptions of recordings utilizing Computerized Language Analysis (CLAN), including: semantic content, sentence length, speaking rate, and fluency. Baseline speech metric Z‐scores were included in the LPA; model fits were evaluated using BIC criteria. T‐tests, chi‐square tests, and ANCOVAs were used to the compare demographic, clinical, cognitive and imaging characteristics of the resulting discourse phenotypes (alpha = .05).

Result

Fit indices suggested a 3‐profile model: normal content‐normal fluency (n = 558), low content‐normal fluency (n = 224), and low content‐low fluency (n = 257) (Figure 1). The three phenotypes differed on gender and cognitive status, with more men and a higher proportion of MCI in the low content‐low fluency phenotype than the other groups; the phenotypes also differed on concurrent neuropsychological tests of language, memory and executive function. In the subset with imaging, the low content‐low fluency phenotype showed the most global atrophy. There were no differences in concurrent estimated amyloid accumulation (Table 2, Figure 2).

Conclusion

Three phenotypes of narrative discourse were identified and were associated with multiple neuropsychological tests, overall cognitive status and global brain atrophy. While connected speech metrics are generally viewed as a promising ADRD digital biomarker, the underlying taxonomy identified here suggests a more precision‐based approach is possible.
Initial Reports of ALLFTD Participant Internet and Social Media Usage Survey
Authors: Forsberg Leah K. , Brushaber Danielle , Heuer Hilary W. , Mester Carly T. , Rao Meghana , Manoochehri Masood , Nelson Kevin M , Huey Edward D , Rosen Howard J. , Boxer Adam L. , Boeve Bradley F.
Published: December 2022

Background

The ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study, is the unification of prior FTD research studies, ARTFL and LEFFTDS. ALLFTD aims to evaluate sporadic (s‐) and familial (f‐) frontotemporal lobar degeneration (FTLD) patients and asymptomatic family members of f‐FTLD patients, characterizing the cohorts longitudinally and informing clinical trial design.

Method

ALLFTD participants completed the ALLFTD‐specific, Internet and Social Media (ISM) Usage Survey. This survey was created to learn more about participants’ ISM habits. The survey asks participants to report on the frequency with which they use ISM for personal reasons and contains additional questions about reasons for use and general gaming and social media habits.

Result

In conjunction with their scheduled ALLFTD visit, 194 participants completed the ALLFTD ISM Usage Survey. Fifty one percent of participants identified as female. The mean age was 56.6 (SD 14.61), and the mean education level was 15.9 (SD 3.53). Most participants reported using ISM 1‐5 hours per day (56.7%). Participants also reported using ISM at less common frequencies: more than 5 hours per day (12.9%), less than 1 hour per day (13.9%), weekly (3.1%), 2‐3 times a week (2.1%), 2‐3 times a month (2.1%), and never (9.3%). “Moderate and Severely impaired” participants (CDR© + NACC FTLD > = 2) reported using ISM less frequently than “mildly symptomatic” participants (CDR© + NACC FTLD = 1, p<0.0001), and those who are “normal and questionably impaired” CDR© + NACC FTLD < = 0.5, p<0.0001). Those who are mildly symptomatic reported using ISM at a similar frequency to those who are normal or questionably impaired (p<0.01). When reporting on personal use, most participants stated that they used the internet for email (45.5%), news (37.5%), social media (32.4%), and entertainment (33.5%). Additionally, most participants reported playing games (56.2%) and using social media (59.8%). Participants predominantly indicated that they use social media to connect with family and friends (90.5%). Comparison of ISM usage frequency to reported anxiety, agitation, or depression on the NPI‐Q found evidence of a difference in ISM usage frequency; directional comparison studies are forthcoming.

Conclusion

Frequency of ISM usage is consistent between ALLFTD participants. Additional analyses of ISM usage are forthcoming.
Adverse Childhood Experiences and Poor Sleep Quality in Older Adults: The Influence of Cognitive Reappraisal
Authors: Sheffler Julia L , Pickett Scott
Published: December 2022

Background

Poor sleep quality is associated with increased risk for developing mild cognitive impairment and Alzheimer’s disease and related dementias in older age. Adverse childhood experiences (ACEs) are associated with sleep impairment across the lifespan, but little is known about modifiable factors that may ameliorate this relationship.

Method

Data were obtained from an online questionnaire completed by a community sample of older adults (N = 267). The questionnaire included the Pittsburgh Sleep Quality Inventory, an Adverse Childhood Experiences questionnaire, the Cognitive Emotion Regulation Questionnaire (CERQ), and measures of pain, health conditions, and other psychosocial information. Moderation analyses were used to examine the interaction between ACEs and the positive reappraisal facet of CERQ on sleep quality in older adults, while accounting for the effects of sex, income, pain, body mass index, and health.

Result

ACEs were significantly associated with worse sleep quality in older adults, and this effect was moderated by positive reappraisal (ps<.05). For individuals reporting greater use of positive reappraisal skills, ACEs had no effect on sleep quality, whereas for individuals reporting less frequent use of positive reappraisal, ACEs were associated with substantially worse sleep quality. This relationship remained significant after accounting for sex, income, pain, body mass index, and health conditions in the model.

Conclusion

The effects of early adversity on sleep quality persist into older age and may ultimately contribute to further health and cognitive problems. However, the modifiable emotion regulation skill of positive reappraisal appears to protect against sleep impairment in individuals with higher ACEs. These findings provide valuable information on techniques that may be beneficial for developing lifestyle interventions for high‐risk older adults.
Spatial Distribution of Rare Missense Variants Within Protein Structures is Associated with AD Risk
Authors: Jin Bowen , Capra John A , Benchek Penelope , Wheeler Nicholas R. , Naj Adam C. , Hamilton‐Nelson Kara L. , Farrell John , Leung Yuk Yee , Kunkle Brian W. , Vardarajan Badri N , Schellenberg Gerard D. , Mayeux Richard , Wang Li‐San , Farrer Lindsay A. , Pericak‐Vance Margaret A. , Martin Eden R. , Haines Jonathan L. , Crawford Dana , Bush William S.
Published: December 2022

Background

Despite large genome‐wide association studies, only ∼30% of the heritability of Alzheimer’s disease is explained. The Alzheimer’s Disease Sequencing Project Whole Exome Sequencing (ADSP WES) has identified millions of genetic variants, over 97% of which are rare (MAF<1%), with 23% appearing in only one person. These rare variants could provide valuable information about new and previously identified risk loci for AD. However, current analysis strategies do not have power to detect associations for such rare variants.

Method

We have developed a protein structure‐based approach that evaluates rare missense variants based on their spatial distribution in a known protein structure rather than on their allele frequency. We hypothesize that AD cases exhibit clustering of rare variants within a protein structure relative to cognitive normal controls. We applied our approach to the ADSP WES Discovery Dataset with 5,522 AD cases and 4,919 controls on 5,969 genes with known structures from the Protein Data Bank (PDB) and 17,450 genes with Alpha Fold2 predicted structures. Only rare variants(MAF<0.05) were included in the analysis. We validated the identified genes within an independent dataset with multi‐ancestry individuals (ADSP WGS Replication) and a European‐ancestry dataset with 15,078 individuals (ADSP validation dataset).

Result

We identified three significant genes (TREM2, SORL1, and EXOC3L4) and one suggestive gene (CSF1R) with AD‐associated spatial clusterings from the ADSP WES data. For TREM2(PDB:6XDS; p‐value = 3.592E‐07) and SORL1(PDB:3WSY;p‐value = 6.701E‐05), two known AD genes, the spatial clusters are significant after excluding known AD risk variants, indicating the presence of additional low‐frequency risk variants within these genes. EXOC3L4(AlphaFold2:Q17RC7;p‐value = 2.504E‐05) is a novel AD risk gene that has a cluster of variants primarily shared by AD cases around the C terminal end of the Sec6 domain. This cluster replicated with significant associations in the ADSP WGS Replication and ADSP validation dataset.

Conclusion

Our result suggests multiple rare missense variants in TREM2, SORL1, EXOC3L4, and likely CSF1R are associated with AD risk by spatial clustering within the protein structure. These spatial clusterings have been replicated in two additional datasets. These spatial patterns may indicate potential functional regions in the protein structure associated with AD risk and are prime targets for further experimental validation.
Neurodegenerative Pathways in Alzheimer's Disease Subtypes
Authors: Wheatley Sophia , Mohanty Rosaleena , Ferreira Daniel , Muehlboeck J‐Sebastian , Levin Fedor , Grothe Michel J. , Westman Eric
Published: December 2022

Background

Biological heterogeneity in Alzheimer’s disease (AD) has been observed and described as subtypes in measures of neurodegeneration (e.g., hypometabolism and atrophy). However, the relationship between these AD subtypes have not been studied. Thus, we aimed to compare and identify pathways associated with hypometabolism‐based and atrophy‐based subtypes.

Method

Cross‐sectional FDG‐PET and MRI scans from 173 amyloid‐positive AD individuals and 120 amyloid‐negative cognitively normal control individuals from the ADNI were included. Subtypes were identified in each neuroimaging modality by random forest hierarchical clustering using FDG‐PET uptake (measuring hypometabolism) and MRI volumes (measuring atrophy) in cortical and subcortical regions. We performed cross‐modal comparisons of atrophy patterns in hypometabolism‐based subtypes and hypometabolism patterns in atrophy‐based subtypes. To identify neurodegenerative pathways corresponding to each subtype, we used event‐based modelling to predict sequential progression of abnormality in hypometabolism and atrophy across brain regions (hippocampus, AD signature, frontal, posterior areas).

Result

Clustering revealed four hypometabolism‐based (two relatively limbic‐predominant: 25.7%, 19.8% and two relatively cortical‐predominant: 25.7%, 28.6%) and three atrophy‐based (diffuse: 18.7%, relatively limbic‐predominant: 28.6%, minimal: 52.6%) subtypes of AD with distinct spatial patterns and demographic and clinical characteristics. Cross‐modally, we found comparable AD‐typical atrophy patterns (involving the hippocampus and temporal regions) across the four hypometabolism‐based subtypes and comparable AD‐typical hypometabolism patterns (involving the retrosplenial cortex) across the three atrophy‐based subtypes. Event‐based modelling showed that each hypometabolism‐based subtype was associated with a unique sequential progression of regional hypometabolism, but not regional atrophy (sequence always initiated with frontal atrophy across all subtypes). Similarly, each atrophy‐based subtype was associated with a unique sequential progression of regional atrophy, but not regional hypometabolism (sequence always initiated with hypometabolism in AD signature areas across all subtypes).

Conclusion

Our findings suggest that hypometabolism‐based and atrophy‐based AD subtypes are not interchangeable. We identified unique metabolic and atrophy pathways specific to each subtype, which supports the notion that neurodegeneration manifests and progresses differentially across subtypes of AD. Despite being measures of neurodegeneration, hypometabolism and atrophy may not share the same extent of heterogeneity, bearing a complex multimodal relationship. Disentangling such relationships and combining complementary biomarkers to investigate heterogeneity could aid personalized treatment of AD.