bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormalities of Cortical Neural Synchronization Mechanisms in Patients With Dementia Due to Parkinson’s and Sintomatic Huntington’s Diseases
Authors: Noce Giuseppe , Percio Claudio Del , Lizio Roberta , Lopez Susanna , Jakhar Dharmendra , Güntekin Bahar , Yener Görsev , Taylor John‐Paul , De Tommaso Marina , Delussi Marianna , Babiloni Claudio
Published: January 2025

Background

Parkinson’s disease and Huntington’s disease are both neurodegenerative conditions involving the basal ganglia area of the brain. Both conditions can cause symptoms that affect movement. Cognitive decline or dementia can also occur in both. Resting state EEG (rsEEG) rhythms reflect neurophysiological mechanisms and operational functions related to the fluctuation of brain arousal and quiet vigilance in humans. The hypothesis was that rsEEG sources may be more abnormal in Huntington’s disease patients in symptomatic stage (S‐HD) than patients with dementia due to Parkinson’s disease.

Method

Clinical and rsEEG datasets in 16 PDD, 18 S‐HD, and 25 matched cognitively unimpaired (Nold) participants ‐ matched as demography, education, and gender ‐ were taken from an international archive. The eLORETA freeware was used to estimate cortical rsEEG sources at delta, theta, alpha1, alpha2, alpha3, beta1, beta2, and gamma frequency bands.

Result

Results showed lower amplitude of the posterior alpha activities and higher amplitude of widespread low frequencies bands (i.e., delta and theta) in the PDD and S‐HD groups than in the Healthy group. As compared to the PDD group, the S‐HD showed greater reductions in the rsEEG alpha 2 rhythms in the frontal and temporal regions (see Figure 1).

Conclusion

These results suggest that cortical sources of rsEEG rhythms might reflect different abnormalities of the core neurophysiological mechanisms underlying brain arousal in quiet wakefulness and low vigilance in PDD, and S‐HD patients. The mentioned rsEEG markers might be clinically useful in the disease staging, monitoring over time, and drug discovery.
Distinct cerebrovascular pathways underlying Alzheimer’s disease‐related neurodegeneration
Authors: Mohanty Rosaleena , Marseglia Anna , Westman Eric
Published: January 2025

Background

Cerebrovascular pathology is an emerging key contributor to neurodegeneration in both non‐pathological and pathological aging. Cerebrovascular pathology manifests as different markers in the brain (gross‐ vs micro‐infarcts, chronic vs acute infarcts, etc.). The relative association or dissociation of these markers with Alzheimer’s disease (AD) pathologies, copathologies and neurodegeneration remains poorly understood. Thus, we investigated how distinct cerebrovascular markers relate to AD pathology, copathologies, and neurodegeneration.

Method

We included 77 individuals with postmortem neuropathologic examination and in vivo MRI (antemortem‐to‐postmortem interval = 5±3 years) from the Alzheimer’s Disease Neuroimaging Initiative. We investigated eight markers of cerebrovascular burden at postmortem including atherosclerosis of the circle of Willis, cerebral amyloid angiopathy (CAA), gross chronic infarcts, gross chronic hemorrhages, chronic microinfarcts, arteriolosclerosis in subcortical white or gray matter, white matter (WM) rarefaction and other vascular changes (acute infarcts, vascular malformation, etc.). Using multiple correspondence analysis, we identified a lower dimensional representation and assessed contributions of these eight markers. Further, we correlated the identified dimensions with other neuropathologic changes (Aβ, tau, neuritic plaques, Lewy body, TDP‐43, hippocampal sclerosis, and atrophy) and antemortem MRI measures (total gray matter volume and white matter hypointensity volume).

Result

Individuals were 83±7 years‐old at death and included 26% women, 56% APOE‐ε4 carriers and 75% individuals with confirmed AD neuropathologic change. Multiple correspondence analysis on the eight cerebrovascular markers resulted in two dimensions (Fig. 1). Dimension 1 was characterized by presence of gross chronic infarcts, chronic microinfarcts, mild WM rarefaction, severe arteriosclerosis, and severe atherosclerosis. Dimension 1 was significantly associated with higher postmortem cortical atrophy (r = 0.2), hippocampal atrophy (r = 0.4), hippocampal sclerosis (r = 0.3) and antemortem WM hypointensity volume (r = 0.3). Dimension 2 was characterized by moderate atherosclerosis, moderate arteriosclerosis, moderate WM rarefaction, severe CAA, presence of chronic hemorrhages and other vascular changes (acute gross‐/micro‐infarcts, microhemorrhage, vasculitis, blood vessel mineralization). Dimension 2 was significantly associated with higher postmortem Aβ (r = ‐0.4), tau (r = ‐0.3), neuritic plaques (r = ‐0.3) and hence, AD neuropathologic change (r = ‐0.3).

Conclusion

We identified two data‐driven cerebrovascular pathways, one AD‐unspecific (dimension 1) and one AD‐specific (dimension 2). Cerebrovascular burden may differentially manifest in individuals depending on the underlying cause of neurodegeneration.
Evaluation of the functional activity in synaptic genes related to polygenic risk for Alzheimer’s disease using a Massively Parallel Reporter Assay
Authors: Perlaza Danna , Gil Laia Lidón , Cervantes‐González Alba , Serrano‐Requena Sara , Tamayo Natalia Valle , Sánchez‐Aced Érika , Álvarez‐Sánchez Esther , Escabias Joaquim Aumatell , Muñoz Laia , Dolcet Sonia Sirisi , Dols‐Icardo Oriol , Lleo Alberto , Belbin Olivia
Published: January 2025

Background

Synaptic degeneration is a primary neuropathological factor associated with cognitive decline in Alzheimer’s disease (AD). In 2021, we generated a synaptic Polygenic Risk Score (PRS) that comprised only 8 variants within 6 synaptic genes (APOE, PICALM, BIN1, PTK2B, DLG2 and MINK1) that predicted AD with 72% accuracy in two neuropathological cohorts. This supports the hypothesis that genetic variants that regulate an individual’s vulnerability to AD‐related synapse degeneration could be used to identify individuals at‐risk for AD prior to the appearance of clinical symptoms. The aim of this study was to determine whether the constituent variants of the linkage disequilibrium (LD) blocks represented by the PRS have regulatory activity in vitro.

Method

We cloned an oligonucleotide library of 137 putative regulatory variants each represented by 5 barcodes per allele into pMPRA1 vector. Then we transfected the plasmids into HEK293 cells (n = 5). We extracted DNA and RNA from the cells and sequenced on an Illumina MiSeq. Using the mpra package in R, we normalized the tag counts to a common size of 10 million reads and computed paired log ratios of RNA/DNA counts for each barcode. We used weighted linear models to test for differential activity of the minor versus the major allele of each SNP using the mpralm function, adjusting for multiple testing using the Benjamini‐Hochberg method.

Result

We acquired approximately 15 million reads of DNA and RNA from 5 independent experiments. We found that 35 out of the 137 SNPs tested had differential activity between alleles (adj. p <0.05, Figure 1A). Three of the SNPs that showed regulatory activity were included in the PRS (BIN1: rs17014923 and rs35114168; DLG2: rs286043) and the remaining 32 are captured on LD blocks within the synaptic PRS.

Conclusion

All LD captured by the synaptic PRS contain SNPs that impact on regulatory activity, thus supporting a potential mechanism by which changes in the expression of these specific loci that encode synaptic proteins could lead to a modified cumulative risk for AD. Further studies to determine the precise mechanism involved in this regulatory activity at the synapse could guide future therapeutic strategies for AD.
Synapse‐enriched miRNA expression in Alzheimer’s disease cortex tissue
Authors: Gil Laia Lidón , Núñez‐Llaves Raúl , Serrano‐Requena Sara , Perlaza Danna , Cervantes‐González Alba , Tamayo Natalia Valle , Álvarez‐Sánchez Esther , Sánchez‐Aced Érika , Dolcet Sonia Sirisi , Dols‐Icardo Oriol , Lleo Alberto , Pérez‐González Rocío , Belbin Olivia
Published: January 2025

Background

Synapse degeneration is one of the earliest changes in Alzheimer’s disease (AD) and is the major neuropathologic correlate of cognitive impairment. The aim of this study was to characterize microRNA (miRNA) dysregulation at AD synapses post‐mortem brain tissue and explore the specificity for AD.

Method

We prepared synaptosomes (SYN) by serial ultracentrifugation of 10 AD (mean age = 77.4±13.3) and 10 control (CN; mean age = 72.3±18.8) temporal cortex samples over a sucrose gradient and saved the homogenates (H). We extracted and quantified miRNA from SYN and H fractions by TaqMan Advanced miRNA Assay‐Openarray system. We calculated deltaCt and performed linear regression to identify differentially expressed (DE) miRNA across AD and CN SYN, adjusting for multiple testing using Benjamini‐Hochberg method (α<0.05). We identified gene targets of the DE miRNA using two predictive databases (TargetScan and miRDB) and performed pathway analysis using the Panther database. We selected miRNA candidates that are DE in AD synapses and performed a follow‐up study in 4 different brain regions of 10 CN (mean age = 80.7±12.9), 10 AD (mean age = 77.4±13.3) and 10 non‐AD tauopathy (mean age = 70.6±6.4) cases to determine the regional distribution and the AD specificity.

Result

Synapse fractions were isolated demonstrating a 3.2‐fold enrichment in the synaptic protein VAMP‐2 (p<0.001) compared to homogenates. We detected 411 miRNA in H and 432 in SYN of the total in the panel with 89% overlap between AD and CN in SYN. Three miRNA from the same family (miR‐132‐3p, miR‐132‐5p and miR‐212‐3p) were under‐expressed and 2 miRNA (miR‐181a‐3p and miR‐1260a) were over‐expressed in AD compared to CN SYN. The gene targets of these miRNA were overrepresented in pathways regulating synaptic and mitochondrial function. In addition, targets of miR‐132 also were overrepresented in pathways related to tau pathology, Aβ production, interleukin production, apoptosis and oxidative stress. We will describe the regional distribution in AD brains post‐mortem and the specificity of the changes to AD by comparing to non‐pathological controls and non‐AD tauopathies.

Conclusion

miRNA that are dysregulated in AD synapses target genes that are involved in pathways related to AD pathogenesis. Future studies will focus on the use of these miRNA as therapeutic targets.
Unraveling the role of Microglia in triggering High Fat Diet‐Induced Cognitive Decline
Authors: de Bem Andreza Fabro , Da Rosa Priscila Batista , Rodrigues Matheus Scarpatto , Engel Daiane F , Lazzarino Gisela Paola , de Oliveira Jade , Engblom David
Published: January 2025

Background

Excessive dietary fat is not only a risk factor for metabolic disorders but also for premature cognitive decline and Alzheimer’s disease. Recent findings from our study revealed that even a few days of a high‐fat diet (HFD) are sufficient to disrupt hippocampal bioenergetics, activate microglia, and induce cognitive decline in mice. We hypothesize that microglia, rather than merely responding to diet‐induced damage, play a critical role in disrupting synaptic homeostasis.

Method

To investigate this hypothesis, we first assessed the effects of a HFD over time on cognitive impairment and hippocampal microglia activation in C57Bl6J male mice. Subsequently, we employed a chemogenetic approach using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) to conditionally inhibit microglia and evaluate the metabolic and behavioral outcomes induced by HFD.

Result

Remarkably, only 10 days of HFD led to changes in hippocampal‐dependent behavioral tasks, such as the novel object recognition test, in 3‐month‐old male C57Bl6J mice, which persisted for 4 and 8 weeks. Sholl analysis and stereology confirmed morphological alterations and reactivation of microglia in the hippocampal CA1 region after 10 days of HFD, while metabolic parameters (adiposity and weight gain) were increased only after 4 and 8 weeks of HFD in C57Bl6J mice. Interestingly, sub‐chronic chemogenetic microglial inhibition (by DREADD) prevented memory impairment, evaluated by novel object recognition and object reallocation tests, in mice submitted to HDF for 7 days.

Conclusion

Together our data support the notion that microglia play a critical role in triggering mechanisms of hippocampal damage induced by HFD.
Novel microglial markers that are specifically increased in early clinical AD stages
Authors: Blujdea Elena Raluca , Vermunt Lisa , Chen‐Plotkin Alice , Irwin David J , Boiten Walter , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Van Bokhoven Pieter , del Campo Marta , Teunissen Charlotte
Published: January 2025

Background

Transcriptomic and pathological studies indicate that microglia play a key role in the progression of Alzheimer’s disease (AD). Throughout the stages of the AD continuum, there may be varying microglia phenotypes, such as the disease‐associated microglia (DAM). Microglia proteins have been detected in cerebrospinal‐fluid (CSF), providing a quantifiable avenue for potential stage‐detection. This study aims to find CSF microglial biomarkers to stage early‐ versus late‐AD.

Method

In total, 637 proteins were measured with proximity extension assay in 564 samples from the Amsterdam Dementia Cohort and from University of Pennsylvania. We defined four clinical groups spanning the AD continuum, as follows: 1) cognitively normal or subjective cognitive decline with negative AD‐ratio of CSF t‐tau/amyloid‐beta42 as controls, and positive AD‐ratio 2) subjective cognitive decline, 3) mild cognitive impairment, and 4) AD‐dementia. We selected 176 microglia‐enriched proteins based on human‐derived single‐cell RNA‐sequencing data and compared the groups by ANCOVA and Tukey’s HSD. Functional characterisation was done by associating proteins of interest to a list of microglial markers per state, such as DAM‐like proteins, that were identified through single‐cell Hierarchical Poisson Factorization.

Results

Overall, proteins showed distinct wave‐like patterns of dysregulation, presented in figure 1. 21 of the 176 microglial proteins were specifically upregulated in the early stages, while 20 were specific to the dementia stage. The proteins increased specifically in early stages consisted of receptors, possibly reflecting increased cellular recruitment, with an increase in DAM‐like proteins, particularly ones associated to MHC class II binding, such as CD4 and CD74, which are related to adaptive innate immune response.

Conclusion

In conclusion, we identify varying microglial protein signatures spanning the AD stages, which may provide a basis for early‐staging biomarkers. Independent cohort and cross‐method validations are ongoing, and are necessary for the understanding of the hypothesized dynamicity of AD inflammation driven by microglia.
Sexual dimorphic synaptic dysfunction and cognition in a mouse model of Alzheimer’s disease
Authors: Findley Caleigh A. , McFadden Samuel A , Hill Tiarra , Peck Mackenzie R. , Quinn Kathleen , Hascup Kevin N. , Hascup Erin R.
Published: January 2025

Background

Glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies support a dynamic shift in excitatory signaling with Alzheimer’s disease (AD) progression, contributing to negative cognitive outcomes. The majority of previous studies have relied heavily on male physiology when determining these alterations in AD mouse models. Here, we examine sex differences in neurotransmission and cognition using the APPNL‐F mouse model of AD.

Method

Male and female APPNL‐F and control C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR) at 2‐4 and 18+ months of age. Afterwards, mice were anesthetized with isoflurane while determining basal, stimulus‐evoked, and clearance rates of extracellular glutamate measures in the dentate gyrus (DG), CA3, and CA1 hippocampal subregions.

Result

Our data support impaired spatial cognition in aged male and female APPNL‐F mice, but only aged females displayed recognition memory deficits compared to age‐matched control mice. Evoked glutamate release was elevated in the DG and CA3 of young APPNL‐F male mice that declined with age compared to age‐matched control mice. Young female APPNL‐F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age‐matched control mice. Both sexes of APPNL‐F mice exhibited decreased CA1 basal glutamate levels, but only males also showed CA3 reductions.

Conclusion

Our findings confirm a sex‐dependent hyper‐to‐hypoactivation glutamatergic paradigm in APPNL‐F mice. Additionally, we observed a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL‐F mice than males. This research mirrors that of human AD pathology and provides further evidence of divergent AD pathogenesis between sexes.
The Effect of a Mediterranean and Western Diet on Cognitive Performance in Middle‐Aged Rats
Authors: Solch‐Ottaiano Rebecca J , Prats Madison , Engler‐Chiurazzi Elizabeth , Bix Gregory J , Maraganore Demetrius M
Published: January 2025

Background

Clinical studies indicate that mid‐life dietary patterns are a risk factor for cognitive decline. Adherence to a Mediterranean diet (MeDi) may promote healthy brain aging in contrast to a Western diet (WD), yet these diets have not been examined in pre‐clinical models. We hypothesized that consumption of the MeDi would have better cognitive performance compared to the Western diet in middle‐aged rats.

Method

A subset of animals that provided diet‐specific fecal samples were used in this pilot study. Four‐month‐old male Fischer 344 rats were randomly assigned to a MeDi (n = 13) or WD (n = 7) for approximately one year. Animals then underwent neurobehavioral assessments including the Y‐maze, Morris water maze, and water radial arm maze to assess aspects of short‐ and long‐term memory. Data were analyzed via Student’s T‐test or Two‐Way Repeated Measures ANOVA where appropriate.

Result

For the Y‐maze, there was no difference in percent correct alternations between diet groups (p = 0.24), but the MeDi group had more total alternations compared to the WD group (p = 0.04). For the Morris Water Maze, the MeDi group had a decreased latency compared to the WD group (p = 0.03). Additionally, there was a Day x Diet Effect where the MeDi group had a decreased latency on days 3‐5 (p ≤ 0.01) compared to the WD group. There was no difference between diet groups for platform probe testing (p = 0.80). For the water radial arm maze, there was no difference in total (p = 0.56), working memory correct (p = 0.73), or working memory incorrect (p = 0.33) errors between diet groups. However, the WD group committed more reference memory errors compared to the MeDi group (p = 0.01).

Conclusion

Middle‐aged animals consuming a MeDi demonstrated better aspects of learning and memory compared to animals consuming a WD. This data helps support clinical data suggesting that mid‐life dietary patterns impact cognitive function.
Role of mTORC1 signaling during memory consolidation in Alzheimer’s disease
Authors: Pereyra Magdalena , Schmidt‐Hieber Christoph , Bathellier Brice
Published: January 2025

Background

Memory consolidation is an essential process for our everyday lives that is severely disrupted in Alzheimer’s Disease (AD). Memories are initially encoded in the hippocampus before being consolidated in the neocortex by synaptic plasticity processes that depend on protein synthesis. However, how molecular pathways affect synaptic signalling during memory consolidation in health and disease is unclear. We hypothesize that mechanistic Target Of Rapamycin Complex 1 (mTORC1), a central regulator of protein synthesis, plays an essential role in the communication between the hippocampus and the prefrontal cortex (PFC), and that mTORC1 dysregulation contributes to memory dysfunction in AD.

Method

We evaluated the role of mTORC1 in memory consolidation using a PFC‐dependent spatial object recognition (SOR) task. We used a mouse model of AD where mice express a human variant of the amyloid precursor protein (hAPP). We extend our results to another amyloid‐based mouse model (5XFAD 6,5 months old). Furthermore, we have evaluated mTORC1 pathway‐associated protein levels by Western Blot in both AD mice models.

Result

First, we found that infusion of rapamycin, a selective mTORC1 inhibitor, into the PFC of WT animals immediately but not 3 hours after training disrupted long‐term memory expression.

We observed that hAPP‐injected animals exhibited impaired long‐term memory expression in the SOR task (tested 6 weeks after hAPP injections in PFC) as well in the novel object recognition task compared to control mice. We evaluated mTORC1 pathway‐associated protein levels by Western Blot in hAPP‐expressing or control mice (1,5 months after viral injections) and found no differences in PFC or hippocampal samples. We repeated biochemical measurements in untrained hAPP or control mice 4 months after injections and found a trend towards downregulation of mTORC1 pathway‐associated protein levels in PFC.

Finally we also observed great memory retention deficits in 5XFAD mice(6,5 months old) as well as a significant downregulation of mTORC1 pathway‐associated protein levels in PFC and hippocampal samples.

Conclusion

Our preliminary data suggest a downregulation of mTORC1 activation in two different AD mice models. Taken together, our results point to a key role of mTORC1 during memory consolidation in PFC that might be disrupted during AD.
Neuroprotective mechanism of syringic acid against traumatic brain injury induced cognitive dysfunction
Authors: Banderwal Rittu
Published: January 2025

Background

Traumatic brain injury (TBI) due to external forces is a major cause of morbidity and mortality among people of all age groups, worldwide. Multiple biological processes like neuroinflammation, mitochondrial dysfunction, oxidative stress, amyloid β (Aβ) production, and tau hyperphosphorylation are involved in the pathogenesis of TBI. The role of neuroinflammation and oxidative stress has been suggested in the pathophysiology of brain injury‐induced cognitive dysfunction. Therefore, the present study was designed to explore the neuroprotective potential of syringic Acid (SA) against TBI.

Method

Sprague‐Dawley male rats were exposed to brain injury using a weight drop model and kept for a rehabilitation period of 14 days after injury. Afterwards, animals were administered with SA (25 and 50 mg/kg; per oral) daily, for 14 days. Further, various behavior parameters (NOR and MWM, locomotor activity and motor coordination), biochemicals (oxidants and antioxidants markers), activities of mitochondrial enzyme complexes and acetylcholinesterase (AChE), proinflammatory markers (TNF‐α, IL‐6) were evaluated in specific brain regions.

Result

Traumatized rats followed by treatment with SA (25 and 50 mg/kg, per oral) for 14 days had significantly improved memory performance (increased time spent in the target quadrant, shortened escape latency to access the platform, and increased discrimination index) in Morris water maze and novel object recognition test when compared to control (TBI) groups. Further, SA treatment significantly restored antioxidant levels, attenuated increased AChE activity, and TNF‐ α levels, and regained mitochondrial capacities. The results of the present study show that the therapeutic effect of syringic acid might involve the inhibition of inflammatory reactions against brain injury‐induced cognitive dysfunction and neuroinflammation in rats.

Conclusion

The current work demonstrates the neuroprotective effect of syringic acid in an experimental model of TBI. The study further suggests that the neuroprotective impacts of syringic acid may be related to its effects on TNF‐α, IL‐6 levels, oxidative stress pathways, and mitochondrial complex capabilities.
Mechanisms underlying AD‐sleep interactions: Recent insight from animal models
Authors: Veasey Sigrid C
Published: January 2025

Epidemiologic studies have revealed a relationship between chronic persistent short sleep and the risk of dementia, yet whether short sleep is an early symptom of dementia or a contributor to dementia in humans has not been resolved. A rapidly growing body of research in animal models, however, strongly supports the concept that chronic disruption of sleep can impart significant injury in the brain consistent with some of the important pathology evident in Alzheimer’s disease (AD), the most common form of age‐related dementia. Transgenic models of AD pathology develop an increased density of amyloid plaques in response to chronic sleep loss, and this response is independent of significant stress. Studies in animal models without a genetic predisposition to AD pathology have identified late‐in‐life neural injury with many features observed in AD, including increased amyloid‐beta in the hippocampus, gliosis, memory impairment and loss of AD‐vulnerable neurons. Moreover, sleep loss impairs microglial capacity to clear amyloid fibrils. The chronically sleep‐deprived brain shows a unique proteomic profile in response to sleep loss, in cerebrospinal fluid (CSF) independent of plaque. Can we now identify who is at risk for AD‐like injury from a sleep disorder by assessing CSF, or identify subtypes of AD based on CSF findings? Noradrenergic locus coeruleus neurons are susceptible to loss in AD and sleep loss, where noradrenaline reuptake and lysosomal dysfunction in the neurons may contribute to injury. We should now determine whether chronic sleep loss in humans increases specific lysosomal markers in the blood or cerebral spinal fluid, and if so, these biomarkers may be used to identify individuals at risk and for early AD. As locus coeruleus activity can now be monitored non‐invasively in humans, this work also highlights novel avenues to detect early neural injury in Alzheimer’s and assess the effectiveness of early therapies. Thus, the time is right to integrate new findings in humans and in animal models of sleep disruption to effectively advance diagnostics and therapies for AD and related dementias.
Post COVID 19 Pandemic –Changing landscape of Dementia Profile A Study from a tertiary care center in India
Authors: Kushwaha Suman , Panda Ashwin Kumar , Singh Mridula , Anthony Aldrin , Maheshwari Siddharth , Kumar Rashi , Dhamija Rajinder
Published: January 2025

Background

SARS CoV‐2, neurotrophic virus in response to neuroinflammation causing varying cognitive deficits in post pandemic period. New onset rapidly progressive cognitive decline and deterioration in degenerative dementia has been seen in clinics in recent times. The paradigm shift of presentation of dementia needs detailed evaluation to facilitate further management.

Method

Duration of study‐ 2 years. Retrospective

All the patients admitted with cognitive impairment were evaluated: Detailed history, Cognitive testing, biochemical and hematological parameters. Neuroimaging in all patients & CSF in selected cases. Accordingly categorized into subtypes. History of COVID 19 was confirmed by Clinically, hospitalization and investigations.

Result

Total Cases – 53. Age Range 50 ‐75 yr. Dementia Subtypes Patients, Alzheimer’s disease –14, Frontotemporal ‐10, Rapidly progressive dementia ‐15, Vascular – 8 and Parkinson’s dementia‐ 6.

History of respiratory symptoms were present in 28 patients while COVID test was positive in 12 patients. Hospitalization for COVID ‐19 in 10 patients. The degenerative dementias have rapid progression of symptoms. The incidence of RPD has increased. Treatable cause of RPD were investgated 12 patient had immune mediated dementia and has partial response on immunomodulation. Seven patients have succumbed.

Conclusion

COVID‐19 has significant effect on cognitive decline. Neuroinflammation is key factor causing degeneration. We need to know how this is resulting in neurodegenerative processes and cognitive functioning. There is need to further explore post pandemic dementia in systematic studies for new onset cognitive decline for facilitating the therapeutic strategies.
Language impairment associated with prognosis in progressive supranuclear palsy
Authors: Cordero Indira Ruth Garcia , Hadian Mohsen , Bayram Ece , Rodriguez‐Porcel Federico , Stephen Christopher , Pantelyat Alex , Iyer Jay , Xie Tao , Boxer Adam L , Gunzler Douglas , Dale Marian , McFarland Nikolaus , Kang Kyurim , Swan Matthew , Wills Anne‐Marie , Lang Anthony E , Tartaglia Maria Carmela
Published: January 2025

Background

Language impairment is common in progressive supranuclear palsy (PSP) and is often overlooked due to the severity of the motor symptoms. We investigated whether language can be used to predict PSP prognosis.

Methods

One hundred‐forty‐six patients with a diagnosis of possible or probable PSP from the Tilavonemab (ABBV‐8E12) clinical trial were evaluated at baseline and week 32 using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the PSP rating scale (PSPRS) and the Schwab and England Activities of Daily Living Scale (SEADL). Percentage of change was calculated for each measure. Using correlations, we evaluated relationships between all RBANS‐subscores (language, attention, memory and visuoconstructional), the PSPRS and SEADL scores at baseline; p‐values were FDR corrected. Linear regression analyses were performed between the RBANS‐language, RBANS‐delayed‐memory and RBANS‐executive at baseline and the percentage of change over time. Grey matter volumes were extracted from three regions of interest based on language (bilateral temporal poles and inferior frontal gyri), executive (bilateral dorsolateral and superior frontal gyri and frontal pole) and memory (bilateral hippocampus, inferior, middle and superior temporal gyri) areas.

Results

Mean age of PSP patients: 68.8 years (49‐86 years), 57 (39%) females. The RBANS language, executive and delayed memory scores at baseline were positively correlated with each other and with visuoconstructional and immediate memory score (all p<0.05). Only the RBANS‐language score at baseline predicted percentage of change in PSPRS (B = ‐0.63, p = 0.003). The percentage of change in the RBANS‐language score was predicted by the RBANS‐language at baseline (B = ‐0.59, p<0.001). Lower age at baseline was associated with a worsening in language score over time (B = 0.51, p = 0.009). Language grey matter volume was associated with the change in RBANS‐language score (B = 0.01, p = 0.02).

Conclusions

language impairment at baseline, in contrast to memory and executive functions, was predictive of functional decline as measured by PSPRS. Atrophy in language areas at baseline predicted language decline. Language impairment may be an independent prognostic factor in PSP.

*Based on research using data from AbbVie that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication.
Association between Hippocampal Volume and Cognition in the Oldest‐Old Individuals from Colombia
Authors: Kaplan Elizabeth , Zuluaga Yesica , Vasquez Daniel , Hincapie Liliana , Aguillon David Fernando , Madrigal Lucia , Baena Ana Y , Vila‐Castelar Clara , Alvarez Sergio , Ochoa‐Escudero Martin , Giraldo‐Chica Margarita M. , Gomez Liliana A Ramirez , Langella Stephanie , Arboleda‐Velasquez Joseph F , Lopera Francisco , Quiroz Yakeel T.
Published: January 2025

Background

Life expectancy is on the rise, accompanied by an increased prevalence of cognitive impairment and Alzheimer’s disease. Despite this global trend, our understanding of the neural mechanisms underlying cognitive changes in the oldest‐old (>80 years old) population remains limited. Unraveling these mechanisms may provide valuable insights and therapeutic interventions for individuals grappling with cognitive impairments in older age. Increased hippocampal volume has been associated with better cognitive function and its sparing in late life has been linked to better cognitive and functional outcomes. In this study, we examined hippocampal volume and cognitive performance in a group of the oldest‐old individuals from Colombia.

Methods

13 participants (9 women, 4 men), with an average age of 94.8 (6.24) years were included in this study. Cognitive performance was measured using the Mini‐Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List Learning Total. Functional impairment was assessed using the Functional Assessment Scale Test (FAST). Structural MRI scans were conducted at the Hospital Pablo Tobon Uribe in Colombia and processed with FreeSurfer (v7.2). Right and left hippocampal volumes were averaged. Linear regression models were used to investigate the relationship between hippocampal volume and cognitive performance.

Results

7 participants were cognitively‐unimpaired (FAST = 1), 3 endorsed subjective complaints (FAST = 2), and 3 met criteria for dementia (FAST ≥3). Participants had a mean hippocampal volume of 2,990 (459 mm³), mean MMSE score of 21.2 (6.15), and mean Memory Score of 10.5 (4.52). Regression models revealed higher hippocampal volume was significantly associated with better memory scores after adjusting for FAST impairment, age, sex, and intracranial volume (p = 0.012). The relationship between higher hippocampal volume and MMSE scores, controlling for the same variables, approached significance (p = 0.06).

Conclusions

Our preliminary findings suggest a positive association between hippocampal volume, a marker of neurodegeneration, and cognitive performance in a cohort of the oldest‐old individuals from Colombia. This study is ongoing and future research, incorporating a larger sample size and additional biomarkers, is needed to validate these results, as well as to further our understanding of the relationship between neural structure in late life and cognition.
APOE genotype‐dependent effects of enhanced BMP signaling on astrocytes and co‐cultured neurons
Authors: Linden Anne K , Affaneh Amira , Kessler John A , Yu Peng Chian‐
Published: January 2025

Background

Apolipoprotein E4 (E4) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD), and aging is the greatest overall risk factor for AD. Many cellular and molecular changes occur within the brain throughout aging, one of which being the increased bone morphogenetic protein 4 (BMP4) signaling. As APOE and BMPs are known to interact in non‐neuronal organs, we hypothesized that enhanced BMP signaling in the brain may interact with APOE in a genotype‐dependent manner to initiate or exacerbate neuropathological cascades relevant to AD.

Method

E4 patient‐derived IPSC, along with CRISPR‐corrected isogenic APOE3 (E3) controls, were virally induced into astrocytes with SOX9 and NFIB overexpression, or neurons with NGN2 overexpression, using previously published protocols. After maturation, astrocytes and neurons cultured alone or in co‐culture, were treated for 72 hours BMP4 or vehicle prior to collection to observe changes.

Result

In the presence of BMP4, E4 astrocytes accumulated larger amounts of lipids in the cytoplasm compared to E3 astrocytes. This accumulation of lipids resulted from enhanced lipid generation, reduced lipid breakdown, and reduced efficiency of beta oxidation compared to E3 astrocytes treated with BMP4. Further, single cell transcriptomic analysis of astrocyte‐neuron co‐cultures revealed that BMP4 promotes astrocyte to neuron cholesterol signaling from E4 astrocytes more than E3 astrocytes, and BMP4 treatment reduces elevated TGFβ signaling from E4 astrocytes to co‐cultured neurons. These BMP4 induced changes coincide with enhanced phosphorylation of tau and reduced oxidative phosphorylation capacity in neurons cocultured with E4 astrocytes compared to E3 astrocytes.

Conclusion

Increased BMP signaling alters the physiology of astrocytes in an APOE‐dependent manner, with E4 astrocytes exhibiting more abnormalities in lipid metabolism than E3 astrocytes. Specifically, BMP‐treated E4 astrocytes have greater lipid droplet accumulation due to increased lipid generation, reduced lipid breakdown, and lack of beta oxidation when compared to E3 astrocytes treated with BMP4. E4 astrocytes exert greater effects than E3 astrocytes on the disease phenotype of co‐cultured AD neurons, with increases in phosphorylated tau and decreases in oxidative phosphorylation efficiency. This suggests that enhanced BMP4 signaling in the aging brain may be one of the contributing factors to development of AD.
The klotho F/C AD risk haplotype drives distinct phenotypes in a novel mouse model
Authors: Sasner Michael , Pandey Ravi S , Kotredes Kevin P , Garceau Dylan , Weber Channing , Agoro Rafiou , Preuss Christoph , Carter Gregory W
Published: January 2025

Background

Apolipoprotein E4 (APOE4), a common variant of APOE, is a major genetic risk factor for Alzheimer’s disease (AD), but APOE4 carriers do not always develop AD. Several large‐scale genetic studies have identified a common haplotype of the aging factor klotho that modify disease risk in APOE4 carriers. In humans, klothoharbors two common missense variants (rs9536314, p.F352V; rs9527025, p.C370S) that define the klotho V/S (KL‐V/S) haplotype, which is protective against AD in APOE4 carriers, and the klotho F/C (KL‐F/C) haplotype, which is not. We sought to understand this genetic interaction using novel mouse models.

Method

Mouse klotho differs at the key amino acid position p.C370S rendering the native mouse haplotype as “KL‐F/S”, matching neither of the observed human haplotypes. We have replaced this with either the homozygous protective KL‐V/S or common KL‐F/C haplotypes using CRISPR/Cas9. We have tested the effects of these klotho haplotypes on klotho expression in serum, brain, and kidney relative to B6 controls and to the amyloidogenic AppSAA AD model, which exhibit significant amyloid neuropathology. We have also run RNA‐seq on whole brain homogenates at 12 months of age.

Result

Secreted p‐KL was decreased in KL‐F/C mice harboring the novel mouse risk haplotype relative to age matched B6 controls and to KL‐V/S mice. In contrast, KL‐V/S mice showed no significant differences in soluble p‐KL serum levels when compared to B6 controls. Secreted p‐KL levels in KL‐V/S mice were significantly elevated when compared to the APPSAA mice, whereas young KL‐F/C mice showed similar levels to the aged APPSAA model. Transcriptional analysis indicated that the KL‐V/S haplotype was anti‐correlated with AMP‐AD human modules, while the KL‐F/C risk haplotype was significantly correlated to AD signatures in modules enriched for neuronal system, cell cycle, myelination, and cellular stress response pathways.

Conclusion

These data suggest the native mouse klotho allele may act similarly to the protective KL‐V/S haplotype, while the KL‐F/C haplotype leads to lower secreted klotho and potentially greater disease risk. These models are therefore suitable for experiments to elucidate how klotho variants protect from AD pathologies, and will enable detailed studies of how this protection is specific to the APOE4 genotype.
Transcriptome Signatures for Cognitive Resilience Among Individuals with Pathologically Confirmed Alzheimer Disease
Authors: Li Donghe , Han Xudong , Farrer Lindsay A. , Stein Thor D. , Jun Gyungah R
Published: January 2025

Background

The molecular mechanisms underlying individuals with neuropathologically confirmed Alzheimer disease (AD) but who were cognitively healthy prior to death (i.e., cognitively resilient) remain largely unknown.

Method

We evaluated brain‐derived RNA sequencing data from 213 individuals with cognitive resilient and 383 symptomatic AD cases. This data included newly generated sequences from Boston University Alzheimer’s Disease Research Center (BUADRC) participants, and existing data from the Framingham Heart Study (FHS), Religious Orders Study, Rush Memory and Aging Project (ROSMAP), and the Mount Sinai Brain Bank (MSBB). Differential gene expression analyses between cognitive resilient and symptomatic AD were conducted in each dataset and then the results were combined by meta‐analysis. Differentially expressed genes (DEGs) at the transcriptome‐wide significance (TWS) level (P<10‐6) in meta‐analysis and nominally significant (P<0.05) in at least two datasets were included in subsequent analyses of pathways and associations with cognitive and neuropathological traits.

Result

We identified 42 TWS genes, including 17 that were meta‐analysis P<5 × 10‐8. The two most significantly DEGs in meta‐analysis, ADAMTS2 (Log2 fold change [Log2FC] = 0.45, P = 2.25 × 10‐14) and SCGN (Log2FC = 0.57, P = 1.84 × 10‐11), were both up‐regulated in symptomatic AD brains. Significant pathways involving alpha‐amino acid catabolic process and chemical synaptic transmission modulation were identified. These genes exhibited distinct patterns of association with domain‐specific cognitive tests, which the most significant association was found with SMPX expression for memory (beta = ‐0.08, P = 0.002). Regarding neuropathological traits, IL2RG expression was the most significant association with pTau181 (beta = ‐3.56, P = 0.002). Of the two most significant DEGs, ADMTS expression was associated with memory (beta = ‐0.013, P = 0.002) and pTau231 (beta = 0.008, P = 0.005), while SCGN expression was associated with language (beta = ‐0.1, P = 0.025) and executive function (beta = ‐0.1, P = 0.02).

Conclusion

We identified multiple DEGs for cognitive resilience, several of which were also associated with measures of cognitive performance prior to death and AD‐related neuropathological traits at autopsy, thus providing important insights into resilience mechanisms and strategies for delaying clinical symptoms of AD. Notably, ADAMTS2 was the top‐ranked DEG in a study conducted in brains from African American AD cases and controls (see Logue et al. abstract for this meeting).
Propagation of distinct tau strains in neuronal systems with physiological tau expression
Authors: Hromadkova Lenka , Urquhart Kiley , Kim Chae , Haldiman Tracy , Safar Jiri
Published: January 2025

Background

Pathological tau forms from Alzheimer’s disease (AD) brains act as seeds, replicating in cells and forming tau aggregates in a template‐like manner. The exploration of this prion‐like pathogenic mechanism has predominantly occurred in transgenic mice and cell systems that overexpress tau protein and its truncated forms with pro‐aggregation mutations. However, these systems do not entirely capture the propagation kinetics and template conformational changes of various tau seeds. Our investigation focuses on tau propagation in cell systems with normal tau levels, emphasizing molecular conformation variability among tau strains, considering them as distinct populations in individual AD cases (Hromadkova et al., Cell Biosci., 2023).

Method

We employed three types of cell systems: mouse primary neurons, differentiated SH‐SY5Y, and iPSCs‐derived neurons. We optimized culture conditions and timing for inoculation with AD‐tau isolates. The amount and conformational state of AD‐tau were characterized using conformational stability assay (CSA) and conformation‐dependent immunoassay (CDI). Subsequently, tau aggregates newly formed in neurons exposed to AD‐tau were subjected to immunostaining and cell lysis. We analyzed the results using confocal microscopy, immunoblot techniques, and CDI.

Result

In all three systems, tau protein showed the tendency to aggregate when exposed to AD‐tau inoculates. During the early stages of inoculation, we noted the formation of tau aggregates with conformational properties resembling those found in the original AD‐tau isolates. Extended inoculation revealed increased aggregation, different from original AD‐tau, suggesting favorable propagation of highly seed‐competent tau entities in long‐term cultures.

Conclusion

Our findings indicate that different tau strains manifest as dynamic entities, exhibiting variability not only in molecular conformations and structural arrangements but also in the kinetics of inter‐neuronal propagation. This diversity might contribute to the observed heterogeneity in AD phenotypes. The presence of different tau strains among AD patients introduces an added layer of complexity to disease progression and outcomes. Consequently, it may be worthwhile to consider more personalized therapeutic interventions tailored to individual patients.
Genetic Analysis of an Amyloid PET‐Negative Autopsy‐Confirmed Alzheimer’s Pedigree
Authors: Talozzi Lia , Peña‐Tauber Andrés , Jensen Tanner D. , Wilson Edward N. , Young Christina B. , Stewart Ilaria , Cobos Inma , Vallejo Kristen , Hefti Marco M , Guen Yann Le , Williams Kennedy , Vossler Hillary , Gorzynski John , Andreasson Katrin I. , Mormino Elizabeth , Ashley Euan , Greicius Michael D
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common form of dementia. Neuropathologically, AD stands out as a mixed proteinopathy. Beta‐amyloid and tau biomarkers can now add in‐vivo support to the AD diagnosis. Rarely, a patient with AD confirmed at autopsy may have a negative amyloid PET. Here we describe a pedigree in whom the index case was amyloid PET‐negative. We performed genetic sequencing of two affected siblings to identify a set of candidate single nucleotide variants (SNVs) and structural variants (SVs) associated with disease and rare in healthy older controls from several large genetic databases.

Method

We performed long‐read sequencing (LRS) to comprehensively evaluate both SNVs and SVs. The index case, an APOE3/E4 male, developed memory trouble at 68 that progressed to probable AD at 72. Notably (Fig. 1) his amyloid‐PET scan, which was confirmed to be of high technical quality, was negative. His tau PET scan was positive and his plasma Abeta42/40 was in the expected range for Stanford AD patients. His family history is extensive and suggestive of an autosomal dominant pattern of late‐onset AD (Fig. 2). The patient’s sister was diagnosed with AD at 62. We filtered their shared heterozygous SNVs keeping those with a minor allele frequency < 0.01 in gnomAD and that were not present in any ADSP healthy controls (HC) over 70y.o. (N = 19771;62.1%females;81±6.4y.o). Shared SVs were kept as candidates if they were not seen in any Stanford LRS HC (N = 95;59%females;72±1.5y.o.)

Result

Neuropathological analysis revealed that both siblings met the A3B3C3 criteria for AD and had cerebral amyloid angiopathy. Among rare mutations on genes expressed in the brain (Table 1), a novel missense in ADNP (Activity‐Dependent‐Neuroprotector‐Homeobox), and a 267bp deletion on TET1 (Tet‐Methylcytosine‐Dioxygenase) were identified. The 3426bp insertion on ATP8A2 (ATPase‐Phospholipid‐Transporting‐8A2) was the longest, rare insertion found. Additionally, a large duplication (∼20Kbp) and inversion (∼160Kbp) were observed.

Conclusion

This study highlights an unusual AD pedigree and emphasizes the potential utility of LRS in identifying causal SNVs and SVs. In future work we plan to perform additional amyloid stains to understand why the index case PET was amyloid‐negative. We are also assessing additional family members to improve our ability to identify a causal mutation.