bluuebunny/crossref_metadata_2025 huggingface dataset:
Data driven criteria for genetic testing result in an efficient selection of patients with genetic dementia in a clinical setting
Authors: Lee Sven J , Hulsman Marc , van Spaendonk Rosalina M.L. , Schaar Jetske , Dijkstra Janna I.R. , van der Flier Wiesje M. , Elting Mariet , Reinders Marcel JT , Rojas Itziar , Haelst Mieke M. , Geus Christa , Pijnenburg Yolande A.L. , Holstege Henne
Published: December 2023

Background

Identification of patients with familial dementia is important as this may explain disease in families, raises the possibility of predictive testing for relatives and enables participation in trials. Previously proposed clinical criteria to offer genetic testing based on diagnosis, age, and familial history do not capture the diversity of clinical presentation of patients. We aimed to develop data‐derived clinical criteria and prospectively validated these by applying them in a memory clinic.

Method

In a 2,5‐year period (1‐1‐2010 until 30‐6‐2012) 1138 patients visited the Alzheimer Center Amsterdam and underwent routine diagnostic work‐up (van der Flier et al 2018). The average age of individuals was 62 years, 41% of the patients being female. Patients provided DNA for research purposes, which allowed us to test 1022 (90%) of the patients for variants in 54 dementia related genes (exome sequencing), APP duplications and C9orf72‐repeat expansions. Data driven clinical criteria for genetic testing were formulated to optimally identify carriers of a causal mutation. Subsequently, we offered genetic testing according to the new clinical criteria to all patients in the Alzheimer Center Amsterdam for 1 year (9‐2021 to 9‐2022).

Result

We identified genetic mutations causing dementia in 34 patients, which accounted for 3.3% of all patients. Previous criteria would have selected 23% of these patients for testing and identified 47% of the mutation carriers. We formulated optimized clinical criteria(as shown in Figure 1), that would have identified 88% of mutation carriers(30/34 carriers) in 26% of all patients. This efficient selection was prospectively validated in 2021. A 149 out of 517 patients(29%) were eligible for genetic testing based on the new criteria. Of these 90 patients(60.4%) opted for testing and 59(39.6%) declined testing or clinicians decided against offering the test. We found 12 out of 90(13%) to carry a mutation. This confirms the efficient selection as 10 mutation carriers were anticipated in the tested group based on our research data.

Conclusion

Data driven clinical criteria for genetic testing efficiently selected individuals with genetic dementia in a real‐life implementation. Memory clinics can adopt these clinical criteria to offer genetic testing to the patients most likely to benefit.
Associations of Gait and Cognitive Impairment and Dementia in Individuals with Down Syndrome
Authors: Gonçalves Aline Souza , Mattar Guilherme Prado , Sant'Ana Livea Carla Fidalgo , da Silva Maria de Fátima Rebouças , Martinez Luana Dongue , De‐Paula Vanessa V.J. , Carvalho Claudia Lopes , Martine Alexandra , Fonseca Luciana Mascarenhas , Forlenza Orestes Vicente
Published: December 2023

Background

Life expectancy of individuals with Down syndrome (DS) has increased considerably over the years. Atypical aging in Down syndrome (DS) is associated with neuropathological characteristics consistent with Alzheimer disease (AD). Significant gait alterations are associated with an increased risk of dementia for the general population. The aim of this study was to determine whether gait performance is associated with cognitive performance and dementia in adults with DS.

Method

This study included 66 individuals with DS over 20 years of age, divided into three diagnostic groups: stable cognition, prodromal dementia, and dementia. They were evaluated with the Performance‐Oriented Mobility Assessment (POMA), Timed Up and Go test, and Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX‐DS), which includes the Cambridge Cognitive Examination (CAMCOG). Logistic regression model was used to assess the effects of gait and balance on the diagnosis (prodromal dementia and dementia versus stable cognition) adjusting for age, sex, body mass index (BMI), degree of intellectual disability and physical inactivity.

Result

The score on the POMA‐Gait subscale score and body mass index (BMI) were found to be independent predictors of prodromal dementia and dementia (Poma‐Gait OR = 0.67, 0.53‐0.85 CI, p<0.001; and BMI OR = 1.12, 1.021.24 CI, p<0.001). A lower POMA‐Total score indicates a higher fall risk. With the exception of perception, all cognitive domains correlated with the POMA total score (P<0.05).

Conclusion

These data indicate that poor gait performance, as assessed by the POMA, as well as a high BMI, were associated with a diagnosis of prodromal dementia or dementia. In those individuals, applying the POMA could facilitate the early diagnosis of dementia, help identify fall risks, and promote the adoption of geriatric interventions focused on improving functional mobility. There is a need for longitudinal studies to characterize the true nature of the associations found, to validate gait instruments specifics to this population, and for future analyses in order to clarify the role that gait and balance play in cognitive decline and the development of dementia.
WITHDRAWN: Understanding the progression of Alzheimer’s Disease in 5XFAD transgenic female mice using 1H‐[13C]‐NMR Spectroscopy
Authors: Nag Rishav ,   NMR Microimaging and Spectroscopy Lab, CCMB, Hyderabad, India
Published: December 2023

The above abstract, published online on 25 December 2023 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors; the journal Editor in Chief, Dr. Donna M. Wilcock, PhD; the Alzheimer's Association; and Wiley Periodicals LLC. The withdrawal has been agreed to because the authors informed the journal that they did not have permission to communicate the data and protocols included in the abstract.
Spatial interplay between synaptic loss, UCH‐L1 deficiency, and pTau accumulation in the retina of MCI and AD patients
Authors: Rentsendorj Altan , Jallow Ousman , Fuchs Dieu‐Trang , Sheyn Julia , Gaire Bhakta Prasad , Davis Miyah R , Shi Haoshen , Black Keith L , Koronyo Yosef , Koronyo‐Hamaoui Maya
Published: December 2023

Background

Synaptic dysfunction occurs early during Alzheimer’s disease (AD) progression and is considered a strong predictor of cognitive decline. However, it has never been investigated in the AD retina. The ubiquitin‐proteasome system (UPS) is a major degradation pathway for damaged proteins and has been implicated in synaptic integrity and AD pathogenesis. Deficiency in ubiquitin hydrolase (UCH‐L1), a vital UPS component known for its neuroprotective and synaptoprotective properties, was previously linked to cerebral Aβ accumulation in AD, yet has never been explored in the AD retina.

Method

We employed a range of histological techniques to evaluate synaptic integrity and retinal pathology in postmortem retinas of patients with mild cognitive impairment (MCI) attributable to AD or AD dementia, compared to retinas from age‐matched individuals who displayed normal cognition (NC). We assessed the presence of amyloidosis, gliosis, tauopathy, apoptosis, in relation to UCH‐L1 levels, and visualized and quantified synaptic density through analysis of pre‐ and post‐synaptic markers while also assessing the spatial and cellular layer distribution of these markers.

Result

We detected extensive pre‐ and post‐synaptic losses in the IPL and OPL layers of MCI and AD patients, particularly in the far peripheral regions. This was accompanied by 2‐ to 4‐fold decrease in levels of UCH‐L1 in the retinal layers of MCI and AD patients, which directly correlated with pre‐synaptic loss (p<0.0001). These changes were inversely correlated with pTau accumulation (e.g., AT8, pS396), colocalizing at sites of synaptic loss in the IPL and OPL layers. Furthermore, there were significant (1.8‐4.2‐fold) increases in apoptotic cell death in the retinas of these patients (p<0.05–0.001). Remarkably, the pre‐synaptic losses significantly correlated with decreased cognitive scores.

Conclusion

Our results reveal a substantial retinal synaptic loss at sites of pTau accumulation in prodromal and clinical AD patients. Expression of retinal UCH‐L1 was significantly reduced in MCI and AD patients and strongly associated with synaptic loss and cognitive decline, signifying its potential role in protecting retinal neurons against AD‐related pathology.
The Genetics of Cognitive Resistance and Resilience in the Ohio and Indiana Amish
Authors: Main Leighanne R. , Song Yeunjoo E. , Laux Renee A. , Miskimen Kristy L. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Osterman Michael D. , Lynn Audrey , Dorfsman Daniel A. , Caywood Laura J. , Prough Michael B. , Adams Larry D. , Clouse Jason E. , Herington Sharlene D. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L.
Published: December 2023

Background

Alzheimer’s Disease (AD) is a leading cause of death in the US, with limited treatment options. Most studies assess risk factors for AD; however, protective mechanisms demonstrate higher success rates as therapeutic targets. Here, we examine the genetics of Amish individuals maintaining cognitive preservation into advanced age, aiming to uncover protective mechanisms against AD.

Method

Our dataset consisted of individuals of Amish descent, between 76 – 95 years of age and cognitively unimpaired (CU) with at least one first‐degree relative determined to be either CU or cognitively impaired (CI). 946 Amish individuals met our criteria, were genotyped across their genomes, and incorporated into a single 13‐generation pedigree containing 8,222 individuals. Their complex familial relationships were considered in linkage and genome‐wide association analyses (GWAS). GENESIS was used for GWAS, with XWAS used for the X chromosome. Several parametric and non‐parametric linkage analyses were also performed utilizing MERLIN software for the autosomes and MINX for the X chromosome.

Result

106 SNPs (representing 64 loci) reached an initial significance threshold (LOD≥3.3) in linkage analyses. Adjusting for number of independent SNPs in our dataset, no SNPs reached significance after GWAS (P≤6.4×10−7), but 12 loci were suggestive (P≤5×10−4). No loci were suggestive/significant on the X chromosome. For a locus to be further investigated, 1) a significant or suggestive LOD score was required in two or more linkage analyses or 2) one significant LOD score and a suggestive GWAS association within a 10 Mb region were required. After applying these criteria, 8 loci, on chromosomes 1, 2, 3, 7, 11, and 17, were selected for further evaluation. Loci on chromosomes 7 and 11 are within 10 Mb of known AD risk and protective loci, EPHA1 and PICALM, respectively. Significant LOD score results on chromosomes 7, 11, and 17 overlap with coding regions for TBXAS1, DLG2, and SPNS3, respectively. These three loci have been implicated in cognitive impairment relating to neurological disorders.

Conclusion

We identified 8 loci potentially harboring genes promoting cognitive preservation. These are under further investigation and represent potential therapeutic targets but require experimental studies identifying their specific mechanisms in relationship to AD.
The Human Brain Nucleus Incertus: A New Target in Dementia?
Authors: de Avila Camila , Intorcia Anthony J , Serrano Geidy E , Suazo Crystal , Nolz Jennifer , Tallant Lauren , Plamondon Julie , Caron Alexandre , Beach Thomas G , Gundlach Andrew L , Mastroeni Diego
Published: December 2023

Background

The brainstem nucleus incertus (NI) or ‘uncertain nucleus’, was originally described by Streeter in 1903 as a midline region in the floor of the fourth ventricle of the human brain with an ‘unknown’ function. A century later, the NI has been shown to play a key role in memory formation in rodents, through direct and indirect inhibition of the hippocampus; and the anatomy of the NI and its projections throughout the brain have been systematically mapped in rats, mice, and primates, but not in humans. In these novel studies, we mapped the human NI using the neuropeptide, relaxin‐3 (RLN3), as neurochemical marker. In rodents, RLN3 is produced mostly in NI neurons with some subsidiary positive cells in the periaqueductal gray and an area dorsal to the substantia nigra.

Methods

Serial, free‐floating coronal sections of formalin‐fixed postmortem tissue were prepared from the pons of an adult female (aged 96 years) without a history of dementia or other neurological disorders, provided by the Banner Brain and Body Donation Program, Sun City, Arizona, USA. Using immunohistochemistry, we first identified the NI by mapping the distribution of microtubule‐associated protein‐2 (MAP2) and RLN3. The specificity of the RLN3 antibody used was verified in a dot‐blot using native RLN3 peptide. We also investigated the presence of markers detected in the NI of rats ‐ glutamic acid dehydrogenase‐65/67 (GAD65/67) and corticotropin‐releasing factor type 1 receptor (CRF1); and used a phosphorylated‐tau (AT8) to determine if the NI displayed tau accumulation.

Results

Detection of MAP2‐immunoreactivity revealed the neuronal distribution throughout the pons. RLN3‐immunoreactivity was detected in neurons in the dorsal, anterior‐medial region, revealing the broad anatomy of the human NI. Neurons within this same area were also positive for GAD65/67‐ and CRF1‐immunoreactivity, in line with previous studies; and AT8‐immunoreactivity was also detected.

Conclusions

RLN3 is present in neurons of the human NI and aspects of its anatomy are shared across species, including the macaque. Accumulation of phosphorylated‐tau in the NI suggests its possible involvement in the pathology of Alzheimer’s disease and related dementias. Further comparative studies are required to better understand the neurochemical anatomy of the human NI.
High dimensional Longitudinal Assessment of Ambient Home Environments and Their Association with Behaviors of People with Cognitive Decline
Authors: Au‐Yeung Wan‐Tai M. , Miller Lyndsey M. , Lindauer Allison , Rodrigues Nathaniel , Guerrero Cierra Leon , Marcoe Jennifer , Gothard Sarah , Steele Joel S. , Wu Chao‐Yi , Dodge Hiroko H , Beattie Zachary T , Kaye Jeffrey A
Published: December 2023

Background

Troubling behavioral symptoms such as mood changes or agitation are highly prevalent during the course of Alzheimer’s disease and related dementias (ADRD). Effective management is dependent upon understanding the causes and precipitants of behavioral symptoms. The objective of our studies is to evaluate the role of the physical ambient environment in instigating symptoms.

Method

Participants are from two studies: 1) MOnitoring DEmentia‐Related Agitation Using Technology Evaluation (MODERATE) which focuses on agitation in people with later‐stage dementia, and 2) Monitoring Apathy, Depression and Anxiety Using Technology Evaluation (ADA) which focuses on apathy, depression and anxiety in older adults with or without cognitive decline. A commercially available, multifunction environmental sensor, Awair Omni, was deployed in the room where the participant sleeps, measuring levels of temperature, humidity, carbon dioxide (CO2), total volatile organic compounds (VOC), particulate matter 2.5 (PM2.5), noise and light every 5 minutes. Additionally, a multi‐sensor array (bed pressure mats, motion sensors, and wearables) is deployed in homes to objectively measure participants’ behaviors. Caregivers in MODERATE report agitation level/event experienced by their partners while participants in ADA self‐report their level of symptoms via weekly online surveys.

Result

To date, 9 dyads (persons with cognitive decline and their caregivers) have enrolled in MODERATE and 9 participants are enrolled in ADA. 3135 days of data have been collected for MODERATE while 849 days of data have been collected for ADA. Mean participant characteristics: age = 75±8 years; 48% women; Blind MoCA = 13.2±7.96. For 4 weeks from 12/19/2022 to 1/15/2023, ambient environmental conditions identified (mean±SD): temperature = 21 ±2.0°C; humidity = 41±7.6%; VOC = 195±263 ppm; CO2 = 651±225 ppm; particulate matter 2.5 = 2.4±13 µg/m3; noise = 52±4.3 dBA; light = 9.5±40 Lux. The home environments are individually heterogeneous with high variability over time across multiple environmental conditions. Reports of behavioral symptoms show high week‐to‐week variability as well. Proposed methods of analyzing such data include generalized linear mixed model.

Conclusion

This in situ environmental sensing approach provides more objective and timely data to enable identifying the relationship between physical environments and the behaviors of older adults at risk of or with ADRD. The knowledge generated will help prevent or mediate symptoms by prospectively modifying environmental conditions.
Relationship between neurofilament light chain and cognitive decline moderated by amyloid‐β status
Authors: Kim Keun You , Shin Jiyoon ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

In this study, we identified whether amyloid‐β (Aβ) moderates the relationship between the plasma level of neurofilament light chain (NfL) and the change of cognition or brain volume.

Method

Of 723 non‐demented participants from the Alzheimer’s Disease Neuroimaging Initiative (mean age 72.1), 341 (47.2%) had cerebral Aβ deposition (Aβ [+]) and 382 (52.8%) had not (Aβ [‐]) determined by Florbetapir PET. Longitudinal changes of cognition was assessed by Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) score, and hippocampal and white matter hyperintensity volume by brain MRI.

Result

Aβ status moderated the relationship between plasma NfL and ADAS‐Cog score (beta = 0.002, P = 0.029), hippocampal volume (beta = ‐0.073, P = 0.004), and white matter hyperintensity volume (beta = 0.673, P = 0.048).

Conclusion

These results suggest the possible interactive effect between plasma NfL and brain Aβ on the longitudinal cognition and brain structure.
Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network
Authors: Wagemann Olivia , Li Yan , Hassenstab Jason J. , Aschenbrenner Andrew J. , Benzinger Tammie L.S. , Gordon Brian A. , Wang Guoqiao , Karch Celeste M. , Renton Alan E. , Cruchaga Carlos , Morris John C , Xiong Chengjie , Perrin Richard J. , Levin Johannes , Daniels Alisha , Bateman Randall J. , McDade Eric , Llibre‐Guerra Jorge J
Published: December 2023

Background

Studies suggest distinct differences in the development, presentation and longitudinal progression of Alzheimer’s Disease (AD) between women and men. However, most of these sex‐specific differences have been explored in symptomatic stages of sporadic AD. We investigated cross‐sectional sex differences in clinical‐cognitive assessments as well as fluid and imaging biomarkers in the spectrum of dominantly inherited AD (DIAD).

Method

319 DIAD mutation carriers of the Dominantly Inherited Alzheimer Network‐Observational study (DIAN‐OBS) were included in the analysis and, according to Clinical Dementia Rating® (CDR®) scores, classified as presymptomatic (CDR = 0, 66,1%) or symptomatic (CDR>0). All participants underwent clinical and neuropsychological assessment; lumbar puncture, structural MRI and 11C‐PiB‐PET imaging for amyloid‐β detection were conducted. Mann‐Whitney‐U‐test, Fisher’s Exact and linear mixed models with fixed effects for sex, estimated age of onset (EYO) and their interaction, a random effect for family, and years of education and CDR Sum of Boxes as covariates (where appropriate) were used to explore cross‐sectional sex differences.

Result

Demographics showed no significant sex differences in presymptomatic (pMC, 56.4% women, p>0.05) or symptomatic mutation carriers (sMC, 52,7% women, p>0.05). In pMC, men showed a worse performance on the Digit Symbol test (p<0.01, Fig.1) than women, and, in interaction with EYO, a better performance in immediate (p<0.05) and delayed (p<0.05) prose recall. In contrast, sMC men performed better on the Animal Naming test (p<0.05), but, in interaction with EYO, worse on the Digit Span forward (p<0.01). CSF analysis did not indicate sex‐related differences in Aβ42/Aβ40‐Ratio, phosphorylated Tau‐181 or total Tau levels (all p>0.05) in either group. In pMC men, PET imaging revealed significantly less tracer binding in the medial orbitofrontal cortex, the frontal pole and the rostral & caudal anterior cingulate in interaction with EYO (all p<0.05, Fig. 2). Furthermore, MRI volume analysis showed a significant reduction in the amygdala in women compared to men (p<0.01) in sMC.

Conclusion

We report preliminary results suggesting cross‐sectional sex differences in presymptomatic and symptomatic DIAD mutation carriers regarding episodic, verbal and working memory; processing speed; as well as differential patterns of PiB‐PET burden within cerebral areas related to emotion, decision making and cognitive flexibility.
Brain‐Penetrable Antibody Probes for in vivo Tau Imaging
Authors: Kelleher Andrew , Richardson Brandon , Banka Vinay , Sehlin Dag , Hultqvist Greta , Sigurdsson Einar M. , Syvänen Stina , Ding Yu‐Shin ,   Ding’s Research Group
Published: December 2023

Background

Antibody‐based PET ligands are desirable due to their high specificity; however, their brain uptakes are limited by the blood‐brain barrier (BBB). We previously demonstrated that transport of antibody across BBB can be facilitated through interaction with the transferrin receptor (TfR)1. We report here the first in vivo PET imaging studies using BBB permeable F‐18 radiolabeled bispecific antibodies specific to tau protein in mice.

Method

We performed multiple PET scans using each of the radio‐probes synthesized via conjugation of [18F]SFB with one of the four bispecific antibody constructs: 1) 6B2G12‐ScFv8D3 (full‐size Tau antibody conjugated with TfR fragment (ScFv8D3); abbreviated as TAUb), 2) ScFv235‐ScFv8D3 (small Tau‐TfR; TAUs), 3) 3D6‐ScFv8D3 (full‐size Aβ‐TfR; Aβb) or 4) ScFv3D6‐ScFv3D6 (small Aβ‐TfR; Aβs). We used a matched control design to compare a WT with one of the two types of transgenic (tg) tauopathy mice [PS19 (P301S) or JNPL3 (P301)] in each scan. Subjects were scanned on a MOLECUBES PET/CT scanner. An initial low‐dose (244 ± 54 μCi) dynamic scan (30 min) was performed, followed by two scans at 8hr and 12hr (20 min each static scans) after injection of a high dose (1832 ± 447 μCi) of the same probe. PMOD and FireVoxel were used for imaging processing. After co‐registration of PET/CT/atlas, data were quantified as SUV and SUVR [CB as a reference], and clearance was estimated as %change/hr.

Result

TAUs probe displayed highest brain uptake with more specific binding retained in the brain, as compared to TAUb and Aβs. TAUs probe showed faster brain penetration in tau‐tg mice than in WT, with differences in amygdala, basal forebrain, and hypothalamus of 66%, 62% and 85%, respectively, at 8hr post‐injection (Fig. 1). Further, higher brain uptakes (TAUs > Aβs) in the same tau‐tg mouse (Fig. 2) suggest the specific binding of TAUs probe, while Aβs probe can serve as a control due to its lack of specific binding in tau‐tg mice.

Conclusion

We have successfully synthesized and evaluated four novel F‐18 bispecific antibodies via in vivo PET. TAUs probe showed most promising BBB permeability and binding specificity to tau antigen with a reasonable clearance.
APOE4 impairs Microglia ‐ Astrocyte Crosstalk in Alzheimer Disease
Authors: Kleemann Kilian , Rosenzweig Neta , Yin Zhuoran , Zhang Xiaoming , Brandao Wesley N , Margeta Milica , Schroeder Caitlin M , Silveira Sebastian , Gauthier Christian , Mallah Dania , Pitts Kristen , Herron Shawn , Shorey Hannah , Aronchik Michael , Wang Chao , Jain Nimansha , Bao Xin , Brouwer Nieske , Baufeld Caroline , Krasemann Susanne , Eggen Bart , Clish Clary , Tanzi Rudolph E. , Madore Charlotte , Wakelin Sam , Rhee Jared , Cheng Yiran , Barry Jen‐Li , Yung Anthony , Gerrits Emma , Deik Amy , Tenen Daniel G. , Santander Nicolas G. , Ikezu Tsuneya , McKinsey Gabriel L. , Sheppard Dean , Arnold Thomas D. , Durao Ana , Holtzman David M. , Butovsky Oleg
Published: December 2023

Background

APOE4 is the major genetic risk factor for late‐onset Alzheimer Disease (AD). APOE signaling is critical for the transition of homeostatic microglia to the neurodegenerative phenotype (MGnD). The intrinsic role of APOE4 in microglia and its contribution to AD is unclear.

Method

Generation of Cx3cr1‐CREERT2 mice crossed to APOE‐KI(APOE3 and APOE4)fl/fl injected with labeled apoptotic neurons (MGnD‐Pardigm) on WT or APP/PS1 background. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq (APP/PS1). Crosstalk between cells was determined using the NichenetR database and validated using 1) Recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) Adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes.

Result

Expression of APOE4 in microglia impaired MGnD‐transition in response to neurodegeneration and in APP/PS1 mice. Conditional deletion of APOE4 in microglia restored MGnD phenotype and reduced plaque pathology. Furthermore, increased astrocytic recruitment towards plaques and their activation by increased Gfap and Serpina3n expression was identified. Microglial Lgals3 was determined as critical crosstalk effector to promote astrocyte response to plaque pathology and acute neurodegeneration. AD female APOE4 carriers showed impaired induction of MGnD signature genes and astrocyte activation, including LGALS3 and GFAP respectively, supporting a conserved disease mechanism in a sex‐dependent manner.

Conclusion

APOE4 impairs MGnD‐microglia in AD and prevents their crosstalk with astrocytes. Lgals3 is identified as important positive regulator for microglia–astrocyte crosstalk in response to AD pathology and provides a potential therapeutic target for treatment of AD.
The Effect of Depression in Instrumental Activities of Daily Living in Mild Cognitive Impairment: The mediating role of cognitive dysfuction
Authors: Jung Na‐Yeon , Ha YoungJi , Eom SungHui
Published: December 2023

Background

Geriatric depression can affect on decline of various cognitive functions including executive function and can lead to disabilities in instrumental activities of daily living (IADL). Decline in IADL was related to conversion to dementia even though there was no decline in screening tests such as MMSE. Therefore it is important to manage the factors affecting IADL. We examined the relationship between depression, cognitive dysfunction and IADL in mild cognitive impairment (MCI) to reveal the effect of depression on IADL.

Method

We recruited 132 patients with MCI who visited the Department of Neurology at Pusan National University Yangsan Hospital from March 2019 to June 2022. Using the Short‐Geriatric Depression Scale (S‐GDS: cuf‐off 8), these patients were divided into 64 depressed groups (mean age 75±6.7) and 68 non‐depressed groups (mean age: 71±8.1). To evaluate cognitive function, the Seoul Neuropsychological Screening Battery, which consists of five domains: attention, language functions, visuospatial functions, memory, and executive functions, was conducted. K‐IADL (Korean Instrumental Activities of Daily Living) was conducted to evaluate IADL. We investigated the mediation effect of cognitive functions between depression and IADL using mediation analysis.

Result

Depression and K‐IADL showed positive correlation (B = 0.023, p < 0.001). Mediation analysis of cognitive function between depression and IADL showed significant effect of executive function (B = ‐0.001, p = 0.019) and visuospatial function (B = ‐0.001, p = 0.045). Memory, language and attention domains had no significant mediation effect between depression and ADL.

Conclusion

In our study, depression related to decline in IADL, and not only the effects of depression but also mediation effects of executive and visuospatial dysfunction could affect IADL. In terms of IADL maintenance, it is necessary to actively manage the depressed mood of MCI patients.
Influence of Insulin Resistance and Metabolic Dysregulation on Synaptic Protein Profile in SH‐SY5Y Neuroblastoma Cells
Authors: Yang Alexander J.T. , Mohammad Ahmad , Finch Michael , Tsiani Evangelina , Spencer Gaynor , Necakov Aleksandar , MacPherson Rebecca EK
Published: December 2023

Background

Brain insulin resistance and metabolic dysregulation are significantly associated with Alzheimer’s disease development[1,2]. Metformin is the most prescribed type‐2‐diabetic drug and has been used to treat peripheral insulin resistance (IR) driven metabolic dysfunction through the activation of AMP‐kinase (AMPK)[3,4], but whether metformin is effective in improving brain metabolism is unknown. We have previously shown that chronic AMPK activation negatively impacts neuronal morphology and impairs synaptic protein content in healthy neurons[5]. However, whether AMPK activation under an IR state will exacerbate neuronal impairments is not known. Thus, we examined the effect of metformin‐driven AMPK activation on SH‐SY5Y cells with and without high‐insulin induced IR.

Methods

Retinoic acid‐differentiated SH‐SY5Y neuroblastoma cells were treated for 48h with either 1) vehicle (Ctl), 2) 100 M insulin (INS, mimicking hyperinsulinemia), 3) 2 mM metformin (MET), or 4) a combination of INS/MET.

Results

INS‐treated cells demonstrated higher Akt S473, mTOR S2448, and p70s6k T389 phosphorylation, indicative of hyperactive mTORC1 signaling associated with brain IR. INS cells had lower insulin receptor‐ (IR‐) content and higher IRS‐1 S636 phosphorylation, further demonstrating insulin signaling abnormalities. MET increased AMPK T172 phosphorylation, and increased phosphorylation of its downstream effectors ULK S555 and raptor S792, which, collectively, is indicative of mTORC1 inhibition. These phosphorylation increases occurred alongside higher IRS‐1 and insulin receptor‐ content and reduced IR‐ content. INS/MET‐treated cells produced no change in AMPK T172 or raptor S792 phosphorylation but produced increased ULK S555 phosphorylation. INS/MET did not recover increased Akt S473, mTOR S2448, p70s6k T389, or IRS‐1 S636 phosphorlyation nor did it recover IR‐ content. No differences were seen between groups for pre‐/post‐synaptic protein content. INS and MET treatments showed reduced NeuN and synaptophysin content. INS/MET treatment showed reductions in synaptophysin. Morphologically, cell size & area, and neurite length & area all increased with INS and MET treatments, however, these increases were absent with the INS/MET treatment.

Conclusion

These findings indicate that IR and MET impact neuronal morphology and reduce the development of mature neurons. These impairments are likely driven through Akt and AMPK signaling seperately and suggest that MET is not effective in treating IR‐driven impairments in the brian.
Brain Volumetry‐based Amyloid PET Positivity Prediction in Subjective Cognitive Decline Patients
Authors: Jung Wooseok , Yang Dong Won , Lee Chunghwee , Hong Yun Jeong , Ho SeongHee , Jeong Jee Hyang , Park Kee Hyung , Kim SangYun , Wang Min Jeong , Choi Seong Hye , Lee Dongsoo , Kang Junghyun , Kim Jinyoung , Lee Yeha ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Amyloid beta PET screening for subjective cognitive decline (SCD) patients would identify a risk factor of Alzheimer’s disease (AD) at an early stage but is generally infeasible due to the high cost and radiation exposure. Brain volumetry using 3D T1 MRI integrated with genetic information can alternatively suggest amyloid positivity in SCD subjects.

Method

Individuals of age between 60 and 85 feeling cognitive decline and scoring 7% to 50% on the memory test while exceeding 7% of the other tests comprises the SCD dataset via Seoul Neuropsychological Battery (SNSB) scheme (n = 119; 26 Aβ+; 24 APOE4+). We measured the volume, volume to intracranial volume ratio, cortical thickness and their normative percentiles of 104 brain subregions, respectively, using VUNO‐Med DeepBrain, an automated brain volumetry and neurodegenerative disease diagnosis‐supporting software. The significance level is set to a = 0.005 to find differentiating regions between amyloid positive and negative groups. Furthermore, four machine learning models (Logistic Regression, Random Forest, XGBoost, TabNet) were trained using the combination of APOE4 information, age, and each of the six different volumetry results to predict amyloid positivity in SCD dataset. The training dataset (n = 102; 36 Aβ+; 31 APOE4+) consists of subjects from significant memory concern (SMC) cohort of ADNI2 and ADNIGO studies.

Result

Swell of the choroid plexus and shrink of the lingual cortex (both p < .005) are statistically significant in Aβ+ SCD patients compared to the Ab‐ patients. The random forest model trained by the volume data plus APOE4 and age information showed the highest performance (accuracy = 0.79, AUROC = 0.75, precision = 0.81, recall = 0.79, F1 = 0.80) in the amyloid positivity prediction task among the 24 models, higher than the model without APOE4 information (accuracy = 0.70, AUROC = 0.71, precision = 0.77, recall = 0.70, F1 = 0.72).

Conclusion

The result indicates a statistically significant difference in choroid plexus volume and lingual cortex thickness between Aβ+ and Aβ‐ SCD patients. In addition, using both APOE e4 information and brain volumetry is crucial for amyloid positivity prediction. This study was supported by a grant from the Ministry of Health and Welfare, HI18C0530.
DETECT‐AD (Digital Evaluations and Technologies Enabling Clinical Translation for Alzheimer’s Disease): A simulated anti‐amyloid clinical trial using digital biomarkers as primary outcome measures
Authors: Kaye Jeffrey A , Marcoe Jennifer , Mar Amanda B , Hanna Elise J , Pierce Aimee , Silbert Lisa C , Shang Yanan , Schwartz Daniel , Gothard Sarah , Mattek Nora , Au‐Yeung Wan‐Tai M. , Steele Joel S. , Beattie Zachary T
Published: December 2023

Background

Early detection and precise monitoring of cognitive and functional decline in persons with Alzheimer’s Disease (AD) in clinical trials is a high priority. Unfortunately, early detection and monitoring of the subtle and slow changes of disease with conventional cognitive testing and self‐report questionnaires has been fraught with poor sensitivity and lack ecological validity. Digital biomarkers using ambient sensing technologies may afford a more effective approach to conducting trials. Remaining to be established is the ability of this approach to fundamentally improve early AD treatment response readout in a formal clinical trial setting. A simulated clinical trial (DETECT‐AD: ClinicalTrials.gov, NCT05385913) is being conducted to determine how well continuously assessed, home‐based digital biomarkers may detect clinically meaningful changes in individuals with changing amyloid (Aβ) burdens in pre‐symptomatic AD.

Method

Clinically prodromal AD patients with estimable rates of AD progression based on Aβ Florbetapir‐PET status are enrolled divided n = 50:n = 50 into Aβ “positive” (higher amyloid burden) patients who predictably progress (as if they were receiving placebo) and Aβ “negative” patients progressing more slowly (representing the treatment group). A study‐provided multivitamin mimics RCT conditions and study drug adherence behavior. Baseline standard clinical and biomarker measures are obtained along with digital biomarkers (DB) captured with passive and active sensors (actigraphy, bed mats, IR sensing, e‐pillbox, computing/phone device use, weekly online reporting/cognitive assessment). Primary outcome is the change in a composite DB composed of measures in 4 domains: mobility, cognition, sleep, and socialization. Secondary measures are the relationship of DB to fluid biomarkers (plasma ptau181/217, amyloid, NfL) and MRI/PET measures.

Result

To date (01/16/2023), 46/100 have been enrolled with mean(SD): follow‐up = 27.0(7.9) weeks (no dropout); age = 78(6.6); 63% women; MoCA = 25.5(2.3); PET SUVR = 1.09(0.20), range: 0.850‐2.07. Exemplary baseline digital biomarker metrics are presented in the Table. Preliminary data shows an inverse Aβ‐SUVR correlation with mean steps/day (r = ‐.41, p = .012) and a positive correlation of MoCA with computer use (r = .61; p = .036).

Conclusion

Home‐based continuous capture of multi‐domain DBs is feasible in a clinical trial setting and may yield early meaningful indicators of clinically relevant changes in older adults with pre‐AD dementia. Further evidence will evolve as sample sizes and longitudinal follow‐up increases.
Circulating cell‐free mitochondrial DNA (ccf‐mtDNA) and memory in mild cognitive impairment (MCI) and Alzheimer’s disease (AD)
Authors: Song Bing Xin , Beroncal Erika , Andreazza Ana C. , Gallagher Damien , Marzolini Susan , Rapoport Mark J. , Charles Jocelyn , Herrmann Nathan , Oh Paul I. , Kiss Alex , Swardfager Walter , MacIntosh Bradley J. , Rajji Tarek K. , Siddiqui Mehreen , Vieira Danielle , Rivet Luc , Lanctôt Krista L.
Published: December 2023

Background

Circulating cell‐free mitochondrial DNA (ccf‐mtDNA), a measure of mitochondrial dysfunction, is emerging as a potential biomarker for early Alzheimer’s disease (AD). Decreased levels of cerebrospinal fluid ccf‐mtDNA concentrations have been detected in early AD patients. Few studies have investigated peripheral ccf‐mtDNA in early AD or with cognitive measures, much less evaluating the role of physical activity within the relationships. Considering the hallmark of episodic memory impairment in early AD, we examined the association between serum ccf‐mtDNA and memory, while considering potential contributing factors, physical activity level and age.

Methods

Participants were diagnosed with mild cognitive impairment (MCI) or mild AD using the Diagnostic and Statistical Manual of Mental Disorders criteria for mild or major neurocognitive disorder. Serum ccf‐mtDNA concentration (copies/uL) was measured using quantitative polymerase chain reaction from circulating cell free DNA purified by spin columns with primer for the MT‐ND4 gene. Memory was assessed using the Word Recall Task from the Alzheimer’s Disease Assessment Scale‐Cog (ADAS‐Cog). Physical activity level was assessed by Leisure‐Time Exercise Questionnaire (LTEQ). Linear regression analyses were used to assess the association between ccf‐mtDNA levels and recall memory with a priori covariates, age and LTEQ score. Ccf‐mtDNA levels were log‐transformed prior to analyses due to significant departure from normality in Shapiro‐Wilk tests.

Results

Of 29 participants [17 (59%) male, 21 (72%) MCI], the mean (SD) age was 74.2 (8.7), years of education was 16.2 (2.2), Montreal Cognitive Assessment (MoCA) total score was 22.1 (3.3), LTEQ score was 36.2 (17.4), and ccf‐mtDNA levels were 2545.8 (2223.6) copies/uL. Higher ccf‐mtDNA was associated with worse recall [F(3,25) = 5.21, R2 = .39, p = .006]. Controlling for LTEQ and age, one log ccf‐mtDNA unit was associated with 1.87 (SE = .71) fewer words recalled (p = .01, f2 = .21).

Conclusion

In this sample, higher serum ccf‐mtDNA concentrations were associated with worse recall, controlling for age and physical activity level. This relationship supports the potential involvement of mitochondrial dysfunction in cognitive functions and neurodegenerative diseases and suggest the need for further research to explore the role of physical activity and age with mitochondrial dysfunction and memory.
Treatment‐Induced Epigenetic Modifications in MCI and Probable Alzheimer’s Disease
Authors: Reading Christopher Lewis , Gordevicius Juozas , Haroon Jonathan , Jordan Kaya , Rindner Elisabeth , Ahlem Clarence N , Mahdavi Kennedy D , Surya Rama , Venkatraman Victoria , Yuan Harvey , Becerra Sergio A , Pourat Bijan , Kuhn Taylor P , Palumbo Joseph , Brooke Robert , Jordan Sheldon E
Published: December 2023

Background

NE3107 is an oral small molecule, blood‐brain permeable anti‐inflammatory insulin sensitizer that binds ERK, inhibits inflammatory NFkB and TNF signaling in macrophage lineage cells, and in clinical studies for AD (NCT04669028) and Parkinson’s disease (NCT05083260). NE3107 does not inhibit homeostatic activity of ERK or NFkB, and has a good safety profile in preclinical, non‐clinical and clinical studies. Safety, clinical, biomarker and neuroimaging results from a 3‐month open‐label phase 2 study of NE3107 treatment of mild dementia (NCT05007820) were reported at CTAD 2022. We report here results of epigenetic clock studies from NCT05007820.

Method

Subjects with CDR 0.5‐1 were consented, and blood was drawn, frozen and shipped for Horvath Clock DNA methylation (DNAm) epigenetic analysis (Horvath 2018 Aging 10:1758) at baseline and 3 months.

Result

The subject’s DNAmSkinBloodAge clock closely matched their chronologic age at baseline (+0.7 years). After 3 months of NE3107 (20 mg BID), the DNAmSkinBloodAge decreased (‐3.3 years, Table). Leptin is lower in AD, and DNAmLeptin is positively correlated with metabolic parameters waist/hip ratio, BMI, CRP, insulin, glucose and triglycerides (Lu 2022 Aging 14:9884). Dinucleotide (CpG) methylation in association with the leptin promotor (DNAmLeptin) decreased in all subjects (‐40%). DNAmPackYears is reported to be negatively correlated with time to mortality in both smokers and nonsmokers, and positively correlated with waist/hip ratio, CRP and triglycerides. DNAmPackYears also decreased (‐39%). Baseline DNAmMonocyte correlated with monocyte frequency but decreased (‐29%) after 3 months treatment without change in monocyte frequency. There were no significant changes in DNAmTcell, DNAmNK or DNAmGran.

Conclusion

NE3107 treatment significantly decreased biological age compared to chronological age and altered epigenetic measures correlating with metabolic parameters known to be associated with cognitive decline. DNAm decreases in monocyte/macrophage are associated with proinflammatory pathways in many disease states but aging epigenetic clocks may select for CpG methylation associated with inhibition of anti‐inflammatory pathways. NE3107 decreases in DNAmMonocyte, DNAmSkinBloodAge, DNAmLeptin and DNAmPackYears in MCI and AD subjects were associated with cognitive, biomarker and neuroimaging improvements. The data suggests that NE3107 may decrease methylation in promoters of monocyte/macrophage pathway regulators that can decrease inflammation and restore metabolic homeostasis in subjects with dementia.
Mapping the spatial transcriptomic signature of the hippocampus during memory consolidation
Authors: Chatterjee Snehajyoti
Published: December 2023

Background

Memory consolidation relies on discrete spatial patterns of transcriptional events in the hippocampus. Despite the emergence of single‐cell transcriptomic profiling techniques, defining learning‐responsive gene expression across sub‐regions of the hippocampus has remained challenging.

Method

We utilized unbiased spatial sequencing to elucidate transcriptome‐wide changes in gene expression in the hippocampus following a learning experience, enabling us to define molecular signatures unique to each hippocampal subregion.

Result

We find that the CA1 pyramidal layer, CA1 stratum radiatum, CA1 stratum oriens, CA2/3 pyramidal layer, and dentate gyrus (DG) granular and molecular layers of the dorsal hippocampus exhibit distinct yet overlapping transcriptomic signatures. While the CA1 region exhibited increased expression of genes related to transcription regulation, the dentate gyrus (DG) showed upregulation of genes associated with protein folding. We demonstrate the functional relevance of subregion‐specific gene expression by genetic manipulation of the Nr4a transcription factor subfamily members selectively in the CA1 hippocampal subregion, leading to long‐term memory deficits. We have also shown that the hippocampus from postmortem Alzheimer’s disease and related dementia (ADRD) and a mutant tau mouse model of ADRD exhibit downregulation of Nr4a family members. We demonstrate the functional relevance of subregion‐specific gene expression by genetic manipulation of a transcription factor selectively in the CA1 hippocampal subregion, leading to long‐term memory deficits and connecting these findings with ADRD.

Conclusion

Our work demonstrates the power of spatial molecular approaches to reveal that the subregions of the dorsal hippocampus respond to learning by exhibiting distinct transcriptomic signatures. Our attempt to elucidate the spatial transcriptomic signature of memory provides the groundwork for future studies to understand the precise gene expression patterns underlying memory consolidation, and whether these signatures are affected in neurodegenerative diseases associated with memory impairments.
Graph theoretical analysis demonstrates associations among cortical network segregation, β‐amyloid status, and reward‐based learning in older age
Authors: Chen Hsiang‐Yu , Hsu Ming , Jagust William J. , Berry Anne S.
Published: December 2023

Background

As humans age, brain networks supporting cognition show alterations in functional connectivity patterns consistent with network dedifferentiation. Here we examined the extent to which Alzheimer’s disease (AD)‐related β‐amyloid (Aβ) pathology exacerbates functional dedifferentiation in aging and is associated with reduced probabilistic reward‐based learning.

Method

27 young and 47 cognitively normal older adults underwent 3T functional magnetic resonance imaging (MRI) while performing a novel probabilistic learning task. The task required participants to learn the identity of real‐estate agents as “winning,” “losing,” or “break‐even” based on their success in selling houses for a profit. We used graph theoretical analysis and applied 400 regions of interest to identify age‐related changes in functional brain networks during early and late learning phases in the task. Older adults were characterized as Aβ‐ (n = 34) or Aβ+ (n = 13) using [11C]Pittsburgh Compound‐B positron emission tomography. Analyses focused on the two graph theory measures commonly linked to dedifferentiation (i.e. loss of segregation): clustering coefficient and modularity.

Results

Young adults showed better learning performance, followed by Aβ‐ older adults and then Aβ+ older adults, but there was no significant age difference between young and Aβ‐ older adults (Fig. 1). Young adults also showed a higher clustering coefficient, which indicates greater network segregation, followed by Aβ‐ older adults and then Aβ+ older adults (Fig. 2A and 2B). Considering the learning phase, we found differences between the young and both Aβ‐ and Aβ+ older adults in the early learning phase (Fig. 2A), and differences between young and only Aβ+ older adults in the late learning phase (Fig. 2B). Analyses of modularity showed similar patterns of results, though the main effect of group was not significant (Fig. 2C and 2D). There was an interaction between network segregation and group to predict learning performance. Only Aβ‐ older adults with higher network segregation exhibited better learning performance (Fig. 3).

Conclusion

These findings indicate Aβ is associated with functional network dedifferentiation and poorer learning performance. For Aβ‐ older adults, successful maintenance of brain network segregation may underlie the preservation of “youth‐like” cognitive performance.