bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of subjective cognitive decline on aging effects in the brain as measured by diffusion tensor imaging
Authors: Flaherty Ryn , Sui Yu Veronica , Masurkar Arjun V. , Rusinek Henry , Lazar Mariana
Published: December 2023

Background

Diffusion tensor imaging (DTI) can separate subjective cognitive decline (SCD) participants who progress to mild cognitive impairment and those who do not 1. We explored the effect age and memory performance has on DTI measures in SCD and controls in the hippocampal cingulum bundle, which is typically affected early in the course of Alzheimer’s disease2.

Method

325 participants Cam‐CAN 3 (127 SCD) older than 55 were included in the analysis. Diffusion imaging data was collected on a 3T Siemens TIM Trio scanner with a 32‐channel head coil for 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions. Preprocessing and calculation of the DTI metrics fractional anisotropy (FA, mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) were completed using MRTrix3, FSL and MATLAB. The hippocampal cingulum bundle regions of interest (ROIs) were extracted from the ICBM‐DTI‐81 atlas. Memory was assessed using the delayed story recall (DSR) task from WMS‐III. Linear regression models were completed in R. Gender was included as a nuisance variable.

Result

There were no differences in gender or age distribution between cohorts, however participants with SCD had a 14% lower DSR score (Table 1). There was a significant interaction effect between age and cohort in MD, AxD, and RD (Figure 1), as well as between memory and age in AxD (Figure 2). In post‐hoc analyses, compared to controls, the SCD group showed a stronger correlation with age in MD, AxD, and RD (Figure 1) while participants with worse memory showed a stronger correlation with age in MD (Figure 2), indicating an accelerated aging effect.

Conclusion

Participants with SCD and worse memory present with an accelerated aging effect, showing steeper variations in diffusion microstructure with age. Since SCD is likely to be a preclinical stage of Alzheimer’s disease, future work will analyze this effect with more advanced diffusion microstructure models to further elucidate the underlying pathophysiology.

1. Selnes P, Aarsland D, Bjornerud A, et al. J Alzheimers Dis. 2013;33(3):723‐36.

2. Jack Jr CR, Knopman DS, Jagust WJ, et al. The Lancet Neurology. 2013;12(2):207‐16.

3. Shafto MA, Tyler LK, Dixon M, et al. BMC neurology. 2014;14(1):1‐25.
Nutrient intake in relation to longitudinal change of blood‐based biomarkers of Alzheimer’s disease
Authors: Hoost Serena S. , Honig Lawrence S. , Kang Min Suk , Sanchez Danurys , Reyes‐Dumeyer Dolly , Lantigua Rafael A. , Dage Jeff L. , Brickman Adam M. , Manly Jennifer J. , Mayeux Richard , Gu Yian
Published: December 2023

Background

Intake of key nutrients is associated with improved cognitive performance and reduced risk of Alzheimer’s dementia (AD). We examined whether omega‐3 polyunsaturated fatty acid (O‐3 PUFA), omega‐6 (O‐6) PUFA, and monounsaturated fat (MUFA) from foods are associated with plasma biomarkers for AD.

Method

We selected 695 participants in a community‐based cohort study who were dementia‐free at baseline, completed the 61‐item semi‐quantitative food frequency questionnaire and had at least three plasma samples collected at different time points. We used linear regression to examine the cross‐sectional relationship between nutrients and AD biomarkers, including phosphorylated Tau‐181 (pTau181), amyloid‐beta (AB) 42/40 ratio, glial fibrillary acidic protein (GFAP) and Neurofilament light chain (NfL). We also examined whether baseline nutrient intake was associated with the longitudinal change of plasma biomarkers using generalized estimating equations. All analyses were adjusted for age, sex, race/ethnicity, total calorie intake, APOEe4 status, years of education, sample storage time and Mediterranean diet score as the overall measure of diet quality.

Result

Participants’ mean age was 74 years, and 69% were women. Participants were non‐Hispanic White (25.2%), non‐Hispanic Black (24.5%), and Hispanic (48.6%). Participants with the highest tertile of O‐3 PUFA intake had low GFAP at baseline (p = 0.023), had a slower increase of P‐tau 181 (p = 0.004) and NfL (p = 0.022) and had a slower decrease of AB 42/40 ratio (p = 0.010), compared to those with the lowest tertile. Those with high O‐6 PUFA intake had a higher baseline AB 42/40 ratio (p = 0.005) and a slower increase in GFAP (p = 0.001) compared to the low O‐6 PUFA intake group. Those with moderate and high O‐6 PUFA intake both had slower increase of pTau181 (p = 0.018 and p = 0.001, respectively), compared to the low O‐6 intake group.

Conclusion

Higher intake of O‐3 and O‐6 PUFAs from foods was associated with lower levels of plasma AD biomarkers cross‐sectionally, and a slower change in biomarker concentrations over time. This suggests that intake of key dietary nutrients may prevent or slow the progression of AD pathophysiology.
Evaluating the Causal Association Between Genetically Proxied Psychiatric Disorders and SuperAging
Authors: Nassan Malik , Piras Ignazio , Geula Changiz , Mesulam Marsel , Huentelman Matthew J , Rogalski Emily J
Published: December 2023

Background

SuperAgers are individuals aged 80+ who have episodic memory capacity that would be considered at least average for those 2‐3 decades younger. The causal factors for SuperAging are not known. Observational studies have linked psychiatric disorders with the risk for late life cognitive decline. It is not known if psychiatric disorders or their genetic liability have a causal effect on SuperAging. We sought to assess the causal relationship between genetically proxied psychiatric disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and SuperAging using a 2‐sample Mendelian randomization (MR). For comparison, we performed secondary analyses for the association of the same exposures with Alzheimer’s dementia (AD), Lewy Body dementia (LBD), and Frontotemporal dementia (FTD).

Method

Genome‐wide significant single nucleotide polymorphisms (SNPs) associated with MD (102 SNPs, 246,363 cases, 561,190 controls), BD (64 SNPs, 41,917 cases, 371,549 controls) and SCZ (287 SNPs, 76,755 cases, 243,649 control), were used as genetic proxies for the exposures. Summary statistics of the genome wide association study (GWAS) for SuperAging was included as the primary outcome (69 SuperAgers, 3,479 controls). Summary statistics were obtained for the largest GWAS studies of neurodegenerative disorders: AD (111,326 cases, 677,663 controls), LBD (2,591 cases, 4,027 controls) and FTD (2,154 cases, 4,308 controls). Inverse variance weighted MR was performed as the main analysis for testing the relationship between the exposures and outcomes.

Result

MR analyses showed a significant association between higher genetic liability to SCZ and lower likelihood of SuperAging (OR = 0.98, P = 0.02), but no significant association between MD or BD with SuperAging (P>0.05). Secondary analyses showed that genetic liability to BD was associated with an increased risk for AD (OR = 1.1, P = 0.003), while genetic liability to SCZ was associated with an increased risk for FTD (OR = 1.16, P = 0.04).

Conclusion

This is the first study to investigate the potentially causal factors for SuperAging. We found that genetic liability to SCZ is causally associated with lower likelihood of SuperAging. We also found that the genetic liability to BP and SCZ are associated with an increased risk for AD and FTD, respectively. Further exploration of causal factors to SuperAging is warranted.
Brazilian Subjective Cognitive Decline (BRASCODE) Cohort: protocol and preliminary results
Authors: Giordani Manuella Edler Zandoná , Souza Victória Tizeli , da Mota Simone Sieben , De Marchi Bruno De Oliveira , Formoso Carolina Rodrigues , Rivas Gabriela Raquel Paz , Carvalho Guilherme Da Silva , De Souza Haniel Bispo , Beltrami Lucas Bastos , Santos Rhaná Carolina , Suwa Samuel Masao , Slaviero Wesley , de Albuquerque Ana Letícia Amorim , Strelow Matheus Zschornack , Borelli Wyllians Vendramini , Carello‐Collar Giovanna , Chaves Marcia L. , Zimmer Eduardo R , Castilhos Raphael Machado
Published: December 2023

Background

Subjective Cognitive Decline (SCD) is a condition characterized by consistent cognitive complaints in cognitively unimpaired (CU) individuals and is associated with progressive cognitive impairment, especially in the context of Alzheimer’s disease (AD). We aimed to show the study protocol and the preliminary results of the Brazilian Subjective Cognitive Decline (BRASCODE) Cohort.

Method

CU individuals with > 65 years old and cognitive complaints were recruited. Exclusion criteria were previous diagnosis of dementia, uncontrolled neuropsychiatric/clinical illness, or cerebrovascular disease. The assessment was performed exclusively by phone calls. It consisted of a brief cognitive (Modified Telephone Interview for Cognitive Status ‐ TICS‐M) and anxiety/depression screenings, in addition to the SCD‐scale (Figure 1).

Result

Between March and November 2022, 52 SCD patients were included, 73.1% (n = 38) women. Their median interquartile range (IQR) age was 70 (68‐73) years old, with 16 (9.25‐19) years of formal education and median score of 28.5 (IQR 26,30) on Mini Mental State Examination (MMSE) (Table 1). Percentage of agreement on the presence of cognitive complaints between informants and patients was 38.5%. The main SCD‐plus criteria were the age at onset of SCD ≥ 60 years old (84.6%, n = 44) and concerns associated with SCD (78.8%, n = 41). The key findings of the neuropsychological assessment are reported in Table 2. Deficits were observed mainly in memory and executive functioning domains. Explorative analysis showed that Cognitive Reserve Scale scores correlated positively with MMSE (rho = 0.311; p = 0.02) and with formal education (rho = 0.541; p<0.001) and negatively with CDR‐sum of boxes (rho = ‐0.307; p = 0.03). The prevalence of APOE ε4 carriers was 29.8% (n = 14) and a dementia family history was more frequent in APOE ε4 carriers ‐ 12 (85.7%) ‐ than non‐carries, 12 (36.4%).

Conclusion

The increase in the sample size, especially with individuals with low education, associated with AD biomarkers analysis and long‐term follow‐up may bring valuable information about the progression of SCD to cognitive decline in Brazil. We estimate that a total of 150 individuals will be included by the end of 2023.
Predictors of hospital mortality in older adults with and without dementia: a necessary step towards personalized prognostication
Authors: Avelino‐Silva Thiago J , Campora Flavia , Curiati Jose A E , Jacob‐Filho Wilson
Published: December 2023

Background

Dementia has been associated with increased risk of hospital mortality (1). However, predictors of hospital mortality for patients with dementia have not been widely addressed. We aimed to investigate predictors of hospital mortality according to preexisting clinical dementia in older adults.

Methods

We analyzed data from a prospective cohort study in Sao Paulo, Brazil. We included acutely ill patients aged ≥60 years admitted to a tertiary university hospital between 2009 and 2020. Candidates underwent comprehensive geriatric assessments in the first 24 hours of hospitalization. Preexisting clinical dementia (after this, referred to as dementia) was determined by a Clinical Dementia Rating (CDR) ≥1 (2). We investigated independent predictors of hospital mortality according to dementia using multivariable Poisson regressions. We further analyzed our multivariable models' accuracy in predicting hospital mortality using area under the ROC curves (AUC).

Results

We included 3,863 participants (mean age = 80; female = 62%). Overall, 1,761 participants (46%) had dementia. Mortality was 11% in participants without dementia and 21% in those with dementia (p<0.001). In participants without dementia, mortality was independently predicted by age, multimorbidity, functional status, delirium, nutritional status, and serum albumin (Table 1). However, in participants with dementia, mortality was also predicted by illness acuity and creatinine. Finally, we observed that our multivariable model had an AUC = 0.88 (95%CI = 0.86‐0.90) in participants without dementia and 0.80 (0.78‐0.83) in those with dementia (Figure 1).

Conclusion

Older adults with dementia were twice as likely to die in the hospital than those without dementia. Moreover, independent predictors of hospital mortality were not necessarily shared between patients with and without dementia. Given the importance of prognostic assessments for decision‐making processes, researchers should consider exploring new algorithms that differ according to baseline cognition.

References:

1. Bouza C, Martínez‐Alés G, López‐Cuadrado T. The impact of dementia on hospital outcomes for elderly patients with sepsis: A population‐based study. PLoS One. 2019;14(2):e0212196. Published 2019 Feb 19. https://doi.org/10.1371/journal.pone.0212196

2. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia.Br J Psychiatry. 1982;140:566‐572. https://doi.org/10.1192/bjp.140.6.566
Analysis of apoE levels in Alzheimer’s disease patients and control subjects of APOE ε4 variant carriers and non‐carriers
Authors: Hurla Mikolaj , Banaszek Natalia , Florczak‐Wyspianska Jolanta , Zasada Aleksandra , Szymanowicz Oliwia , Kozubski Wojciech , Dorszewska Jolanta
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common progressive dementia disease in people over 60 years of age. The pathogenesis of AD is thought to be complex and depends on environmental and genetic factors. The most important genetic factors responsible for AD include variants of the APOE gene, which encodes the protein apolipoprotein E (apoE). There are 2 polymorphisms in the APOE, which presence of three alleles: protective ‐ ε2, neutral ‐ ε3, and pathogenic ‐ ε4. On the other hand, the presence of the ε4 allele is associated with an approximately four times higher risk of developing AD in people with a heterozygous system and a twelve times higher risk in ε4/4ε. Disorders of epigenetic mechanisms affecting the concentration of apoE may participate in the development of AD. Disturbed levels of apoE may impair clearance of Aβ from the brain and exacerbate disease progression. It is not known what level of apoE ensures the removal of Aβ and whether genetic and familial predispositions can regulate the efficiency of protective mechanisms. So far, there is little information on the level of apoE in AD patients and controls who are and are not APOE ε4 carriers.

The aim was to analyze genetic variants of the APOE gene and apoE protein concentration in AD patients, control subjects related to AD cases (CR), and controls subjects without a family history of AD (CU), carriers and non‐carriers of the APOE ε4 variant.

Method

The studies were conducted on 156 individuals (AD and controls). The APOE genotype was determined by real‐time PCR. The apoE concentration was determined by the ELISA method.

Result

The highest concentration of apoE was found in CR compared to AD and CU (p<0.001). In both APOE ε4 carriers (p<0.05) and non‐carriers (p<0.001), the highest levels of apoE were found in CR. At the same time, in all tested subjects, carriers of APOE ε4, the level of apoE was lower compared to non‐carriers of this pathogenic variant.

Conclusion

It seems that the ε4 pathogenic variant of the APOE gene may lead to the development of AD by regulating the level of apoE.
Prevalence of subjective memory complaints at age 90+ and their cross‐sectional association with cognition: The 90+ Study
Authors: Melikyan Zarui A. , Aguirre Colette , Al‐Darsani Zeinah , Jiang Luohua , Kawas Claudia H. , Corrada María M. M.
Published: December 2023

Background

Subjective memory complaints (SMC) present in 8‐33% of older adults younger than 90, and associated with worse cognition in cross‐sectional studies. However, the prevalence of SMC and its cross‐sectional association with objectively measured cognition at age 90+ are unknown. The aims are to: (1) determine the prevalence of SMC and (2) examine the cross‐sectional association of SMC with cognitive diagnosis and cognitive test scores in individuals aged 90 and older.

Method

We analyzed data from 1,112 participants of
The 90+ Study
, a longitudinal study of aging and cognition in people age 90 and older. SMC was assessed at baseline using an item from the Geriatric Depression Scale (GDS): “Do you think you have more problems with memory than most?” Cognitive diagnosis was determined from a neurological exam without knowledge GDS scores and catergorized as normal, cognitive impairment no dementia (CIND), and dementia. Cognitive tests measured verbal memory, verbal fluency, and executive function. We assessed the association between SMC and cognitive diagnosis using multinomial logistic regression and estimated the odds ratios of having CIND or dementia in those with SMC vs. No SMC. We used linear regression models stratified by congitive diagnosis to analyze the relationship between SMC and test scores. All analyses were adjusted for age, sex, education, and total GDS.

Result

Mean age was 93 years, 68% were women, 46% had college education or higher, and 16% had SMC. Participants reporting SMC had 1.69 times higher odds of a CIND diagnosis and 4.07 times higher odds of a dementia diagnosis compared to No SMC (Figure). SMC was associated with worse performance on memory and animal fluency in normal, and on memory only in CIND. SMC was not associated with performance on cognitive tests in participants with dementia (Table 2).

Conclusion

In this cohort of adults aged 90+, SMC prevalence was comparable to reports in older adults <90. Cross‐sectionally, SMC was associated with higher odds of cognitive impairment, and with poorer performance on memory in participants without dementia, potentially reflecting insight into their cognition. Our findings suggest that SMC is a useful indicator of memory impairment after age 90.
Ethnoracial differences in the prevalence of amyloid abnormality
Authors: Jansen Willemijn J. , Oomens Julie Elisabeth , Vos Stephanie J. B. , Maserejian Nancy Nairi , Verhey Frans R.J. , Reiman Eric M. , Visser Pieter Jelle ,   the Amyloid Biomarker Study Group
Published: December 2023

Background

Prevalence estimates of amyloid positivity in persons across the AD clinical spectrum are important to reduce screen failure rates and improve recruitment efficiency in anti‐amyloid trials. We have previously estimated the prevalence according to age, sex, education and APOE genotype. It is however unknown whether these prevalence estimates generalize to diverse ethnoracial groups. We here aim to estimate the prevalence of amyloid abnormality in Black, White and Asian persons without dementia and examine associations with age, sex, educational level and APOE‐e4 carrier status.

Method

We selected 7,419 participants (6,083 with normal cognition; 1,336 with MCI) from 9 Amyloid Biomarker Study cohorts, including 291 Black, 6,310 White and 818 Asian participants. Amyloid positivity was determined with a PET (n = 5,714) or CSF (n = 1,705) biomarker, using data‐driven or study‐specific cutoffs. Generalized estimating equations were used to estimate the age‐related prevalence by ethnoracial group and to evaluate moderation by APOE‐e4 carrier status while adjusting for sex and education.

Result

The mean age was 70.9+‐7.4 years, 3,848 (57%) were women, and 20% were APOE‐e4 carriers. In persons with normal cognition, the age‐related prevalence of amyloid positivity was higher for White (25%) than for Black (17%) and Asian (16%) participants (p = 0.016). Among APOE‐e4 carriers with normal cognition, the prevalence of amyloid abnormality was again higher for White (46%) than for Black (29%) and Asian (30%) participants (Asian vs Black p‐value = 0.046, Asian vs White p‐value<0.001, Black vs White p‐value<0.001). Among APOE‐e4 noncarriers, no differences among the ethnoracial groups were identified (p = 0.56). In persons with MCI, White (59%) and Asian (60%) participants had abnormal amyloid more often than Black participants (43%; p<0.001). Ethnoracial differences were similar for APOE‐e4 carriers and noncarriers with MCI.

Conclusion

In persons with normal cognition, the prevalence of amyloid abnormality among APOE‐e4 carriers was ∼15% higher for White than for Black and Asian participants, while among APOE‐e4 noncarriers no ethnoracial differences were found. In persons with MCI, both White and Asian participants ∼15% more often had abnormal amyloid than Black participants, irrespective of APOE‐e4 carrier status. Ethnoracial status may be an important factor to consider in the design of AD clinical trials.
In vivo data‐driven patterns of Tau accumulation associated with AD progression using 18F‐MK‐6240 PET
Authors: Fonov Vladimir S , Nazneen Tahnia , Rosa‐Neto Pedro , Collins D Louis
Published: December 2023

Background

Alzheimer’s disease is a neurodegenerative disease associated with accumulation of amyloid beta and tau neurofibrillary tangles following a pattern known as Braak stages (Braak 1995,2011). Recent papers (Pascoal 2020) indicate possibility to recapitulate Braak histo‐pathological stages in vivo using tau tangles PET tracer 18F‐MK‐6240, using manually defined regions of interest. This study analyzes patterns of Tau accumulation associated with AD in a completely data‐driven fashion.

Method

We used T1w MRI and 18F‐MK‐6240 Pet scans from healthy controls in the community or outpatients at the McGill University Research Centre for Studies in Aging. The following number of datasets from each diagnostic group [n scans total (m unique participants)]: cognitively normal: 347(194), mild cognitive impairment: 163(99), Alzheimer’s disease dementia: 114(77).

T1w MRIs were pre‐processed (non‐uniformity correction, intensity normalization, stereotaxic registration, brain masking, tissue classification); FALCON (Fonov 2020) was used to extract the mid‐cortical surface.

PET scans were linearly registered to the T1w MRI and the standardized uptake value ratio (SUVR) was calculated using whole cerebellum grey matter as the reference. SUVR values were sampled along cortical mid‐surfaces and geodesically smoothed with a 10mm gaussian and resampled to the cortical surface of MNI2009c template (Fonov 2011).

Result

Figure 1 shows Mean SUVR values on top of Figure 1, and latent factors at the bottom. Overall low values of tau in the temporal, partial and occipital region are associated with normal cognition (F1). Tau changes in the temporal lobe (F2, similar to stage 1&2) are associated with a slight cognitive change. Change in parietal and posterior temporal areas (F3, similar to stage 3&4) are associated with even more cognitive loss. Finally changes in the motor strip and ventral portion of the occipital lobe and remaining cortex (F4 and F5) are associated with the very advanced stages (5&6) of cognitive decline.

Conclusion

We discovered patterns of tau accumulation associated with progression of cognitive decline in a completely data‐driven fashion .
ALZpath Dx: A novel accessible, validated, and scalable phosphorylated‐tau 217 (pTau217) assay in blood
Authors: Portbury Stuart D , Chaby Lauren , Jeromin Andreas
Published: December 2023

Background

Blood‐based biomarkers for phosphorylated tau demonstrate strong diagnostic accuracy and compare favorably with current corresponding CSF and neuroimaging biomarkers. Of the four major pTau assays in use (pTau181, pTau217, and pTau231, Nfl), pTau217 appears to be the most robust marker, consistently outperforming plasma pTau 181, neurofilament light, and imaging markers. pTau217 has been shown to correlate with post‐mortem AD pathology, with the ability to differentiate AD from other types of dementia and predict future progression from both normal cognition and mild cognitive impairment to AD.(1,2) Additionally, pTau217 can be used to monitor AD progression because longitudinal increases in pTau217 is indicative of worsening of brain atrophy and cognition in AD.(3) pTau217, therefore, represents a cost‐effective and accessible blood‐based biomarker for tau pathophysiology, that can transform the AD diagnostic field.

Method

ALZpath has developed reagents for pTau217 and establish a robust and scalable fit for purpose plasma‐based ultra‐sensitive assay utilizing a proprietary monoclonal pTau217 antibody.

Result

The ultra‐sensitive blood‐based ELISA assay, using a peptide calibrator, has been developed on the semi‐automated single‐molecule array Simoa® platform. The assay has been launched for clinical use as laboratory‐developed test (LDT). Evaluation in independent clinical cohorts with multiple co‐morbidities is currently being established to advance to an in‐vitro diagnostic (IVD).

Conclusion

The ALZpath pTau217 Simoa® assay is now a fit for purpose validated assay now available for commercial use. Clinical use of this assay is described in Snyder et al. Gouda et al. and Ashton et al. AAIC 2023.
Passively monitored smartphone battery percentage relates to disease severity in frontotemporal dementia: A proof‐of‐concept study
Authors: Paolillo Emily W. , Casaletto Kaitlin B. , Clark Annie L , Taylor Jack C , Heuer Hilary W. , Wise Amy B. , Dhanam Sreya , Sanderson‐Cimino Mark E. , Saloner Rowan , Kramer Joel H. , Kornak John , Kremers Walter K. , Forsberg Leah K. , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. , Staffaroni Adam M. ,   the ALLFTD Consortium
Published: December 2023

Background

Frontotemporal dementia (FTD) is a leading cause of dementia in individuals under age 65. Due to limitations in access to in‐person evaluations, there is an urgent need to examine remote, accessible, and low‐burden assessment techniques for FTD. Unobtrusive monitoring of at‐home computer use in older adults has shown that those with mild cognitive impairment (MCI) have significant declines in computer use over time. To extend these findings, we characterized daily trajectories in smartphone battery percentage, a proxy of smartphone use, and examined relationships with clinical indicators of disease severity in FTD.

Method

Participants included 250 adults enrolled in the ALLFTD Mobile App study (mean age = 53.9 [SD = 14.9]; 59% women; 94% White). To assess clinical disease severity, all participants completed the FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD), a brief neuropsychological battery, the Neuropsychiatric Inventory Questionnaire (NPI‐Q), and brain MRI. The ALLFTD Mobile App was installed onto participants’ smartphones for remote, passive, continuous monitoring of smartphone use (average days of monitoring = 82 [range = 7‐541]). Battery percentage was collected every 15 minutes. Linear mixed effects models examined linear, quadratic, and cubic effects of time of day (i.e., hour; modeled as person‐specific random effects) and their interactions with each measure of disease severity on battery percentage. Models covaried for age.

Result

57% of participants were clinically normal, 21% had MCI, and 22% had dementia. CDR®+NACC FTLD Global score interacted with hour such that participants with MCI and dementia had flatter battery curves (i.e., less change in battery percentage throughout the day – a proxy of less smartphone use) than clinically normal participants (ps<0.001). Additional models showed that worse memory (hour3 x memory score: 𝛃 = 0.59, p<0.001) and executive functioning (hour3 x executive score: 𝛃 = 0.64, p<0.001), more neuropsychiatric symptoms (hour3 x NPI‐Q: 𝛃 = ‐0.22, p = 0.004), and smaller gray matter volumes (controlling for intracranial volume; hour3 x volume: 𝛃 = 0.49, p<0.001) were also statistically significantly related to less battery usage throughout the day.

Conclusion

These findings are proof‐of‐concept that passively acquired smartphone data, specifically battery usage, can provide insights about disease progression in FTD. Results support future research focusing on the development of passively collected digital metrics sensitive to clinical declines in neurodegenerative disease.
The impact of breathing patterns on CSF flow and global brain BOLD signal while awake: A study using real‐time phase‐contrast MRI and fast rsfMRI
Authors: Lee Jeyeon , Kang Daehun , In Myung‐Ho , Shu Yunhong , Bernstein Matt A , Ghatamaneni Sujala , Nunez Nicolas A , Park John G , Maihle Nita J , Nedelska Zuzana , Ganji Sandeep , Cogswell Petrice M , Gunter Jeffrey L. , III John Huston , Botha Hugo , Graff‐Radford Jonathan , Jones David T. , Petersen Ronald C. , Lowe Val J. , Min Hoon‐Ki
Published: December 2023

Background

The cardiac and respiratory cycles have been suggested as major drivers of cerebrospinal fluid(CSF) flow. The glymphatic system, one of the mechanisms for the clearance of amyloid‐beta and tau proteins, relies heavily on the movement(flow) of the CSF, and thus, investigating the forces that modulate the CSF flow is essential for understanding the glymphatic flux. Because breathing is trainable through exercise and self‐directed methods, various breathing methods may enhance the CSF flow.

Method

Real‐time phase‐contrast MRI(pc‐MRI) was used to measure the CSF flow at the foramen magnum on a 3T. Fast resting‐state fMRI(rsfMRI;TR400ms) was conducted on a compact 3T. Under an IRB‐approved protocol, participants were instructed to breathe slowly and deeply, and subsequently switch to their spontaneous breathing. For rsfMRI data preprocessing, we performed motion correction, skull stripping, spatial smoothing(4mm), temporal filtering(0.01 to 0.1Hz), and linear and quadratic temporal trends removal. fMRI time courses were then normalized to Z‐score at each voxel before being averaged. On the pcMRI, the phase was summed in a CSF region‐of‐interest and plotted vs time. Additionally, we confirmed for possible confounding effects such as head motion or motion‐induced susceptibility changes.

Result

rsfMRI findings showed that deep breathing promoted large oscillations in the CSF flow in the ventricles, while spontaneous breathing did not(Figure 1). Additionally, deep breathing resulted in large oscillations in lobar cortical regions. Similar results were observed in the pcMRI, with larger CSF velocity through the foramen magnum during the deep breathing compared to the spontaneous breathing(Figure 2A‐B). The cumulative summation result showed that the volume of CSF flow was increased during deep breathing(Figure 2C).

Conclusion

This study provides new evidence that slow and deep breathing promotes CSF flow and global brain BOLD signal, which may be useful in promoting circulation in the brain. The study’s findings also open new avenues for research in the field of neurovascular coupling and mechanisms associated with glymphatic clearance. As hampered CSF flow and/or worsen glymphatic clearance have been shown to associate with pathological aging and dementia, including Alzheimer’s disease and Parkinson’s disease, future research is needed explore the potential of breathing training methods as a non‐pharmacological intervention to support brain health.
REAL AD – A realistic screening approach for preclinical Alzheimer’s disease
Authors: Blennow Kaj , Heeman Fiona , Kern Silke , Moscoso Alexis , Zetterberg Henrik , Schöll Michael
Published: December 2023

Background

For disease‐modifying treatments to be successful in Alzheimer’s disease (AD), it is essential to identify individuals in the early phases of the disease, characterised by first biomarker abnormalities. At present, most AD diagnoses in Sweden are made within primary care which is not equipped for detecting individuals who are at risk of developing AD dementia. Considering current treatment developments, it will be essential to have access to biomarkers to aid an informed diagnosis already in primary care. REAL AD will evaluate the feasibility of a screening approach for preclinical AD using remote cognitive testing and blood‐based biomarkers in a naturalistic setting.

Method

REAL AD is a collaborative initiative between the Swedish Västra Götaland County Council (VGR), VGR Primary Care, the Sahlgrenska University Hospital, the University of Gothenburg and pharmaceutical industry partners. A targeted PR‐campaign will facilitate reaching a recruitment goal of a minimum of 3000 socioeconomically and ethnically diverse individuals aged 50‐80 years without AD dementia. All participants will perform remote cognitive testing at home and undergo blood sampling at a local primary care unit on two occasions. Based on baseline blood biomarker profiles, a subgroup of participants will be enrolled into a validation study and further undergo CSF sampling, neuroimaging and clinical and neuropsychological assessment, also on two occasions.

Result

Longitudinal remote cognitive assessment and blood sampling will be conducted at baseline and after 18 months, the blood samples will be analysed for a range of established and novel biomarkers. Within the validation study, results of the screening approach will be validated against established neuropsychological, CSF, MRI and [18F]RO948 tau PET assessments, and the feasibility of implementing this approach in the existing primary care infrastructure will be evaluated. We plan to present first data on recruitment and implementation at AAIC.

Conclusion

REAL AD aims to evaluate the applicability of a population‐based screening method to detect preclinical AD in a naturalistic setting and to inform the implementation of recent biomarker developments in clinical routine.
Effect of COVID‐19 and telehealth implementation on Patient Centered Outcome Measures completion by patients with Alzheimer’s and related disorders in an academic memory center
Authors: Gubler Boston , Finch Kelly , Holden Samantha K. , Mullen Rebecca , Matlock Daniel D , Pressman Peter S.
Published: December 2023

Background

Patient Centered Outcome Measures (PCOMs) are increasingly recognized as a means of improving clinical efficiency, particularly when completed electronically ahead of clinic visits. However, PCOM completion is often far from consistent. The shift to telehealth introduced by the Covid‐19 pandemic changed how patients and caregivers engaged with medical care, possibly encouraging increased participation in electronic assessments. We questioned how the pandemic influenced electronic PCOM completion by our patients with Alzheimer’s disease (AD) and their caregivers.

Methods

Patients and caregivers were routinely invited to fill electronic PCOM questionnaires prior to visits both before and during the Covid‐19 pandemic. PCOMs assessed the predominant cognitive domain of concern, other diagnostically useful symptoms, disease severity, neuropsychiatric symptoms, and caregiver wellbeing. A date of 3/15/2020 was set as the onset of the pandemic for this study, after which time our clinic converted to telehealth visits only. We tallied rates of completion of electronic surveys by patients and/or caregivers three and a half months before and after that time, comparing completion rates by two proportion Z‐test.

Results

During this timeframe, across a total of 402 visits (total: 333 individuals, 69 returns; AD: 73 individuals, 6 returns), caregivers and/or patients were offered an opportunity to fill PCOMs ahead of the visit. Across all clinical diagnoses combined, the probability of a visit being associated with filled PCOMS was greater after switching to only telehealth (caregivers: P = 0.005,patients: P = 0.016). Additionally,after the shift to telehealth, AD‐related visits were twice as likely to have completed preclinical electronic PCOMs (caregivers: P = 0.002, patients: P = 0.008). Approximately 33.3% of PCOMS to be filled by AD caregivers were completed before the telehealth shift, and 67.5% were afterwards. Approximately 26.7% of patient PCOMs were filled before the change, and afterwards this percentage rose to 55.0%.

Conclusion

The beginning of the Covid‐19 pandemic and subsequent shift towards telehealth‐only practice was associated with greater use of electronic PCOMs by all patients, including those with AD and their caregivers. Increased acceptance of electronic PCOMs seems to offer promising opportunities for remote assessment in the future of dementia diagnosis and care.
Comparison of Event‐Related Potential Markers in Amyloid Positive vs. Amyloid Negative Patients with Mild Cognitive Impairment (MCI) and Dementia in a general neurological clinic
Authors: Levy Igor
Published: December 2023

Background

We used an automated Event Related Potentials (ERP) technique to compare ERP responses in amyloid positive and negative group of 75 patients with Mild Cognitive Impairment (MCI) and Dementia in a general neurological outpatient clinic. Over the years, research labs have repeatedly reported abnormal ERP markers in patients with MCI and dementia. Recent advances in technology have made ERP testing safe, easy to use and low cost, thus rendering it suitable for clinical use. Indeed, ERPs have become more routinely used in clinical assessment of neurological patients with cognitive changes. The possibility that ERP could help identify amyloid status in MCI and dementia patients adds to the potential clinical utility of these biomarkers.

Method

Patients with a history of cognitive complains underwent an auditory oddball ERP paradigm in conjunction with routine neurological evaluation and imaging studies. Standard neuropsychological testing were available in most cases. Amyloid PET imaging was done as part of the IDEAS (Imaging Dementia ‐Evidence for Amyloid Scanning) study and provided the readings for amyloid load.

ERP responses were analyzed in the context of beta amyloid readings, and in relation to the patients’ degree of cognitive deficits.

Result

Final data analysis will be presented at the time of the conference

Conclusion

The possibility that ERP could help identify amyloid status in MCI and dementia patients adds to the potential clinical utility of these biomarkers. possibility that ERP could help identify amyloid status in MCI and dementia patients adds to the potential clinical utility of these biomarkers.
Characteristics associated with progression to probable Dementia with Lewy Bodies in a cohort with late onset psychosis
Authors: Gibson Lucy L , Mueller Christoph , Stewart Robert , Aarsland Dag
Published: December 2023

Background

A psychiatric‐onset prodrome is increasingly recognised in Dementia with Lewy Bodies (DLB) and while late‐onset psychosis is associated with increased risk of developing dementia, it is not clear what proportion of patients with psychotic disorders go onto develop DLB. Among patients with late onset psychosis, we aimed to identify the proportion who developed DLB and to characterise the clinical features and characteristics of those who convert to DLB.

Method

Anonymised data collected between 2006‐2021 was retrieved from clinical records from a large London mental health service for patients who were ≥50 years when first diagnosed with a psychotic disorder. Patients with dementia diagnoses >3 months later were identified and a natural language processing (NLP) algorithm was used to identify patients with probable DLB, with two of the core features (visual hallucinations, parkinsonism, fluctuations or sleep disturbance) identified in the free text at the time of dementia diagnosis. Predictors of progression to DLB were investigated including demographic factors, Health of the National Outcome scale for older people (HoNOS65+) and key clinical features at the time of psychosis diagnosis identified with NLP.

Result

In 3784 patients with late onset psychosis, 321 (8.5%) received a diagnosis of dementia from mental health services during the follow‐up period (mean time to dementia diagnosis 3.66±3.13 years). A high percentage (30.5%, n = 98) of those who developed dementia met criteria for probable DLB. Presence of hallucinations, falls, parkinsonism, fluctuations or drowsiness at the time of late onset psychosis diagnosis was associated with an increased relative risk of later developing probable DLB. Adjusted multivariate Cox proportional hazard models suggested that older age and higher scores on HoNOS cognitive and hallucinatory items at baseline were significant predictors of faster progression to DLB.

Conclusion

DLB is overrepresented in patients with late‐onset psychosis who later develop dementia; a psychiatric prodrome in dementia should give a high index of suspicion for DLB. In patients with late‐onset psychosis, risk factors for future progression to DLB include cognitive impairment, older age, hallucinations, falls, fluctuations, parkinsonism and drowsiness. Where these hallmarks are present at the time of psychosis, close follow up could facilitate the earlier identification of DLB.
Jedi‐1/MEGF12‐mediated phagocytosis controls the pro‐neurogenic properties of microglia in the ventricular‐subventricular zone
Authors: Morrison Vivianne E , Houpert Matthew G , Trapani Jonathan B , Brockman Asa A , Kingsley Philip J , Katdare Ketaki A. , Layden Hillary M , Hiebert Scott W , Nguena‐Jones Gabriela , Trevisan Alexandra J , Maguire‐Zeiss Kathleen A , Marnett Lawrence J , Bix Gregory J , Ihrie Rebecca A , Carter Bruce D
Published: December 2023

Background

The act of engulfing cellular debris profoundly shapes phagocyte phenotypes and, thus, determines tissue‐specific phagocyte function. A population of microglia with unique characteristics resides in the ventricular‐subventricular zone (V‐SVZ) neurogenic niche in neonatal mice. It is unclear whether these microglia perform phagocytosis and to what extent their phagocytic activity would support neurogenesis. We asked whether V‐SVZ‐resident microglia phagocytose apoptotic neurons and investigated whether the novel receptor Jedi‐1 mediates this process.

Method

Whole brain tissue or micro‐dissected V‐SVZ was collected from wild‐type and Jedi‐1 knockout (JKO) pups at postnatal day 7 (P7) and processed for immunofluorescent labeling, cytokine analysis, LC‐MS analysis of lipid mediators, microglia‐enriched culture and engulfment assays, or bulk RNA sequencing. Proliferating cells were labeled during a one‐hour pulse of EdU, delivered to the pups subcutaneously at P7. Microglia‐specific deletion of Jedi‐1 was induced with Tamoxifen, administered to the lactating dam twice daily from P1‐P3. In vivo rescue was performed via intracerebral injection of interleukin‐1 receptor antagonist at P4, followed by tissue collection at P7 for downstream analysis.

Result

We show that V‐SVZ microglia express Jedi‐1 and that Jedi‐1 is necessary for microglial phagocytosis both in vitro and in vivo. Furthermore, we show that loss of Jedi‐1 transforms microglial identity, leading to a neuroinflammatory phenotype consistent with that observed in neurodegenerative diseases and the aging brain. We demonstrate that loss of Jedi‐1 reduces the proliferation and neuronal differentiation of neural precursor cells in the V‐SVZ and that this effect is due to the loss of Jedi‐1 specifically in microglia. Finally, we provide evidence that the neurogenesis deficit is due to elevated interleukin‐1β levels and that in vivo inhibition of IL‐1 signaling rescues neurogenesis in the Jedi‐1 knockout V‐SVZ.

Conclusion

The discovery that Jedi‐1 activation engenders pro‐neurogenic microglia reveals previously unknown aspects of postnatal neurogenesis and microglial function. It also provides a platform for future research on pathways that dictate microglial phenotypic changes at all life stages, both in health and in disease. Finally, these findings may provide opportunities to explore neuroprotective/neuroregenerative microglial‐targeted therapies.
PET biomarkers in behavioral variant Frontotemporal dementia: analysis of an Argentine cohort.
Authors: Guimet Nahuel Magrath , Falasco German , Bagnati Pablo Miguel , Vazquez Silvia , Bérgamo Yanina , Herrera Julio Jose , Fernandez Laura , Urrutia Leandro , Mendez Patricio Chrem , Allegri Ricardo Francisco
Published: December 2023

Background

Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by early and progressive changes in behavior, emotional processing and executive control. This entity represents a diagnostic challenge in which positron emission tomography (PET) may play a key role in the diagnosis and follow‐up in vivo with a minimally invasive method. The aim of this work is to evaluate PET biomarkers in a cohort of patients with a clinical diagnosis of bvFTD.

Method

21 normal controls (NC: 64 ± 9 years) and 20 patients with a diagnosis of probable bvFTD (65 ± 7 years) were evaluated by: neurological, neuropsychological, neuropsychiatric evaluation and PET imaging biomarkers: [18F]‐FDG, [18F]‐AV1451 (TAU), [11C]‐PIB. For neuroimaging processing and analysis, they were spatially normalized to an FDG template. Group comparisons (voxel‐based) of each biomarker were performed by t‐test (SPM12) using cerebellar gray matter as reference tissue, and for inter‐biomarker uncoupling comparison a covariate of uptake in total cortex was used.

Result

In the statistical comparison between NC vs. bvFTD groups (p<0.05), hypometabolism is observed at the frontotemporal level and hypermetabolism in the precentral region (FDG). Amyloid marker (PIB) uptake shows no significant difference between groups in much of the cortex, except in the precentral region. TAU uptake shows a significant difference, greater in bvFTD, at frontal, parietal and precuneus levels. In the uncoupling between FDG and TAU biomarkers, it is observed that hypometabolism is related to an increase in TAU uptake in medial and inferior temporal regions. Differences between PIB and TAU are mainly observed in frontotemporal regions. There was an association between clinical symptoms (mainly apathy) and the anatomical distribution of [18F]‐FDG, [18F]‐AV1451 radiotracers (TAU).

Conclusion

PET biomarkers are a valuable tool in the diagnosis of bvFTD. The [11C]‐PIB may be of paramount importance in the differential diagnosis of FTvc FTD with Alzheimer’s disease. FDG is a very sensitive biomarker of neuronal metabolism and its variations, sometimes losing specificity. Advances in tracers such as [18F]‐AV1451 (TAU) can provide important information on the underlying neuropathological process. The combined use of these tools brings us closer to understanding the biological phenomena behind the cardinal symptoms of bvFTD.