bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling neuropathology of Alzheimer’s disease in aged patient‐derived neurons through 3D direct neuronal reprogramming
Authors: Sun Zhao , Chen Shawei , Cates Kitra , Kwon Ji‐Sun , Sviben Sanja , Ren Yudong , Lv Xinguo , Karahan Hande , Sato Chihiro , Houlden Henry , Karch Celeste M. , Bateman Randall J. , Mennerick Steven , Kim Jungsu , Diamond Marc , Tanzi Rudolph E. , Holtzman David M. , Yoo Andrew S
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common form of adult‐onset neurodegenerative diseases characterized by three hallmarks of neuropathology including the extracellular deposition of amyloid β (Aβ), intracellular tau tangles, and neurodegeneration. The mechanisms that underlying the late‐onset AD (LOAD), the most common form of AD, remain largely unresolved due to the complexity of risk factors underlying the disease. Currently, endogenously recapitulating these events in patients‐derived neurons remains a major challenge, limiting our ability to understand the biology of the disease.

Method

By optimizing the potency of microRNA‐mediated direct neuronal conversion of patient fibroblasts, we developed a matrigel‐based three‐dimensional (3D) culture system for generating cortical neurons, a subtype known to be susceptible to develop AD pathologies. For characterizing AD‐associated phenotypes such as amyloid β(Aβ) plaques, tau pathology, and neurodegeneration in the reprogrammed cortical neurons, we carried out immunofluorescence staining, RNA‐sequencing and other biochemistry‐based assays.

Results

The 3D reprogrammed neurons derived from familial AD and LOAD patients endogenously displayed all three AD hallmark pathologies, including increased extracellular Aβ deposition, phosphorylated tau, dystrophic (beaded) neurites characterized by the colocalization between Ubquitin‐K63 and pTAU, as well as spontaneous neuronal cell death in culture without additional cellular insult. By using this 3D reprograming model, we found that treating AD neurons with β or γ secretase inhibitors at pre‐Aβ aggregation phase, significantly ameliorated Aβ formation and subsequent tauopathy and neuronal cell death, whereas treating during the post‐Aβ aggregation phase only had a mild effect. Additionally, comparative transcriptomic analysis between AD neurons and age‐matched healthy control neurons showed enrichment of genes involved in inflammatory pathways.

Conclusion

We established a novel patient derived neuronal 3D direct reprogramming model which robustly recapitulates key AD hallmarks including the extracellular deposition of Aβ plaques, formation of intracellular Tau tangles, and neurodegeneration. By using this 3D platform, we further demonstrated that inhibition of Amyloid β formation reduces tauopathy and neuronal cell death. Our unique patient specific 3D model system provides opportunities to investigate the interplay between AD pathological events and could serve as a platform for screening compounds and developing personalized therapeutics for AD.
Association between the use of antihypertensive medication and amyloid‐beta deposition in older adults with hypertension
Authors: Keum Musung , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Jung Gijung , Jung Joon Hyung , Kong Nayeong , Lee Jun‐Young , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young ,   KBASE Research Group
Published: December 2023

Background

Recent evidences suggest that the use of antihypertensive medications (HTNmed) may decrease the incidence of Alzheimer’s disease (AD) dementia. We investigated whether the use of HTNmed is associated with in vivo AD pathologies, particularly cerebral beta‐amyloid (Aβ) deposition, and whether the relationship between HTNmed and cerebral Aβ deposition differs according to the characteristics of HTNmed in older adults.

Method

Participants were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. Both cognitively normal and cognitively impaired older adults (age range: 55‐90 years) who met the following criteria of hypertension (HTN) were included for this study: i) clinical diagnosis of hypertension or ii) systolic blood pressure higher than 130mmHg or diastolic blood pressure higher than 80mmHg measured at baseline. All participants underwent comprehensive clinical assessment and [11C] Pittsburgh Compound B positron emission tomography PET for measuring Aβ deposition.

Result

Among total 413 older adults with hypertension, 227(54.8%) were taking HTNmed. Overall, individuals taking HTNmed showed significantly lower Aβ deposition compared to those without HTNmed (B = ‐0.104, p = 0.007), even after controlling age, sex, apolipoprotein E e4 positivity, and mean arterial blood pressure(MAP). Drug‐class specific analyses showed that the use of renin angiotensin system (RAS) inhibitor (i.e., angiotensin converting enzyme inhibitor and angiotensin receptor blocker) was associated with less cerebral Aβ deposition among older adults with HTNmed (B = ‐0.142, p = 0.006), but the use of other HTNmeds was not. In addition, the blood‐brain barrier permeability of HTNmed also did not have any relationship with Aβ deposition.

Conclusion

The present finding suggests that the use of HTNmed, particularly RAS inhibitor, is associated with less Aβ deposition in older adults with hypertension. Further studies to explore the mechanism underlying the effect of RAS inhibitor on Aβ accumulation may provide clues for new therapeutic targets of AD.
Interpreting trial results in an era of disease‐modifying therapies: Efficacy of approved anti‐amyloid drugs in the context of the long‐term Alzheimer’s trajectory
Authors: Raket Lars Lau , Cummings Jeffrey L. , Moscoso Alexis , Schöll Michael , Villain Nicolas
Published: December 2023

Background

Early‐stage Alzheimer’s disease (AD) typically presents with slow progression of clinical symptoms. Approved high‐potency anti‐amyloid‐β (Aβ) therapies have demonstrated changes in the disease trajectory in these early stages and offer potential benefits beyond the period for which they have been studied in trials.

Methods

Based on published results, the time‐slowing of disease progression based on change in CDR sum of boxes (CDR‐SB) was approximated. Disease progression modeling using long‐term cohort data was used to estimate the natural history trajectory of CDR‐SB in AD from the preclinical stages to severe dementia. Modeling of trial inclusion criteria was used to estimate the interval of the natural history trajectory of AD that were included in trials and different scenarios for long‐term treatment effects were explored.

Results

In positive phase 3 studies, the high‐potency anti‐Aβ therapies appeared to slow disease progression 20‐30% resulting in a 4‐6‐month delay of progression during the 18‐month study period. Included patient populations were found to differ substantially, with the EMERGE and ENGAGE studies including an earlier group of patients than CLARITY‐AD. Consistent with trial subgroup analyses, natural‐history modeling suggested that more progressed patients would see an apparent greater absolute benefit during 18 months, but less absolute benefit over longer durations. Under an assumption of continued slowing beyond the study period, a treatment slowing disease progression by 30% (5.4 months delay in disease progression after 18 months) would lead to treatment differences on CDR‐SB of ‐0.42 and ‐0.72 points for typical MCI and mild dementia patients. With continued slowing beyond the length of the trial, typical MCI patients would have a treatment effect of ‐0.96 points once reaching the same disease stage as the mild dementia patients. Five‐year treatment differences would be approximately ‐2.5 and ‐3.2 points, well beyond all estimates of clinically meaningful differences. Even in the most conservative disease‐modifying scenario assuming no increased time delay after 18 months, observed treatment differences would still increase beyond 18 months due to the nonlinear trajectory of CDR‐SB.

Conclusion

Disease‐modifying effects of the magnitude observed in recent trials can potentially translate into clearly meaningful differences over a longer duration.
Early locus coeruleus degeneration impairs the longevity of fear memory in APPswe/PS1dE9 mice
Authors: Kushwaha Srishti , Choudhury Rupsa Roy , Karunakaran Smitha
Published: December 2023

Background

The locus coeruleus (LC), a brainstem noradrenergic nucleus is known to modulate cognitive functions and behaviour. LC is one the first sites of appearance of misfolded tau protein which later develops into neurofibrillary tangles. Hyperphosphorylated tau and amyloid β are best protein correlates of cognitive decline in Alzheimer’s disease (AD). In early onset AD, subtle cognitive deficits develop <25 years before the patients develop dementia. Loss of LC neurons and its innervation has been found to be significantly associated with behavioural deficits observed during prodromal stage of AD. However, the extent and consequences of LC‐noradrenergic system degeneration during early stages of AD pathogenesis are still under investigation.

Method

To address this question, we have performed contextual fear conditioning (cFC) behavioural task to test fear memory in 2‐month‐old APPswe/PS1dE9 (APP/PS1) mice, a transgenic amyloidogenic model of AD. We further investigated the status of LC terminals and the distribution of β‐adrenoceptors (β‐AR) in the hippocampus using dopamine‐β‐hydroxylase (DBH), tyrosine hydroxylase (TH), and β‐AR immunohistochemistry respectively. Finally, we checked if stereotaxic delivery of β‐AR agonist to the hippocampus could rescue the impairments in long‐term fear memory.

Result

Our study demonstrates that 2‐month‐old male but not female APP/PS1 mice exhibit impaired long‐term fear memory in cFC task. Immunohistochemical analysis of DBH and TH positive nerve terminals revealed loss of noradrenergic and dopaminergic terminals in male but not female APP/PS1 mice hippocampus. Further, male APP/PS1 mice were found to have low levels of β‐AR in the hippocampus and intra‐hippocampal administration of isoproterenol hydrochloride, a β‐AR agonist, immediately before cFC could restore long‐term contextual fear memory.

Conclusion

LC‐noradrenergic system degeneration displayed an inherent sex‐specific difference on longevity of fear memory with deficits occurring only in male APP/PS1 mice during early stages of AD.
Olfactory impairment and domain‐specific cognitive decline: A 12‐year population‐based study
Authors: Laukka Erika J , Palmquist Eva , Ekström Ingrid , Olofsson Jonas , Dintica Christina S. , Bäckman Lars , Larsson Maria
Published: December 2023

Background

Olfactory impairment has been associated with both cognitive impairment and dementia and Alzheimer’s disease (AD). This study aimed to investigate the association between olfactory dysfunction (OD) and change trajectories in different cognitive domains in aging.

Method

Participants (n = 2473, mean age = 72 years, 61% female) from the population‐based Swedish National study on Aging and Care‐Kungsholmen (SNAC‐K) were repeatedly assessed with tasks measuring episodic memory, semantic memory, verbal fluency, and perceptual speed across 12 years. OD was measured at baseline and participants were categorized as normosmic, hyposmic, or anosmic based on the Sniffin’ Sticks odor identification task. Linear mixed‐effects models were used to assess the associations between baseline OD and rates of cognitive decline.

Result

OD was related to poorer baseline performance and faster rates of decline during follow‐up in all examined domains, as well as in global cognition. Associations were generally more pronounced for anosmia compared to hyposmia.

Conclusion

Olfactory impairment is associated with accelerated decline in aging across a wide range of cognitive domains.
Imaging diagnosis and emotion recognition relationship in mild cognitive impairment
Authors: Cháfer‐Pericás Consuelo , Álvarez Lourdes , Gandia‐Ferrero M Teresa , Adrián‐Ventura Jesús , Torres‐Espallardo Irene , Martínez‐Sánchez Begoña , Ferrer Inés , Baquero Miguel
Published: December 2023

Background

Recent research has focused attention on social cognition impairment in Alzheimer Disease (AD). Specifically, emotion recognition can be evaluated with Reading the Mind in the Eyes Test (RMET). Some neuroanatomical changes could be related with social and cognitive deficits in patients. Therefore, future research combining cognitive indicators (RMET) with brain structure and function parameters (volumes, glucose metabolism, blood flow, amyloid deposits…) is required.

Method

Participants are patients from the Neurology Unit (Hospital Universitari i Politècnic La Fe). They were neuropsychologically evaluated, and CSF samples were obtained to determine some biomarkers (β‐amyloid‐42, β‐amyloid‐40, p‐Tau…). Also, brain imaging techniques (magnetic resonance (MR) and Positron Emission Tomography with [18F]Fluorodeoxyglucose (FDG‐PET/CT)) were applied to obtain brain structural and functional information, and to evaluate the relationship between them and emotion recognition evaluation (RMET). Imaging data were processed following SPM and CAT12 pipelines, a brain parcellation based on the Hammers atlas was used. Finally, 166 patients (with MR and/or FDG‐PET/CT) diagnosed with mild cognitive impairment (MCI) were included in the study.

Result

The correlation analysis between FDG‐PET/CT and RMET results showed significant correlations. Specifically, with prefrontal medial L and R (r = 0.36), posterior cingulate L and R (r = 0.34), parietal inferior L and R (r = 0.31), anterior cingulate L and R (r = 0.32), prefrontal lateral L and R (r = 0.32), insula R (r = 0.31) and basal ganglia R (r = 0.3). So, they are considered potential brain function biomarkers in MCI. Regarding the correlation analysis between MR (GM volumes (TIV‐corrected)) and RMET results, some significant correlations were observed. Specifically, with the straight gyrus L (r = 0.40), superior frontal gyrus L (r = 0.37), insula anterior inferior cortex R (r = 0.36), fusiform gyrus R (r = 0.36), anterior cingulate gyrus R (r = 0.36), insula anterior short gyrus L (r = 0.36), posterior and anterior cingulate gyrus L (r = 0.36, 0.35), and anterior orbital gyrus L (r = 0.35). So, they are considered potential brain structure biomarkers in MCI.

Conclusion

The relationship between brain imaging parameters and emotion recognition impairment variables could provide important information for further biomarkers identification, as well as to identify potential physiopathological mechanisms involved in neurodegenerative development since early steps.
CSF Aβ42/40 is associated with neurodegeneration independently of CSF p‐tau in the earliest AD continuum
Authors: Cacciaglia Raffaele , Falcon Carles , Shekari Mahnaz , Salvadó Gemma , Milà‐Alomà Marta , Huguet Jordi , Garcia Marina , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

Background

Soluble Aβ dyshomeostasis is thought to be the earliest detectable alteration in AD, but is believed to have little impact on neurodegeneration. Conversely, the onset of tau pathology in the presence of Aβ drives subsequent neurodegeneration. Here, we aimed to assess the independent contribution of soluble Aβ and tau dyshomeostasis to neurodegeneration, in the earliest stages of the AD continuum.

Method

The first 330 consecutive participants of the ALFA+ study with available longitudinal (3.45±0.24 y) MRI, CSF Aβ42, Aβ40, p‐tau181, and NfL at baseline were included. CSF biomarkers were assessed with the Roche NeuroToolKit robust prototype immunoassays and p‐tau181 with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). Gray matter volume (GMv) changes were computed voxelwise using SPM12 on T1w scans. Hippocampal subfields were segmented using ASHS on high‐resolution acquisitions. To detect regions showing early neurodegeneration, correlations between CSF NfL and GMv changes were sought. Then, GMv and hippocampal subfields changes were sought in association with CSF Aβ42/40 and CSF p‐tau181, both alone and after controlling for the other biomarkers. The interactive effect of CSF p‐tau181 and Aβ status (CSF Aβ42/40 < 0.071) on brain structure was determined.

Result

Table 1 shows sample’s characteristics. CSF NfL concentrations were associated with longitudinal GMv atrophy in the medial and inferior temporal areas (Fig. 1A). CSF Aβ42/40 significantly predicted GMv atrophy in the hippocampus bilaterally, alone and when controlling for CSF p‐tau181 and NfL (Fig. 1B‐C). CSF p‐tau181 interacted with Aβ status to predict GMv atrophy in the posterior hippocampus bilaterally (Fig. 1D). Longitudinal GMv atrophy in the hippocampal subfields were confirmed in association with CSF Aβ42/40 in the bilateral CA1, dentate gyrus and BA35 (Table 2).

Conclusion

Independently of p‐tau, early Aβ dyshomeostasis is associated with longitudinal GMv atrophy in AD‐sensitive brain areas in the early AD continuum. As expected, tau levels were associated with additional atrophy in these regions in Aβ+ individuals. Pathophysiological alterations other than Aβ, but correlated with CSF Aβ levels, might contribute to the observed atrophy patterns. Control of the earliest pathophysiological alterations in AD may have a relevant impact on neurodegeneration, even at the earliest preclinical stages.
Evaluating the sensitivity of Centiloid quantification to pipeline design and image harmonization
Authors: Shekari Mahnaz , García David Vállez , Collij Lyduine E. , Heeman Fiona , Roé‐Vellvé Núria , Bullich Santiago , Buckley Christopher , Barkhof Frederik , Farrar Gill , Pemberton Hugh , Gispert Juan Domingo ,   the AMYPAD consortium
Published: December 2023

Background

The Centiloid scale is a well‐established standardized metric for estimating amyloid load in clinical and research settings. In this study, we evaluated the stability of Centiloid to pipeline design options, tracer, and image harmonization.

Method

A total of 670 participants of the AMYPAD DPMS and PNHS multicenter studies with either [18F]flutemetamol or [18F]florbetaben PET scans and T1‐weighted MRI were included (Table1). PET images were harmonized to achieve an 8 mm Full‐Width‐at‐Half‐Maximum(FWHM) effective image resolution. Using SPM12, 32 Centiloid pipelines were created, calibrated and validated, based on combinations of four reference regions (Whole Cerebellum[WCB], Cerebellar Gray[CG], Whole Cerebellum+Brainstem[WCB+BSTM], Pons), two target VOI types (standard GAAIN vs subject‐based), two reference region types (standard GAAIN vs subject‐based) and two analysis spaces (native vs MNI). Generalized Estimating Equations (GEE) were used to evaluate the impact of the different factors on Centiloid. First, a base model including only the pipeline design factors was defined. Then, harmonization status (original vs harmonized PET images), tracer, and grey matter volume, as a measure of cerebral atrophy, were added to the base GEE model. Analyses were performed in the two cohorts separately and changes >5 Centiloid were considered relevant.

Result

Quantification space, target VOI, and reference region type had a small impact on Centiloid. Selection of reference region had the largest impact on Centiloid as using the Pons resulted in ∆Centiloid∼‐12.00 compared with using the standard reference region, WCB (Table2). Harmonization status affected Centiloid only for some reference regions: CG and Pons were sensitive to harmonization status (∆Centiloid∼ 5.45 and ‐5.70 respectively). In contrast, Centiloid was minimally affected by harmonization when using WCB and WCB+BSTM (Table3). Tracer and atrophy had a minimal effect on Centiloid for both DPMS and PNHS cohorts.

Conclusion

Centiloid quantification is robust against differences in analysis space, reference region type, target VOI, tracer and the presence of atrophy. However, choice of reference region can significantly influence Centiloid, with the Pons having the largest impact on Centiloid relative to other reference regions. Centiloid is stable against harmonization status and image resolution heterogeneities while using WCB as reference region.
A Centiloid cut‐off to help predict true amyloid accumulation
Authors: Bollack Ariane , Collij Lyduine E. , García David Vállez , Shekari Mahnaz , Altomare Daniele , Payoux Pierre , Dubois Bruno , Grau‐Rivera Oriol , Rovira Mercè Boada , Nordberg Agneta K , Walker Zuzana , Scheltens Philip , Schöll Michael , Wolz Robin , Schmidt Mark E , Gismondi Rossella , Stephens Andrew W. , Buckley Christopher , Frisoni Giovanni B , Hanseeuw Bernard J , Visser Pieter Jelle , Vandenberghe Rik , Drzezga Alexander , Yaqub Maqsood , Boellaard Ronald , Markiewicz Pawel J , Cash David M , Farrar Gill , Gispert Juan Domingo , Barkhof Frederik ,   the AMYPAD consortium
Published: December 2023

Background

Longitudinal amyloid‐PET‐based imaging endpoints are often included in clinical trials, where they provide critical evidence of treatment efficacy. We assessed the longitudinal variability of the Centiloid (CL) scale and its ability to predict early amyloid accumulation.

Method

Longitudinal amyloid‐PET with 18F‐flutemetamol and 18F‐florbetaben (N = 711 at follow‐up 1, time interval: 3.0±1.3years; N = 98 at follow‐up 2, 5.1±0.7years) was conducted in predominantly cognitively unimpaired participants of the AMYPAD Prognostic and Natural History Study (PNHS). Quantification of scans was performed using the MR‐based CL pipeline and visually read (VR) by local certified assessors. Longitudinal change in CL was modelled using linear mixed effects models corrected for age, sex, and education. Subjects were classified based on VR status over time (i.e., Stable VR‐, VR‐Converters or Stable VR+) and based on amyloid accumulation over time (i.e., Accumulator or Non‐accumulator; Accumulator if annualised rate of change [ARC]>95th percentile of a subset of 110 subjects for whom no amyloid accumulation was expected, selection criteria in Table‐1). Finally, a baseline CL cut‐off to identify future Accumulators was derived from a receiver operating characteristic (ROC) curve analysis.

Result

Participants had a median age of 65 years, 57% were females, 41% were APOE‐ε4 carriers, and 18% had baseline VR+ scan (Table‐1). The 95th percentile of ARC in the stable 110 subjects was 2.7 CL/year. Baseline CL was higher in Accumulators compared to Non‐accumulators (24.8 versus 8.7 CL, p<.001). Based on the ROC analysis, the optimal baseline CL threshold to predict Accumulators was 12.1 CL (sensitivity = 67% and specificity = 74%, Figure B‐C‐D), in line with the baseline CL threshold that best predicts VR conversion (11.6 CL). Baseline CL values and ARC were also higher in Stable VR+ and VR‐Converters compared to Stable VR‐ (p<.001), but no significant difference in ARC was found between VR‐Converters and Stable VR+ (Table‐1, Figure A). Results were robust across tracers.

Conclusion

Increases over 2.7 CL/year can be indicative of reliable amyloid accumulation. A CL cut‐off of ∼12CL can help identify subjects more likely to accumulate amyloid in the short future. Annualised rates of change in amyloid deposition where highly comparable across tracers.
TREM2 Agonism Affects Human Microglia Response in the Presence of Amyloid Pathology In Vivo
Authors: Geric Ivana , Jendresen Charlotte , Sans Laura , Afrang Negin , Misbaer Anke , Nair Arya , Dalby Maria , Balice‐Gordon Rita , Strooper Bart De , Plath Niels
Published: December 2023

Background

Pharmacological activation of TREM2 represents a novel therapeutic approach to slow Alzheimer´s disease (AD) progression. Mutations in microglial gene, TREM2, confers increased risk to developing late‐onset AD. Moreover, animal studies demonstrate the loss‐of‐of function variants or complete absence of Trem2 aggravates amyloid pathology. Genetic ablation of TREM2 function has been shown to lock microglia in a homeostatic state, preventing a switch to the disease‐associated state supporting the phagocytic clearance of misfolded proteins and cellular debris. Due to low gene sequence and protein structure homology between mouse and human TREM2, as well as phenotypical disparities between mouse and human microglia, monitoring the impact of TREM2 activation in vivo requires humanized animal models.

Method

Here we studied the impact of TREM2 agonism on xenografted human microglia in a mouse model of amyloid pathology. We systematically treated 7‐month‐old transgenic AppNL‐G‐F mice transplanted with human embryonic‐stem‐cell‐derived microglia with TREM2 small molecule agonists. Human microglia were sorted from the brain and subsequently assessed using multi‐omics technologies.

Result

The activation of TREM2 lead to increased expression of cytokines and chemokines in xenografted human microglia in the presence of amyloid pathology in AppNL‐G‐F, but not in wild‐type mice. Other changes in the transcriptome profile indicated shifts in microglia populations in TREM2‐agonist‐treated AppNL‐G‐F mice. These effects were observed at exposures consistent with activation of TREM2 in vitro assessed by pSYK and sTREM2 levels.

Conclusion

All together, we show the human microglia xenograft mouse model is a valuable tool to study the impact of pharmacological TREM2 activation in the presence of AD neuropathology.
Computerised cognitive testing and multi‐domain structural Magnetic Resonance Imaging in patients with idiopathic Normal Pressure Hydrocephalus and Alzheimer’s disease
Authors: Giovane Martina Del , Parker Thomas D , David Michael CB , Kolanko Magdalena A , Giunchiglia Valentina , Trender William , Carswell Christopher J , Malhotra Paresh A , Sharp David J , Hampshire Adam
Published: December 2023

Background

Idiopathic normal pressure hydrocephalus (iNPH) is characterised by gait disturbance, urinary incontinence and cognitive impairment. Symptoms are potentially reversible via cerebrospinal fluid (CSF) diversion; thus early and accurate diagnosis is crucial. Symptoms and imaging features of iNPH often overlap with Alzheimer’s disease (AD) and other neurodegenerative conditions, which represent a major diagnostic challenge. We aimed to demonstrate the utility of computerised neuropsychology testing to aid iNPH diagnosis, as well as exploring the neuroanatomical correlates of cognitive dysfunction in iNPH.

Method

iNPH (N = 11) and Alzheimer’s disease (N = 14) patients underwent online computerised cognitive testing (Figure 1) and MRI scanning. Raw cognitive scores were converted into ‘deviation from expected’ (DfE) scores using a novel normative approach, training linear models to N = ∼200,000 norms while accounting for demographics. T‐tests against 0 were conducted on the DfE scores to identify tasks sensitive to iNPH and/or AD. ANOVAs were used to identify differences in regional brain volumes and tract‐specific fractional anisotropy (FA) values in AD and iNPH relative to 10 age‐matched healthy controls (HC). General linear models were used to investigate whether cognitive tasks sensitive to iNPH and AD could predict the identified MRI abnormalities.

Result

AD patients demonstrated significant impairments in all tasks, while iNPH patients scored significantly lower than controls in motor control, processing speed, visuospatial, and executive function tasks (Figure 2). One‐way multivariate ANOVA identified cognitive differences between groups (F(22,554) = 14.47, p<0.001), with iNPH performing significantly better on memory and language tests relative to AD. Compared to HC, iNPH patients had lower FA in the corpus callosum and skeleton, reduced cingulate cortex volume and higher total ventricular volume. AD patients, instead, had reduced FA in the inferior longitudinal fasciculus and skeleton, with lower temporal and parietal volumes relative to HC (Figure 3). For iNPH, target detection and words delayed recall predicted corpus callosum FA, while visuospatial tasks predicted ventricular and cingulate volumes. In the AD group, no statistically significant link was detected between task performance and structural changes following multiple comparisons correction.

Conclusion

Remote computerised cognitive testing can discriminate between AD and iNPH and has the potential to predict disease‐related MRI abnormalities.
R953C Mutation in SORL1 Gene Causes Functional Abnormality of the Protein
Authors: Fazeli Elnaz , Young Jessica E. , Andersen Olav M. , Jayadev Suman
Published: December 2023

Background

The SORL1 (Sortilin Related Receptor 1) gene encodes for an endosomal sorting receptor, SORLA, and recent genetic studies have shown that it is the gene most frequently affected in patients with Alzheimer’s disease (AD). In the current study, we have identified a variant, R953C, (residing in the YWTD‐domain of SORLA) in a family where it segregates with early‐onset AD. We used cell biological assays to evaluate maturation and sorting defects of the mutant receptor.

Method

To investigate molecular consequences of R953C mutation, we transiently expressed SORLA‐WT and SORLA‐R953C in HEK293 and N2a cell lines. We analyzed the maturation and shedding of the receptor by Western blotting. Using flow cytometry, we determined the cell surface expression of the mutant compared to WT. Finally, the intracellular localization of the mutant was assessed by immunocytochemistry and confocal microscopy.

Result

We observed a significant decrease in the maturation and shedding of the mutant receptor, leading to an overall 80% reduction in soluble SORLA present in the culture media of cells transfected with R953C construct compared to WT. Our flow cytometry analysis demonstrated that in 80% of the cells expressing the mutant receptor, the SORLA protein is retrained intracellularly. In comparison, only 10‐15% of cells expressing the WT receptor showed intracellular retention. Within the cells, the R953C mutant receptor was primarily localized to the endoplasmic reticulum (ER) whereas the WT was mainly localized to the endosomes, suggesting the retention of the mutant in the ER and uncovering possible defects in entering the endosomal sorting pathway.

Conclusion

In conclusion, we have elucidated some of the molecular mechanisms that appear to have a role in pathogenicity of R953C mutation.
T‐cell population and PD‐1 expression in Alzheimer’s disease patients do not follow the age trend of normal individuals
Authors: Chu Cheng‐I , Wu Ching‐Tse , Wang Feng‐Yu , Yang Hui‐Yu , Chang Chien‐Chung , Chang Chuang‐Rung
Published: December 2023

Background

Destruction of cerebral neurons may relate to atypical immune responses. These intracerebral immune responses were induced by various antigens, such as viral DNA fragments or misfolded proteins. Aging is the major risk factor for Alzheimer’s disease (AD). Throughout the aging process, people experienced repetitive microbial infections and misfolded protein accumulation. But not every individual developed AD during aging. Immune regulation may contribute to determining whether the brain could clean unfavorable misfolded proteins and maintain homeostasis. T cell populations and programmed death 1 (PD‐1) are involved in immune pathology. In our study, we examined T cells and PD‐1 between normal aging and AD individuals to elucidate the role of immune regulation in aging‐related AD.

Method

Sixteen normal aging individuals (age range between 65‐91 years old) and 16 AD patients (age range 69‐88 years old) participated in this study. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood. Antibodies against T cells and PD‐1 molecules were used to classify PBMC with flow cytometry.

Result

(1) T cell population is different between normal and AD individuals

The normal aging group had significantly fewer adaptive immune T cells and fewer helper T cells (TH). However, these immune features were not present in AD patients.

(2) PD‐1 pattern in PBMC is different between normal and AD individuals

Natural killer T (NKT) cells with CD56 (neural cell adhesion molecule) had increased PD‐1 expression with normal aging. But AD patients did not show this trend of regulatory changes. These trends of suppressive phenotypic changes were absent in AD patients.

Conclusion

Our study demonstrated that the T‐cell population was shrinking progressively with normal aging. Nerve‐adherent NKT cells exhibited a higher inhibitory receptor (PD‐1). These findings suggested that T‐cell immune population tended to be suppressed with normal aging. However, these characteristic transitions of immune cells were not present in AD patients, suggesting that T cells were prone to activate in older AD patients. These distinctive immunomodulatory features of AD might be potential biomarkers of late‐onset AD, and predictive factors for developing AD in normal aging individuals.
Different astrocyte phenotypes mediate the pathological cascade early in the Alzheimer’s disease continuum
Authors: Pelkmans Wiesje , Shekari Mahnaz , Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Grau‐Rivera Oriol , González Escalante Armand , Kollmorgen Gwendlyn , Carboni Margherita , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

Background

Glial fibrillary acidic protein (GFAP) and chitinase‐3‐like protein 1 (YKL‐40) are biomarkers of different astrocyte phenotypes, both of which are elevated in the dementia phase of Alzheimer’s disease (AD). However, the specific contribution of these astrocyte phenotypes early in the AD continuum is not fully understood. Here, we studied how these two astrocyte phenotypes mediate the early pathogenic cascade in the preclinical stage of AD.

Method

We assessed 384 cognitively unimpaired individuals from the ALFA+ study with amyloid‐β (Aβ)42/40, phosphorylated tau (p‐tau181), neurofilament light (NfL) and YKL‐40 measured in cerebrospinal fluid (CSF) and GFAP measured in plasma, as well as [18F]flutemetamol positron emission tomography (PET) and neuropsychological testing (Annual change in the Preclinical Alzheimer’s Cognitive Composite [PACC]). Path analysis using structural equation modelling was used to quantify the relationships between biomarkers of reactive astrogliosis and Amyloid‐Tau‐Neurodegeneration biomarkers, while incorporating age, sex, and apolipoprotein E (APOE) ε4 effects. Direct effects with FDR‐corrected p‐values below .05 were considered significant.

Result

CSF Aβ42/40 was associated with Aβ aggregation as measured by PET and with CSF p‐tau181, respectively. The latter was associated with CSF NfL, but no associations were found between any biomarkers and PACC changes in this early sample (Figure 1; Table 1). Plasma GFAP mediated the association between CSF Aβ42/40 and Aβ‐PET. Additionally, CSF YKL‐40 mediated the association between Aβ‐PET and p‐tau181 and between p‐tau181 and NfL. APOE ε4 had a direct association with CSF Aβ42/40 only, whereas age had independent associations with CSF Aβ42/40, NfL, GFAP and YKL‐40. Male sex was associated with higher CSF NfL levels, independently of other variables tested.

Conclusion

Our results suggest that astrocyte phenotypes that release GFAP into the blood influence the aggregation of soluble Aβ into fibrillary plaques. On the other hand, those releasing YKL‐40 into the CSF appear to play a role later in the pathological cascade, mediating downstream tau pathology and neuronal damage. These results indicate that different astrocyte phenotypes are specifically involved in distinct stages of the early pathological cascade in preclinical AD. Interventions targeting astrocyte dysfunction in preclinical stages may prevent or delay the onset of AD dementia.
PSP/DEGESCO: A Progressive Supranuclear Palsy Genome‐Wide Association Study in the Spanish Population
Authors: García‐González Pablo , de Rojas Itziar , Rabano Alberto , Bullido María J. , Puerta Raquel , Olivé Clàudia , Álvarez‐Martínez Victoria , Perez‐Tur Jordi , Mendioroz Maite , Fortuño Maria Antonia , Belbin Olivia , Compta Yaroslau , Sanchez‐Juan Pascual , Tárraga Lluís , Boada Mercè , Ruiz Agustin
Published: December 2023

Background

Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy. We genotyped all the available histopatologically confirmed PSP cases from the Spanish National Biobank Network and patients with a probable PSP diagnosis recruited from research groups linked to the Dementia Genetics Spanish Consortium (DEGESCO). Here, we present the results of the genome‐wide association study (GWAS) performed after the first stage of this project.

Method

DNA samples were genotyped by the Centro Nacional de Genotipado (Santiago de Compostela, Spain) using the Affymetrix Axiom 815K Spanish biobank array. After quality control, we kept 156 histopathological (discovery) and 197 clinical (validation) PSP samples. Then, we selected 650 and 800 sex‐matched controls from GR@ACE/DEGESCO for stratified genome‐wide association of the discovery and validation sets, respectively (Table 1). We ran PC1‐4 adjusted logistic regressions with plink v2.00 and meta‐analyzed the discovery and validation sets using METAL. Finally, we meta‐analyzed our results with 36 previously reported SNPs1 reaching the largest PSP sample size to date (N = 3053).

Result

We found a strong genome‐wide significant (GWS) signal associated to the MAPT H1/H2 haplotype (rs8070723 G: OR = 3.40; 95%CI = 2.64‐4.39; p = 2.60·10−20, Figure 1) and identified a previously unreported signal in chromosome 7p13 (rs76827509 T: OR = 0.45; 95%CI = 0.35‐0.58; p = 3.09·10−10). We replicated, with nominal significance, 5 GWS SNPs reported in previous GWAS (Table 2) and found significant effects for NFASC and TOMM40. Because APOE and TOMM40 are in strong linkage disequilibrium, we also checked the effect of APOE variants. We found a protective effect (OR = 0.66; 95%CI = 0.48‐0.90; p = 9.75·10−3) of the rs429358 C allele (APOE ε4) in our dataset.

Conclusion

The strong GWS signal of the H1 haplotype confirms the validity of our GWAS results2. We were able to replicate several PSP loci (Table 1). The NFASC variant reached borderline GWS significance after meta‐analysis and is a good PSP risk factor candidate. Finally, the APOE ε4 allele was protective for PSP in our cohort. The second stage of PSP/DEGESCO genotyped 218 additional PSP samples.

1 Sanchez‐Contreras, M. Y. et al. Mol. Neurodegener. (2018)

2 Höglinger, G. U. et al. in Nature Genetics (2011)
The impact of amyloid‐PET and FDG‐PET on the progression from amnestic MCI to AD dementia in clinical practice
Authors: Echeveste Beatriz , Arbizu Javier , Guillén Fernando , Riverol Mario
Published: December 2023

Background

Alzheimer disease (AD) is the most common cause of dementia worldwide. It is known that cerebral amyloid aggregation and neurodegeneration are first steps in the physiopathology of AD. In the prodromal phase, a clinical diagnosis of amnesic mild cognitive impairment (aMCI) can be stablished, but not all subjects with MCI have a prodromal AD. The objective of this study was to determinate the impact of amyloid and FDG PET on the progression from aMCI to AD dementia.

Methods

From October 2013 to March 2021, we prospectively selected 145 patients with a diagnosis aMCI. We excluded subjects older than 85 and those with structural brain lesion on brain MRI. Participants went through an amyloid and an FDG‐PET scans and were classified as positive or negative for amyloid and neurodegeneration. Patients were followed to stablish progression to AD dementia, 118 patients were followed up more than 36 months. Statistical analyses were done with STATA with significance set at p<0.05. All analyses were adjusted by age, gender, and education.

Results

Demographics are shown on table 1. Sensibility, specificity, negative predictive value, and positive predictive value during the 4 years are shown on table 2. 88 patients were A+ and 74 patients were A‐. We divided the patients in 4 groups: A+/FDG+ (n:54), A+/FDG‐ (n:34), A‐/FDG‐ (40), A‐/FDG+(4). The mean of conversion were 39.95 months, this time depends on the result of the biomarkers. A‐ patients converted less and latter with a mean of 75.07 (IC 56.54→81) month, than A+ patients, that converted earlier (chi2 = 20.37 Pr>chi2 = 0.0000). A+/FDG+ converted with a mean of 27.79 (20.40‐33.21) months while A+/FDG‐ converted earlier with a mean of 37.38 (20.73‐48.26) month. (chi2 = 4.16 Pr>chi2 = 0.0415).

Conclusions

Amyloid and FDG PET can help us to stablish prognosis in aMCI patients. We have observed that a positive amyloid PET is associated with an increased risk of progression to AD dementia. Even more, aMCI patients with both, amyloid PET and FDG, positive PETs progressed more often and earlier to AD dementia than those who have a positive amyloid PET but a negative FDG‐PET.
Functional connectivity in Alzheimer’s disease: A resting‐state EEG study
Authors: Kehm Christina S. , Fassbender Ronja V. , Onur Oezguer A.
Published: December 2023

Background

Alzheimer’s disease (AD) is mainly associated with amnestic deficits. Imaging studies revealed a disruption of functional networks in AD, which plays a crucial role for the cognitive deficits. There is also evidence from resting‐state Electroencephalography (rsEEG) studies, which found altered functional connectivity measuring EEG coherence in AD (Babiloni et al., 2021; Wang et al., 2015). This was especially seen for the Alpha frequency band, which is known for its diagnostic potential in the disease. Furthermore, studies suggest that Alpha band marker correlate with cognitive decline in AD (Babiloni et al., 2010). The main aim of the current work is to gain a better understanding of the functional connectivity in Alzheimer’s disease based on EEG given a very high temporal resolution.

Method

The sample consisted of 15 patients (AD, 72.3 ± 8.28 years, 66.7% male) with mild cognitive impairment to mild dementia with a typical cerebrospinal fluid profile of Alzheimer’s disease or pathological Amyloid‐PET and 15 age‐matched healthy controls (HC, 72.93 ± 7.17 years, 53.3% male). All participants underwent a neuropsychological examination and rsEEG. The rsEEG was recorded with the Neurowerk Amplifier using an elastic cap with 19 electrodes (10‐20 system). Raw data were preprocessed and further analyzed with regard to functional connectivity focusing on the Alpha frequency band (Brainstorm, SPSS, EEGlab). Functional connectivity was calculated by the magnitude squared coherence. Coherence was further clustered in global coherence and coherence per electrode. Finally, coherence scores were evaluated in relation to neuropsychological scores.

Results

Centers of functional connectivity were found in frontal‐frontal and frontal‐parietal/occipital electrode pairs. Alpha frequency band (8 – 13 Hz), particularly Alpha1 frequency band (8 – 11 Hz), yielded the highest coherence scores. When comparing AD and HC, patients showed reduced coherence in Alpha2 (11 – 13 Hz) and Beta (13 – 20 Hz). Additionally, moderate correlations of global coherence and behavioral measures were found mainly for the Alpha1 frequency band.

Conclusion

Alzheimer’s disease can be associated with poorer functional connections of certain brain areas and rsEEG coherence might be a potential biomarker for AD.
Ex vivo identification of transcriptional regulation landscape and potential therapeutic targets against oxidative stress using Alzheimer’s disease patient‐derived dermal fibroblast: findings from BICWALZS cohort
Authors: Nam You Jin , Yoon Sunwoo , Kim Yeojin , Park Sunghong , Hong Sunhwa , Cho Yong Hyuk , Roh Hyun Woong , Son Sang Joon , Hong Chang Hyung
Published: December 2023

Background

Reactive oxygen species (ROS) is considered as a central pathophysiology for neurodegeneration in Alzheimer’s disease (AD). Many studies using in vitro cell line or in vivo mouse model have shown the possible association between ROS defense mechanisms and cellular damage. However, that connection was not elucidated well in AD patient‐derived cell or brain organoids. In this study, we aimed to identify transcriptional regulation landscape and potential therapeutic targets against oxidative stress using AD dementia patient‐derived dermal fibroblast

Methods

For the purposes of ex vivo research, we performed skin biopsy and stabilized dermal fibroblasts in vitro. Total of 20 AD dementia patients and 22 cognitively normal older adults were assessed. All of AD dementia patients were amyloid positive on PET imaging, APOE e4 carrier, and cognition was imparied. On the contrary, all of cognitively normal older adults were amyloid negative on PET imaging, and APOE e4 non‐carrier. We applied H2O2 (600 uM) to dermal fibroblast for 24 hours as an oxidant agent to promote oxidative stress. After that, to identify transcriptional regulation landscape against oxidative stress, RNA sequencing was performed.

Results

Total of 406 transcripts (up = 61, down = 345) were commonly differentially expressed in both of AD dementia and cognitively normal older adults derived dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to cell division, cell cycle, and DNA repair. Interestingly, 133 transcripts (up = 41, down = 92) were only differentially expressed in AD dementia dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to DNA duplex unwinding, cell division, and DNA replication. Total of 147 transcripts (up = 67, down = 80) were only differentially expressed in cognitively normal older adults dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to negative regulation of cell proliferation, notch signaling pathway, and NMDA glutamate receptor signaling pathway.

Conclusion

We identified transcriptional regulation landscape by ROS‐H2O2 in AD dementia and cognitively normal older adults dermal fibroblast. Further bioinformatic analysis with computational tools and validation experiments will be performed to find potential therapeutic targets against oxidative stress.