bluuebunny/crossref_metadata_2025 huggingface dataset:
SORL1 regulates tau trafficking
Authors: Cooper Joanna M , Lathuiliere Aurelien , Su Enming J , Jo Youhwa , Migliorini Mary , Lawrence Daniel A , Hyman Bradley T. , Strickland Dudley K
Published: December 2023

Background

While LRP1 is a cellular receptor that mediates tau uptake and potentiates tau seeding, we observed LRP1‐independent uptake of tau in LRP1‐genetically deficient cells and hypothesized that the sortilin‐related receptor (SORL1) could also be involved in tau processing.

Method

Surface plasmon resonance was used to assess tau binding to SORL1. 125I‐labelled tau uptake assays were used to investigate the role of SORL1 in endocytosis. The P301S FRET biosensor was used to assess SORL1’s role in cytosolic tau seeding, using both WT and AD‐associated mutations in the SORL1 gene (G511R and N1358S). Confocal microscopy was used to investigate colocalization and intracellular trafficking of tau and SORL1. Finally, we investigated the impact of SORL1 on tau processing in vivo by injecting human pathogenic tau isolated from AD patients into the hippocampus of SORL1 knockout vs wildtype mice and analyzing via immunohistochemistry.

Result

We confirmed high‐affinity binding of tau to SORL1 and found that fluorescently labeled tau colocalizes with overexpressed SORL1 in H4 neuroglioma cells. When we knocked down SORL1 expression using siRNA in H4 cells, we observed a significant increase in the LRP1‐mediated degradation of 125I‐labeled tau, revealing that SORL1 directs tau away from lysosomal degradative pathways. To determine if this occurs in vivo, we injected pathogenic forms of human tau into the hippocampal region of WT and SORL1‐deficient mice. Two days following injection, preliminary results suggest less human tau retention in the brains of SORL1‐deficient mice when compared to WT controls. Together, these data suggest that SORL1 may have a dual function in tau metabolism: impacting both uptake of tau, and trafficking of pathogenic tau to lysosomes. We also found that SORL1 promotes cytosolic tau seeding induced by pathogenic forms of tau. The AD‐associated N1358S mutation SORL1 gene demonstrated a significant increase in tau seeding when compared with WT SORL1.

Conclusion

These studies identify SORL1 as a sorting receptor for tau that contributes to seeding of pathogenic tau. Furthermore, they indicated that SORL1 directs tau away from lysosomal degradation pathways, and identify promotion of tau seeding as a potential mechanism by which the SORL1 N1358S mutation contributes to AD.
Neuropathological correlates of neuropsychiatric symptoms in the Brains for Dementia Research study
Authors: Lawson Anna , Matthews Fiona E , Erskine Daniel , Hamilton Calum Alexander , Thomas Alan J
Published: December 2023

Background

Neuropsychiatric symptoms are a common feature of many dementia syndromes, and are frequently associated with poor clinical prognosis, reduction in quality of life, earlier institutionalisation, greater disability, and increased caregiver distress, particularly during later stages of disease. It has also been postulated that NPS may occur during prodromal stages of dementia, preceding or alongside early cognitive symptoms. Clinical profiles of dementia are both heterogenous and intersecting, which may reflect that up to 90% of cases have multiple pathologies post‐mortem. Comprehensive clinicopathological studies of neuropsychiatric symptoms in dementia are lacking, thus this study sought to investigate potential neuropsychiatric profiles resulting from mixed underlying pathology.

Method

This analysis aimed to identify pathological correlations of neuropsychiatric symptoms and included 840 post‐mortem brains donated to the Brains for Dementia Research project, a longitudinal study with post‐mortem neuropathological assessment across several brain banks, between 2008 and 2020. Patterns of neuropsychiatric symptoms were compared between pathology subtypes using clinical data including the Neuropsychiatric Inventory (NPI‐Q) and Clinical Dementia Rating scale, and neuropathological assessment of degenerative pathologies and vascular features. Confirmatory factor analysis was used to identify latent variables for psychosis, mood, and behaviour. Associations between pathological variables assessed at autopsy and neuropsychiatric features during life were explored using bivariate and multivariate statistical methods.

Result

Almost 80% of the 494 dementia cases included had at least one neuropsychiatric symptom across the course of disease. Apathy (51.2%) and aggression (41.7%) were the most prevalent neuropsychiatric features across all dementia subtypes. Preliminary results indicate that different underlying pathologies, including neurodegenerative pathologies (amyloid, neurofibrillary tangles, Lewy bodies, TDP‐43 inclusions) and vascular features may be associated with increased likelihood of specific neuropsychiatric symptoms, such as psychosis, mood and behaviour, during life. Co‐occurring substantial AD and Lewy body pathology was associated with the presence of anxiety, depression, and aberrant motor activity during life. AD in the absence of substantial Lewy body pathology, was associated with agitation, apathy, and disinhibition. Lewy body pathology, in the absence of substantial AD pathology, was associated with hallucinations, depression and sleep disturbances.

Conclusion

The interaction of multiple pathologies may contribute to differing neuropsychiatric profiles during life.
The Many Faces of Dementia in Canada: Findings from the Landmark Study
Authors: Armstrong Joshua J. , Sivananthan Saskia , Guimond Josée , Stiff David , Smetanin Paul
Published: December 2023

Background

With the rapidly increasing size of the dementia population, it is important to get a better understanding of the similarities and differences that are found across the people living with dementia. This work expands on the first report from the Landmark Study and takes a closer look at the many faces of dementia in Canada by highlighting some of the diversity that is found within the national projections for dementia.

Method

Using the Canadian Centre for Economic Analysis’s socio‐economic statistical analysis platform, a simulation model was developed using demographic characteristics and risk factors for dementia to forecast the numbers of people living with dementia in Canada from 2020‐2050. Here, we will examine findings related to sex, Indigenous Peoples, ethnic origins, and young‐onset dementia.

Result

In 2020, 61.3% of dementia diagnoses were in females and this sex ratio is projected to stay relatively constant over the three decades. By 2050, 1.08 million females and 637,000 males are projected to be living with dementia. For Indigenous Peoples of Canada, dementia numbers are estimated to increase by 273% (2020: 10,800; 2050: 40,300). By 2050, the ethnic background of people living with dementia will be quite different than today. People of Asian origin will increase from 8% of people living with dementia in 2020 to 24% by 2050. The changes are driven both by future immigration, and by people who have already immigrated to Canada in the past few decades. While most cases of dementia are found in older age groups, by 2050, the Landmark Study projects that there could be over 40,000 people under the age of 65 living with dementia in Canada, compared to the 28,000 in 2020.

Conclusion

This study illustrates the changing landscape of dementia in Canada. The characteristics examined in this study, as well as other distinctions between people, can profoundly affect the way in which dementia is experienced and their care needs. When it comes to these differences, we propose that the best way forward is to examine them, generate evidence, listen closely to the recommendations that come from these communities, and collectively advocate for systemic change.
Role of primary cerebrovascular cilia in the pathogenesis of blood pressure and Alzheimer’s disease manifestations
Authors: Aboualaiwi Wissam
Published: December 2023

Background

Primary cilia are solitary membrane‐bound organelles emanating from the apical surface of most mammalian cells. They serve as sensory organelles sampling the extracellular environment and reprogramming the transcriptional machinery in response to changes in fluid flow. Ciliopathies, a group of genetic disorders characterized by disrupted cilia structure and/or function, share common phenotypes such as vascular dysfunction and cognitive impairment. Ciliopathies present with a broad range of clinical symptoms, including hypertension (HTN), developmental delays and cognitive and memory deficits, symptoms also observed in Alzheimer’s Disease (AD). This suggests that cilia may house signaling cascades critical for vascular integrity and learning and memory and may also be important contributors to AD and HTN. Therefore, investigation of cilia function in the vascular system may reveal cilia‐modulating mechanisms in neurodevelopmental processes. We propose a bold idea to look at the pathophysiological roles of cerebrovascular ciliary receptors in BP and AD.

Method

Immunofluorescence of human brain endothelial cells (HBECs) were employed to study AChM3R localization and its downstream effectors. Cilia length and function (eNOS activation) studies were carried out to examine if mAChRs activation would enhance cilia structure and function. siRNA‐mediated knockdown of Tulp‐3 was performed to block AChM3R trafficking to primary cilia and study its activity. HBECs were exposed to synthetic Aβ to study their effect on cilia structure and ciliogenesis. Vascular‐specific cilia and AChM3R knockout mice were generated to study blood pressure and AD manifestations.

Result

We discovered that AChM3R, PIP2, and eNOS localize to primary cilia. mAChR‐specific activation increases cilia length in HBECs and cilia formation in cilialess Tg737 cells and was also associated with an increase in eNOS activity. Exposure to 2.5 μM human Aβ42 resulted in significant reduction in primary cilia length and ciliation percentage. RNAi‐mediated knockdown of Tulp3 caused a significant decrease in AChM3R trafficking to the cilia, associated with altered activity, suggesting that ciliary AChM3R localization is important for its activity. Vascular‐specific AChM3R and Tg737 KO mice developed high BP. Preliminary studies to examine cognitive function indicate altered cognitive function associated cerebrovascular cilia dysfunction.

Conclusion

Primary cilia play an important sensory role for the regulation of blood pressure and cognitive function.
Participating in leisure time physical activity across adulthood and later‐life brain health: 30 years follow‐up in 1946 British Birth Cohort
Authors: James Sarah‐Naomi , Nicholas Jennifer M , Chiou Yu‐Jie , Parker Thomas D , Lu Kirsty , Murray‐Smith Heidi , Cash David M , Malone Ian B , Sudre Carole H , Keshavan Ashvini , Coath William , Flores‐Guerrero Jose L , Orini Michele , Almeida‐Meza Pamela , Fox Nick C , Richards Marcus , Schott Jonathan M
Published: December 2023

Background

We assess if, and at which ages during 30 years of adulthood, undertaking leisure time physical activity (LTPA) is associated with brain health at age 70, and to what extent brain health metrics explain the positive association between LTPA and later‐life cognition.

Method

Participants from the British 1946 birth cohort prospectively reported LTPA five times between ages 36 and 69. Metrics were categorised into: not active (no participation/month); active (participated once or more/month); and summed. Participants underwent 18F‐florbetapir Aβ‐PET and MRI at age 70 (n = 468, 49% female). Regression analyses examined associations between LTPA metrics and later‐life brain health including Aβ‐PET, TIV‐adjusted brain, hippocampal and log‐transformed‐white matter hyperintensity (WMH) volume, adjusting for sex, scan age, childhood cognition, education, and childhood socioeconomic position. Effect modification by sex and APOE‐ε4 were examined. The relationship between cumulative LPTA and later‐life cognition (Addenbrooke’s cognitive Examination (ACE‐III)) was assessed adjusting for brain health measures.

Result

Participation in LTPA was associated with better brain health at age 70. For brain volume and WMH volume, the strongest associations were with LTPA at age 69 (Figure 1). Being active in one or more period across adulthood was linked to larger hippocampal volume (Figure 1); this relationship was modified by APOE‐ε4 (p<0.01), with a stronger effect shown in ε4 carriers (Figure 2). LTPA at age 43 was also associated with larger hippocampal volumes. There was no evidence of associations with amyloid status. The positive association between cumulative LTPA and better cognition was not attenuated by any of the brain health measures (Figure 3).

Conclusion

We provide evidence that LTPA across adulthood is linked to brain health at age 70; being active throughout adulthood was associated with larger hippocampal volume, particularly in APOE ε4 carriers; and being active in later‐life was linked to less WMH and larger brain volume at age 70. However, these brain health metrics did not explain the relationship between LPTA and better cognitive scores, suggesting that these pathways may not underlie the inferred cognitive benefit at this age. Our findings warrant further research to shed light on the mechanisms of physical activity as a potential disease‐modifying intervention of brain health.
Aorta‐carotid hemodynamics and cognitive function in the U.S. POINTER Neurovascular ancillary study
Authors: Brinkley Tina E , Mitchell Gary F , Garcia Katelyn R , Leng Xiaoyan , Tegeler Charles H , Baker Laura D , Snyder Heather M , Bailey Margie J , Shaltout Hossam A
Published: December 2023

Background

The brain is particularly sensitive to excessive pressure and flow pulsatility. Disproportionate stiffening of the aorta can reduce wave reflection at the aorta‐carotid interface and facilitate transmission of excessive pulsatile energy into the cerebral microcirculation, leading to impaired cognitive function. The U.S. POINTER Neurovascular (POINTER‐NV) ancillary study is an ongoing study designed to evaluate vascular structure and function in participants from the U.S. POINTER trial. Here we describe the baseline characteristics of the POINTER‐NV participants, focusing on aortic and carotid variables and their association with cognitive function.

Method

Ultrasound and tonometry were used to assess aortic and carotid measures. Hemodynamic and structural variables were compared according to cognitive status using the baseline Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) score categorized as normal (CDR‐SB = 0) or possibly impaired (CDR‐SB>0). Linear regression was used to assess cross‐sectional associations between aortic and carotid variables and composite scores for global cognition, executive function, memory, and processing speed, with and without adjustment for age, sex, race, and ethnicity.

Result

Aortic and carotid hemodynamics were available for 165 POINTER‐NV participants (mean age: 67.9±5.1 years, 70% female, 37% people of color). A large proportion of the participants had evidence of subclinical cardiovascular disease based on a carotid intima‐media thickness ≥1.0 mm (n = 109/165, 66.1%) or increased aortic stiffness based on a carotid‐femoral pulse wave velocity >10 m/s (n = 70/131, 53.4%). There were no significant differences in aortic or carotid structure and function between participants with normal cognition (n = 109) and those with possible cognitive impairment (n = 56). Higher carotid‐femoral pulse wave velocity was associated with lower global cognition, executive function, and processing speed, even after adjustment for age, sex, race, and ethnicity (all p<0.05). Although there was some suggestion that higher carotid pulsatility, higher carotid transmission, and lower aorta‐carotid reflection may be associated with worse cognition, these associations were not consistent across cognitive domains and did not hold up after covariate adjustment.

Conclusion

Age‐related changes in vascular structure and function can promote cognitive decline and dementia. Our data are consistent with prior evidence suggesting that higher aortic stiffness may be particularly important in this regard.
Neuroinflammation and cognitive decline: a TSPO‐PET imaging study.
Authors: Crook Harry , Calsolaro Valeria , Edison Paul
Published: December 2023

Background

Neuroinflammation is a key driving factor of the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). Microglia, a major immune cell of the central nervous system, may exert protective effects in the early stages of AD, while may damage the brain milieu in later stages of the disease continuum. The microglial response is mirrored by an increase in the detection of translocator protein (TSPO), a mitochondrial membrane protein that can be targeted with positron emission tomography (PET) imaging. Here, we aim to assess the impact of neuroinflammation on cognition across the AD continuum.

Method

48 participants (23 patients with AD, 14 patients with mild cognitive impairment (MCI), and 11 cognitively normal controls (CN)) underwent TSPO‐PET (flutriciclamide, [18F]GE180) imaging, magnetic resonance imaging (MRI), and neuropsychological testing. All participants were either high‐ or mixed‐affinity binders for TSPO‐PET tracers, as revealed by TSPO genotyping. The spectral analysis generated a flutriciclamide impulse response function at 90 minutes (IRF90) image, which reflects its volume of distribution. Region of interest and voxel‐wise analyses were conducted to explore the relationship between IRF90 and neuropsychological assessment performance on a group‐level.

Result

TSPO‐PET binding was significantly higher in patients with AD compared to CNs across the whole brain, while patients with MCI demonstrated greater TSPO‐PET binding in the hippocampus and medial temporal lobe, compared to CNs. Significant negative associations were observed between neuropsychological assessment scores and IRF90, particularly in the temporal lobe (table 1). At a voxel level, negative correlations were seen between mini‐mental state examination score and IRF90 in temporoparietal regions (figure 1).

Conclusion

Microglial response, a marker of neuroinflammation, is elevated in patients with AD and MCI, as measured using TSPO‐PET (flutriciclamide, [18F]GE180) imaging. Heightened neuroinflammation, measured by TSPO‐PET, may exert damaging effects on the brain, as highlighted here by the negative association between TSPO‐PET binding and neuropsychometric assessment performance. This study emphasises the requirement to improve our understanding of the role of neuroinflammation in AD in order to identify pharmacological targets in the future.
Longitudinal biomarkers in Dementia with Lewy bodies: A systematic review and meta‐analysis
Authors: Pozzi Federico Emanuele , van Alphen Juliette Louise , van der Flier Wiesje M. , Lemstra Afina W.
Published: December 2023

Background

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease (AD). DLB is a clinically and biologically heterogeneous disease, and little is known about longitudinal trajectories of patients with DLB. Disease progression can be measured with biomarkers capturing structural, functional, and pathological processes, aiding in understanding disease mechanism and discovering potential drug targets. We aimed to perform a systematic review to explore longitudinal patterns of biomarkers in DLB.

Methods

Searches were conducted within five different databases, including cohort studies and case series on DLB patients with repeated measures of fluid or imaging biomarkers, and at least six months follow‐up. Fourteen studies were included (Figure 1), reporting data on longitudinal MRI, DaT‐Scan, PiB and flortaucipir‐PET, plasma p‐tau, and HMPAO SPECT, with up to 2,5 years of follow‐up (Table 1). No data on cerebrospinal fluid biomarkers were available. We could only perform a meta‐analysis on annualized brain atrophy rates, with a random effect model and standardized mean differences (SMD).

Results

Progressive putaminal atrophy is seen in DLB patients, even when DaT‐scans are initially normal. In the meta‐analysis, brain atrophy rates were not significantly higher in pure DLB compared to cognitively unimpaired controls, with the exception of accelerated ventricular expansion rates (SMD 0.57 [0.03‐1.10], p = 0.04, 2 studies, 58 patients). Autopsy‐confirmed AD copathology resulted in greater global atrophy rates compared to pure DLB (SMD 0.72 [0.21‐1.31], p = 0.006, Figure 2), similar to AD. AD copathology accelerates temporal lobe and striatal atrophy rates. In one study, brain amyloid accumulation in DLB initially accelerated and then decelerated, similar to AD and cognitively unimpaired subjects, with absolute SUVr lower than AD. In another study, brain tau accumulation rate correlated with brain atrophy rates in the middle temporal pole in DLB patients.

Conclusions

Only a few studies reported longitudinal data on biomarkers in DLB. DLB patients do not have significantly higher brain atrophy rates compared to controls, while the presence of AD copathology accelerates global and regional atrophy. Future studies with longer follow‐ups and multimodal biomarkers are needed to further characterize disease progression and elucidate clinical and biological heterogeneity.
Amygdalar pathology in early neuropsychiatric phenotypes due to 3R‐Pick disease
Authors: Keszycki Rachel M , Kawles Allegra , Minogue Grace , Zouridakis Antonia , Macomber Alyssa , Lubbat Vivienne , Coventry Christina , Rogalski Emily J , Weintraub Sandra , Flanagan Margaret E , Castellani Rudolph J , Mesulam Marsel , Geula Changiz , Gefen Tamar
Published: December 2023

Background

Persons with dementia syndromes such as primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD) often develop neuropsychiatric symptoms (NPS). Various neurodegenerative diseases may cause PPA or bvFTD, including frontotemporal lobar degeneration (FTLD) with 3‐repeat tau pathology (Pick disease, “PiD”). Limbic regions implicated in mood and behavior, such as the amygdala, are highly impacted in FTLD with PiD. This study quantified Pick bodies and activated microglia in the amygdala of individuals with antemortem diagnosis of PPA or bvFTD and postmortem PiD neuropathology and examined associations with initial NPS.

Method

We identified 16 right‐handed cases from the Northwestern University Alzheimer’s Disease Research Center brain bank with bvFTD (N = 8) or PPA (N = 8) due to PiD with unilateral amygdala tissue (basolateral region) available. Fifteen cases had data on 12 NPS assessed via the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q) from their earliest visit. We performed AT‐8 or HLA‐DR immunohistochemistry on amygdala sections to visualize Pick bodies or HLA‐DR+ activated microglia, respectively. We quantified the density of Pick bodies per mm3 via modified unbiased stereology and used HALO software (Indica Labs) to quantify percent area of HLA‐DR immunopositivity. We assessed differences between clinical groups via Welch’s t‐test (Pick bodies) or repeated‐measures two‐way ANOVA (HLA‐DR). Pearson clinicopathologic correlations were examined between Pick bodies or HLA‐DR immunopositivity and initial endorsement of total (out of 12) or behavioral/comportmental (apathy, disinhibition, motor stereotypies, or appetite disturbance) NPI‐Q symptoms.

Result

Amygdalar Pick body densities were similar between PPA (M = 28,822/mm3) and bvFTD (M = 29,114/mm3) cases. Compared to bvFTD, PPA cases trended towards a lower percent area of HLA‐DR immunopositivity (5.54% vs. 2.39%, p<0.10). There was no significant relationship between Pick Body density and initial NPIQ symptoms endorsed across all cases. However, area of HLA‐DR immunopositivity was positively correlated with initial endorsement of total (r = 0.47, p<0.10) and behavioral/comportmental (r = 0.54, p<0.05) NPI‐Q symptoms.

Conclusion

Our findings suggest that microglial pathology in the amygdala contributes to early neuropsychiatric presentations in PiD, particularly symptoms reflective of behavioral/comportmental disturbance. Future study will investigate the impact of neuronal size and density in the amygdala on NPS in these dementia syndromes due to PiD.
Investigating the interplay between age and apolipoprotein E
Authors: Liu Jun , Ulm Brittany , Bonnechère Bruno , Nevado‐Holgado Alejo J , Amin Najaf , Van Duijn Cornelia M
Published: December 2023

Background

Age is the major driver of dementia and aging is considered to be an independent, causal risk factor of dementia and Alzheimer’s disease (AD). We have examined whether the effect of age on dementia and AD is modified by genetic risk factors including the apolipoprotein E gene (APOE).

Method

We studied 204113 participants of the UK biobank who were over age 37 years at baseline (mean 64 years, SD=2.85) and were followed up with for dementia over time (mean 10.2 years). The study is based on 4,578 patients with dementia, including 1,741 with Alzheimer disease. We investigated whether APOE and other genes implicated in dementia modified the effect of age on dementia and AD. To study the effect of the other genes, a genetic risk score (GRS) was constructed for the genes other than APOE based on Bellenguez et al. Those in the highest and lowest quintile were compared across four APOE genotype groups (APOE22/23, APOE33, APOE34/APOE24, and APOE44).

Result

The effect of age on the risk in all dementia and AD differed significantly between carriers of the APOE44 and APOE24/34 and non‐APOE*4 carrier (APOE33 and APOE22/23) groups. Within the APOE44 genotype, the effect of age on the risk of dementia also differed significantly between those in the highest and lowest quintile of the GRS. In APOE24/34 carriers, a similar pattern was seen. In APOE22/23 carriers, we found that the association between age and dementia and AD does not differ between those in highest and lowest quintile of the GRS.

Conclusion

In UK Biobank, the association between age and the risk of dementia and AD is modified by APOE genotype and other genetic risk factors. Our data show that calendar age by itself is not a sufficient cause of dementia or AD but that the effect of age is conditional of the person’s APOE genotype and other genetic risk factors.

Bellenguez C, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022 Apr;54(4):412‐436. doi: 10.1038/s41588‐022‐01024‐z.
Insulin family receptors (IR and IGF‐IR) in astrocytes exert different Alzheimer’s‐like pathology and effects on behavior
Authors: Zegarra‐Valdivia Jonathan Adrian , Fernandes Jansen , Aleman Ignacio Torres
Published: December 2023

Background

Pleiotropic actions of insulin and insulin‐like growth factor I (IGF‐I) in the brain are context‐ and cell‐dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF‐I receptor (IGF‐IR), respectively), is less clear.

Methods

We compared mice lacking IR or IGF‐IR in glial fibrillary astrocytic protein (GFAP)‐expressing astrocytes in a tamoxifen‐regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons.

Results

We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross‐bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF‐IR in GFAP astrocytes (GFAP‐IGF‐IR KO mice) show cognitive disturbances, maintained mood tone, and show control‐dependent changes in AD‐like pathology.

Conclusions

These observations confirm that the role of IR and IGF‐IR in the brain is cell‐specific and context‐dependent.
The Early Detection of Neurodegenerative diseases initiative: emerging insights from the initial implementation of a digital toolkit
Authors: Whitfield Tim , Bhogal Sharandeep , Wing Kieran , Bond Simon , Morrell Rachel , Bass Nicholas , Chouliaras Leonidas , Wilson Sarah , Beswick Emily , Slight Sarah , Everson Richard , Hinds Chris , Chan Dennis , Llewellyn David J , Walker Zuzana ,   The Early Detection of Neurodegenerative diseases (EDoN) initiative
Published: December 2023

Background

The benefits of the early detection of the neurodegenerative and vascular pathologies which cause dementia are widely acknowledged. These include the opportunity to initiate risk‐reduction strategies, disease‐modifying therapies, and future care planning. However, current pathological biomarkers have several important drawbacks, as they are typically invasive, expensive, impractical, insensitive, or lack real‐world validation. Conversely, the targeted utilization of non‐invasive and inexpensive digital technologies which can be integrated into everyday life raises the possibility of capturing a ‘digital‐fingerprint’ of early disease.

Method

The Early Detection of Neurodegenerative diseases (EDoN) initiative is a meta‐cohort study spearheaded by Alzheimer’s Research UK. EDoN is acquiring high‐dimensional data from a ‘digital toolkit’ comprising a smartwatch (Fitbit Charge 4/5), smartphone software (Mezurio and Longevity), and an electroencephalography headband (Dreem 3). In combination with conventional digital, cognitive and biological markers, these data will inform the development of powerful machine learning models to detect dementia‐causing diseases at the very earliest stages. The initial phase, incorporating four cohorts across three continents, is already underway, and will recruit nearly 900 participants. Cohorts are recruiting healthy individuals, as well as patients with subjective/mild cognitive impairment, or established dementia. Data from version‐1 of the toolkit is being collected over two‐week periods at 3‐monthly intervals for a minimum of 12 months.

Result

We will present early insights from the implementation of the EDoN digital toolkit version‐1. These will include sample characteristics, feasibility and acceptability, and participants’ compliance. PPI data confirmed good acceptability but the potential for inequity due to technical problems and poor digital literacy. Pilot data indicate that six‐month adherence to the EDoN digital tools varies between 82‐89%. The forthcoming AAIC presentation will include important recruitment, toolkit acceptability and analytic updates.

Conclusion

The initial implementation of the EDoN digital toolkit suggests that it is feasible and acceptable to collect high‐dimensional digital data over a six‐month period. These ‘digital‐fingerprints’ will form the basis of the initial development of machine learning models to identify dementia‐causing pathologies substantially earlier. The insights gained will also inform the development of version‐2 of the EDoN digital toolkit which will be incorporated into the next meta‐cohort prospective study of around 4,000 participants.
Relationship of peripheral inflammation and discrimination with memory: a study of Black and Latinx middle‐aged adults
Authors: Seblova Dominika , Higgins Cesar , Mazen Jessica , Starks Tiara M. , Kraal A. Zarina , Turney Indira C , Adkins‐Jackson Paris AJ , Elyaman Wassim , Bradshaw Elizabeth M , Brickman Adam M. , Manly Jennifer J.
Published: December 2023

Background

Minoritized groups experience higher stress due to structural racism and discrimination. These exposures have been linked to lower cognitive test scores and inflammation is a potential biological pathway underlying this association. Yet studies with multiple inflammatory markers in diverse populations remain limited.

Method

We assessed 635 community‐dwelling adults (mean age = 54.5, SD = 11; 66% women; 67% Latinx, 33% non‐Latinx Black) from the Offspring Cohort. We characterized peripheral inflammation using principal component analysis on 33 serum inflammatory markers. Discrimination was ascertained by the Everyday and Major Discrimination Scales. Episodic memory was measured using the Selective Reminding Test and working memory by the Digit Span Test. Linear models stratified by racialized/ethnic group tested the cross‐sectional relationship between inflammation and memory adjusting for age, sex, and diabetes. Further, we examined if relationship between discrimination and memory (adjusted for age, gender, and education) was attenuated when inflammation was added. Due to smaller sample size, the magnitude of associations corresponding to change in cognitive score associated with >1 year of chronological age, rather than statistical significance, was used to highlight important associations.

Result

Two inflammatory factors were derived, with component 1 including FGF2, Fractalkine, GM‐CSF, IFNg, IL13, MCP3, TNFa, and TNFb, and Component 2 including IFNa2, IL1b, IL1ra, IL5, IL9, and MIP1a. Among Spanish‐speaking participants racialized as Latinx, both inflammatory factors were associated with lower memory scores. Only the first factor was associated with lower memory for English‐speaking participants racialized as Latinx. For participants racialized as Black, only the second factor associated with lower memory. Among Spanish‐speaking Latinx, Everyday Discrimination was associated with lower working memory. Everyday Discrimination was associated with lower episodic memory among Black respondents; this association was attenuated by 20% with inclusion of the inflammatory factor 1 in the models. Several associations that were opposite to hypothesized relationships were observed.

Conclusion

Elevated peripheral inflammation was associated with worse memory among individuals racialized as Black and Latinx. Our results indicate peripheral inflammation may contribute to disparities in cognition and may be one of the ways in which disadvantage due to structural racism and discrimination is embodied among minoritized groups in the United States.
Psychometric evaluation of the Everyday Discrimination Scale in KHANDLE
Authors: Deters Kacie D , Medina Luis Daniel , Corrada María M. M. , Pa Judy , Tommet Douglas , Vila‐Castelar Clara , Tsoy Elena , Gilsanz Paola , Whitmer Rachel A. , Mungas Dan M.
Published: December 2023

Background

Structural racism manifests in differential experiences of everyday discrimination for racialized and minoritized groups. The Everyday Discrimination Scale (EDS) assesses subjective experiences of unfair treatment in everyday social situations. The goal of this study is to evaluate the psychometric performance of the EDS within racialized groups and specifically to evaluate if the EDS measures a unidimensional construct.

Method

Data was from a diverse sample of community‐dwelling older adults in Northern California (N = 1,590 participants) from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study (Non‐Hispanic (NH) Black = 411; NH Asian = 380; NH white = 477; LatinX = 322). The EDS is a 9‐item scale with six response categories that range from “almost everyday” to “never”. The EDS was administered to each participant at baseline. We used confirmatory factor analysis to evaluate unidimensionality in the combined sample and in the 4 racialized subgroups. We identified model modifications that improved fit in a random 50% subsample of each group and tested fit of the modified model in the other random 50%.

Result

Loadings for all items on the main factor were > 0.50 for each racialized group and for the full sample. There were issues with model fit with the full sample, which were improved when residual correlations were set between items “courtesy” and “respect” and between “insult” and “threat”. Cross‐validated model fit was improved after adding these parameters to the model and was best in groups racialized as Black and LatinX (Table 1).

Conclusion

The EDS is a commonly used assessment in aging studies purporting to capture effects of discrimination on a variety of health and psychosocial outcomes. Our study show that all EDS items are strongly associated with underlying construct of discrimination in all groups, though differentially. Further work is needed to determine if the identified residual correlations point to additional factors that are important to measure. Model fit suggests the EDS is better suited to capture discrimination in groups racialized as Black and LatinX groups, which is consistent with the development of the scale. This study expands the literature by carefully examining the measurement properties of the EDS among four racialized groups.
Protective effects of gestational folic acid and egg yolk powder solution intubation on motor coordination, anxiety, cognition, acetylcholinesterase activity and DNA fragmentation in prenatal alcohol exposed rats
Authors: Obajuluwa Adejoke Olukayode , Iyiola Oluyinka , Morakinyo Joseph Akintade , Obajuluwa Tiwalola Madoc
Published: December 2023

Background

Development of neurobehavioural disorders can occur in the postnatal life of foetuses prenatally exposed to alcohol, regardless of the alcohol type consumed during pregnancy. Hence, the need to investigate the efficacy of proposed pharmaco‐nutritional therapy in mediating potential behavioural and cholinergic impairments in prenatal alcohol exposed (PAE) fetuses.

Method

We investigated whether PAE exacerbates anxiety, motor coordination, cognitive function, cerebral cortex acetylcholinesterase (ACh) activity, DNA fragmentation and assessed associations among parental and PAE rats’ cerebral cortex ACh activity. Thirty female Wistar rats were mated in the following groups (n = 6): 1: Negative control (distilled water only), 2: Positive control (40% EtOH), 3: local gin (LG), 4: local gin+egg yolk solution(LGEY) 5: local gin +egg yolk solution+folic acid(LGEYFA). Statistical significance of obtained data was measured at p<0.05 using regression model, ANOVA and Tukey’s PostHoc tests (GraphPad 5).

Result

When compared to the negative control, all alcohol groups (supplemented or not) had significantly lower latency of fall, working memory, percentage alternation etc. Although the brain weight of PAE rats in group 2 (positive control) did not change significantly (p = 0.159), critically reduced brain weights seen in group 3 (LG, p<0.001) were normalized in the supplemented groups (4‐LGEY and 5‐LGE). Cortex protein levels was unchanged in all maternal rats regardless of alcohol intubation. However, ACh cerebral cortex activity was significantly reduced in PAE rats from non‐supplemented groups (2 and 3). Necrosis and fragmentation were also seen in agarose gel electrophoregram (AGE) of gDNA isolated from PAE rats’ brain.

Conclusion

Prenatal alcohol exposure predisposes to severe neurobehavioural and cognitive deficits while gestational folic acid+egg yolk solution may be a therapeutic target for high risk PAE pregnancies.
The dirt under the rug: prevalence and adverse outcomes associated with undiagnosed dementia during hospitalizations
Authors: Aliberti Márlon Juliano Romero , Avelino‐Silva Thiago J , Covinsky Kenneth E , Silva Vinicius B. O. , Suemoto Claudia Kimie ,   CHANGE Study Group
Published: December 2023

Background

While dementia affects about 40% of older people admitted to hospitals and requires adaptations in acute care, many cases remain undiagnosed. Nevertheless, the occurrence and consequences of undiagnosed dementia during hospitalizations have received little attention. We estimated the prevalence and adverse outcomes associated with undiagnosed dementia in hospitals.

Method

We used data from the CHANGE Study, an ongoing cohort of people aged 65 years and older admitted to 21 acute hospitals throughout Brazil. Participants underwent comprehensive assessments on admission. Previous dementia diagnosis was determined by reviewing hospital records and asking patients and families. Trained investigators also completed the Clinical Dementia Rating (CDR) with family informants, using the patients’ cognitive status three months before admission as the reference, avoiding possible effects of acute cognitive impairments. Combining clinical history and CDR scores, we defined patients as: without dementia (no previous diagnosis and CDR = 0), with diagnosed dementia (previous diagnosis and CDR ≥1), and with undiagnosed dementia (no previous diagnosis and CDR ≥1). We investigated whether patients with undiagnosed dementia were associated with prolonged stays, delirium (brief‐CAM on admission + CHART‐DEL assessments at discharge), and mortality in hospitals than those without dementia and those with diagnosed dementia using Poisson regression models adjusted for age, sex, race/ethnicity, education, Charlson comorbidity index, and study center.

Result

We included 736 patients (mean age = 81±8 years; women = 62%; non‐White = 44%). We observed that 230 (27%) had diagnosed dementia, but 122 (14%) had undiagnosed dementia, meaning that 35% of patients with preexisting dementia were undiagnosed. During hospitalizations with a median of 9 days (interquartile range = 5; 19), 317 (43%) presented delirium at some point, and 119 (16%) died. Patients with undiagnosed dementia were associated with more prolonged stays, higher delirium occurrence, and mortality in hospitals than those without dementia (Figure 1). Comparing diagnosed and undiagnosed dementia, we found similar risks of delirium and mortality, but patients with undiagnosed dementia had more prolonged stays (Figure 2).

Conclusion

One in three hospitalized older adults with dementia in Brazil had not been diagnosed before admission. Hospital providers should be attentive to identifying patients with undiagnosed dementia and be aware that they might present worse outcomes.
Predicting change in depressive symptoms using longitudinal regional amyloid and cognition in cognitively unimpaired older adults
Authors: Munro Catherine E , Farrell Michelle E. , Hanseeuw Bernard J , Rentz Dorene M. , Buckley Rachel F. , Properzi Michael J , Vannini Patrizia , Amariglio Rebecca E. , Quiroz Yakeel T. , Blacker Deborah , Sperling Reisa A. , Johnson Keith A. , Marshall Gad A , Gatchel Jennifer
Published: December 2023

Background

Depression is a neuropsychiatric symptom of Alzheimer’s disease (AD) and has been linked to greater cortical amyloid burden in preclinical AD. We sought to examine whether amyloid accumulation in brain regions subserving emotional control and changes in cognitive performance may contribute to increased depressive symptomatology over time.

Method

155 cognitively unimpaired participants who were below the cortical amyloid (<0.86DVR) and clinical depression thresholds (<12 on Geriatric Depression Scale (GDS); mean age = 72.6) at baseline were included from the Harvard Aging Brain Study, with annual GDS and Preclinical Alzheimer Cognitive Composite (PACC) assessment and MRI/PiB‐PET every three years (mean years follow‐up = 7.06). PiB slopes were calculated for FreeSurfer‐defined bilateral regions of interest (ROI) implicated in emotional control: amygdala, medial and lateral orbitofrontal cortices (mOFC, lOFC), superior and middle frontal (MFC) cortices, anterior cingulate (ACC), posterior cingulate (PCC), and isthmus cingulate (IC). Linear mixed‐effects models assessed whether main‐effects of ROI PiB slope and PACC slope predicted longitudinal GDS scores for each ROI, covarying for age, sex, education, and random intercept/slope, adjusted for multiple comparisons. Post‐hoc linear regression models assessed relationships between PiB and PACC slopes.

Result

Steeper PiB slopes in the mOFC, MFC, ACC, and IC were associated with increasing GDS scores over time, while a decreasing PACC slope was predictive of increasing GDS scores over time in all regions (Table 1). Post‐hoc analyses indicated that PiB slopes were not significantly correlated with PACC slope (Figure 1).

Conclusion

In a cohort of cognitively unimpaired older adults with low cortical amyloid and no/subclinical depressive symptoms at baseline, increasing depressive symptoms over time were significantly associated with both amyloid accumulation in specific regions associated with emotional control (i.e., mOFC, MFC, ACC, and IC) and worsening cognitive performance. Furthermore, changes in cognition were not significantly associated with changes in amyloid accumulation in regions involved in emotional control, suggesting that different factors may be independently influencing trajectories in depression versus cognition over time. These results shed light on the neurobiology of depression in older individuals and underscore the importance of monitoring new and increasing neuropsychiatric symptoms in addition to cognitive symptoms when screening for AD.
Impact of type 2 diabetes on the association between amyloid and 1‐year change in everyday functioning in older Veterans
Authors: Durazo Alin Alshaheri , Bangen Katherine J. , Weigand Alexandra J. , Membreno Rachel , Mudaliar Sunder , Thomas Kelsey R.
Published: December 2023

Background

The prevalence of diabetes in Veterans is 25%, which is double that of the civilian population. Type 2 diabetes (T2D) is associated with greater rates of dementia and has been shown to exacerbate the impact of Alzheimer’s disease (AD) risk factors including genetic risk and cerebrospinal fluid markers on declines in daily functioning. Amyloid‐β, a hallmark pathology in AD, consistently shows associations with future declines in cognition and everyday functioning. The goal of this study was to determine whether T2D moderates the association between amyloid positron emission tomography (PET) and 1‐year change in everyday functioning in older Veterans.

Method

Two‐hundred‐seven predominately male Veterans without dementia from the Department of Defense‐Alzheimer’s Disease Neuroimaging Initiative with (n = 75) and without (n = 132) T2D completed amyloid PET imaging and everyday functioning measures, including the Everyday Cognition (ECog) questionnaire and Clinical Dementia Rating–Sum of Boxes (CDR‐SB). Linear mixed effects models, adjusting for age, education, race/ethnicity, posttraumatic stress disorder, depressive symptoms, traumatic brain injury history, and Hachinski score, examined whether T2D moderated the association between amyloid PET and 1‐year change in everyday functioning.

Result

Neither T2D nor amyloid PET were independently associated with change on the ECog or CDR‐SB (ps>.05). However, the T2D x amyloid PET x time interaction was significant for both the ECog (β = .118, 95% CI [.018, .217], p = .021) and CDR‐SB (β = .262, 95% CI [.147, .377], p<.001) such that greater amyloid burden was associated with greater increases in functional difficulties over time, but only in people with T2D. This pattern of results was also significant for the memory (β = .171, 95% CI [.065, .277], p = .002) and language (β = .141, 95% CI [.028, .255], p = .015) subscales from the ECog.

Conclusion

Higher amyloid is only associated with declines in everyday functioning over 1 year in people with T2D. On the ECog, these results were driven by memory and language domains, which may be consistent with AD‐related changes. Given that people with T2D are more likely to have co‐occurring cerebrovascular disease, the combination of multiple pathologies may result in faster declines. Future studies are needed to examine how diabetes duration, severity, and medications impact these associations.