bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid and tau deposition is associated with performance on tests of auditory processing in the brain
Authors: Stevenson Alyssa , Rahmouni Nesrine , Leigh Samantha , Stevenson Jenna , Rosa‐Neto Pedro , Niemczak Chris , Buckey Jay
Published: December 2023

Background

Alzheimer’s disease pathophysiology may affect sound processing (central auditory function) in the brain. This study aims to investigate the link between tests of central auditory function, such as dichotic digits, and brain pathology in older adults at high risk for developing dementia.

Method

28 individuals (13 cognitively unimpaired (CU) and 15 mild cognitively impaired (MCI)) were enrolled (Table 1). Amyloid deposition was assessed with [18F] AZD4694 PET and tau accumulation was assessed with [18F]MK6240 PET. Standard uptake value ratios (SUVR) were determined using the cerebellar and the inferior cerebellar cortex as reference region for amyloid and tau PET, respectively. Hearing assessments were conducted using a custom audiological testing system from Creare LLC. Voxel‐based regression models evaluated the association between dichotic digit scores and amyloid and tau deposition as assessed by PET, adjusting for Pure Tone Average (PTA) and a control condition for speech in noise (Triple digits score). Random field theory (RFT) was used to correct for multiple comparisons.

Result

In the voxel‐wise analysis, negative associations between dichotic digits scores and amyloid‐PET were found in the temporal, occipital and parietal areas. Negative associations between dichotic digits scores and tau‐PET were present in the temporal area, with higher t‐values in the primary and secondary somatosensory cortices (Figure 1, panel A). Negative correlations were found between dichotic digits scores and both amyloid (p<0.001) and tau (p<0.05) SUVRs (Figure 1, panel B). In addition, dichotic digits scores were significantly lower in MCI individuals (p<0.001) (Figure 1, panel C).

Conclusion

This study is the first to assess associations between central auditory hearing in CU and MCI individuals using PET biomarkers. These findings highlight the link between central auditory deficits and AD hallmarks in auditory processing‐related brain regions. This suggests a potential decreased capacity for interhemispheric transfer in mildly cognitively impaired individuals.
Tau deposition patterns within the medial temporal lobe follow the connectivity of the entorhinal cortex – a combined post‐mortem and 7T fMRI study
Authors: Franzmeier Nicolai , Berron David , Binette Alexa Pichet , Grande Xenia , Hansson Oskar , Ossenkoppele Rik
Published: December 2023

Background

In aging, tau pathology develops in the medial temporal lobe (MTL), but spreads extensively to the cortex in the presence of amyloid‐beta, driving neurodegeneration and Alzheimer’s disease (AD) dementia development. This suggests that earliest age‐related MTL tau is a pre‐requisite for cortical tau spreading and the development of AD. Using tau‐PET in AD, we found previously that functional connectivity routes the cortical expansion of tau, supporting the concept of trans‐neuronal tau spreading. However, it is unclear whether MTL tau accumulation follows within‐MTL connections, in particular those of the entorhinal (EC) and transentorhinal cortex (A35), i.e. the earliest sites of tau accumulation. To address this, we combined post‐mortem histopathological MTL tau assessments with high‐resolution 7T functional MRI to determine MTL subregional connectivity.

Methods

We included 3D post‐mortem quantitative histopathological tau assessments of 14 MTL subregions (Fig.1A) in 18 participants with overall low AD neuropathological change to capture earliest tau (Fig.1B), and 7T resting‐state fMRI from young and healthy controls (n = 29) to characterize MTL functional connectivity. Using post‐mortem data, we assessed the covariance of AT8‐stained tau among MTL subregions (Fig.1C) and assessed the correlation with functional connectivity among the same regions (Fig.1D). Further, we determined seed‐based connectivity to determine which MTL subregions connectivity pattern was the best predictor of MTL‐wide tau patterns.

Results

Post‐mortem tau levels were highest in the amygdala, followed by A35 and the EC (Fig.2A). As hypothesized, we found an association between MTL connectivity and covariance in MTL tau (r = 0.42, p<0.001, Fig.2B), where closely connected regions showed correlated tau. When assessing seed‐based connectivity as a predictor of MTL tau patterns, EC connectivity was the best predictor for MTL tau deposition patterns (Fig.2C).

Conclusions

Closely connected MTL subregions show correlated histopathologically‐assessed tau load, suggesting connectivity to route earliest within MTL tau spreading. Despite highest tau in the amygdala, EC connectivity was the best predictor of MTL tau patterns, suggesting that the EC is a key source for within MTL tau spreading. This can be critical to assess EC connectivity as a potential treatment target to prevent cortical tau spreading and thus neurodegeneration and cognitive decline in AD.
MRI Markers for Detecting Accelerated Alzheimer’s Disease after Neurotrauma
Authors: Hua Ning , Minaeva Olga , Parsons Douglas , Moncaster Juliet A , Goldstein Lee E
Published: December 2023

Background

A history of traumatic brain injury (TBI) is linked to an earlier onset of Alzheimer’s disease (AD) (Nemetz et al., 1999). Evidence showed that the more severe the injury, the greater risk of developing AD (Johnson et al.,2010). However, systematic evaluation of in vivo MRI markers in the monitoring of AD progression after trauma is lacking. Here, we investigated the performance of various MRI markers in tracking AD progression after neurotrauma in a mouse model of AD. The following MRI sequences were investigated: dynamic contrast‐enhanced (DCE) MRI, Fluid attenuated inversion recovery (FLAIR) MRI, Quantitative Susceptibility Mapping (QSM) and diffusion MRI.

Method

3xTg‐AD mice (Jackson Laboratory, ME) were bred and maintained at Boston University. Unanesthetized mice were pretreated with a non‐sedating dose of the analgesic buprenorphine (0.2mg/kg, i.p.) prior to TBI. Male and female 3xTg‐AD mice were subjected to left‐lateral closed‐head impact injury at 10‐12 weeks of age as described in our previous work (Tagge et al., 2018). MRI data were acquired at 1 day, 3 days, 1 month and 3 months post TBI. DCE‐MRI was analyzed using in‐house software programmed in Matlab (Mathworks, MA). The volume of white matter hyperintensity was measured using manual contours in ImageJ (NIH). QSM data was analyzed using JHU/KKI QSM Toolbox (Li et al, 2019). Diffusion MRS was analyzed in DSI Studio (http://dsistudio.labsolver.org). Age, gender matched 3xTg‐AD mice without TBI were used as controls.

Result

Increased blood‐brain permeability was detected by DCE‐MRI and changes of white matter susceptibility detected by QSM were observed in the subacute phase (1‐3 days) post TBI. Accelerated development of white matter hyperintensity was observed as early as 1 month post TBI.

Conclusion

MRI markers provide valuable measures of the integrities of blood‐brain barrier and white matter after neurotrauma in vivo, and have the potential to facilitate the management of neurotrauma subjects with a risk of accelerated AD development.
Use of cerebrospinal fluid biomarkers for accurate diagnosis of Alzheimer’s disease in a tertiary care memory center
Authors: Natalya Yarovinsky , Tanne David , Ben‐Hayun Rachel , Hadad Rafi , Levavi Michal , Kogan Olga , Raya Maison Abu , Aharon‐Peretz Judith
Published: December 2023

Background

Accurate clinical‐biological diagnosis of dementia and of Alzheimer’s disease (AD) is important for exclusion of treatable modifiable conditions, to differentiate AD from conditions with similar clinical manifestations, and for consideration of novel disease‐modifying therapeutic agents. Recently, it has become possible to measure protein biomarkers that reflect the pathology of AD. Our aim was to examine our initial experience of running a “cognitive” CSF biomarker service and bank at our institute.

Method

The service operates since June 2020. All subjects underwent physical, neurological and cognitive evaluation, imaging and laboratory work‐up. Consenting patients presenting at young age or with atypical or unclear manifestations of cognitive and/or behavioral deterioration underwent lumbar puncture for CSF examination, tailored according to the clinical differential diagnosis [cells, protein, glucose, chloride, cytology, AD biomarkers‐ total tau (tTau), 181‐phosphorylated tau (pTau181), amyloid‐β42 (Aβ42)]. When appropriate, antibody analysis and microbiological studies were added.

Result

AD biomarkers results were available for 63 subjects presenting with cognitive/behavioral impairment, mean age 59 (range 31‐78) years, 34 (54%) were men. Mean MMSE score was 21/30 (range 6‐30), mean MoCA score was 18/30 (range 6‐28). Pre CSF analysis, 27 (43%) subjects were clinically diagnosed with possible AD (CDAD) and 36 (57%) with clinically diagnosed possible non‐AD (CDNAD) (FTD, LBD, CBD, vascular disease, autoimmune encephalopathy, unclear etiology). In our sample 28 (44%) were biomarkers positive for AD. Among 27 subjects with CDAD in 5 AD was excluded and among 36 with CDNAD 6 were biomarker positive AD (clinical sensitivity 78%, false positive 18.5%, false negative 16.6%).

Conclusion

Our study emphasizes the added value of biomarker supported diagnosis in subjects with cognitive/behavioral impairment, to avoid incorrectly labeling AD or misdiagnosis and for disclosure recommendation in the era of disease‐modifying therapies.
Investigating phenotypic modifiers of Alzheimer’s disease utilizing cellular and transcriptomic signatures of PSEN1 mutation carriers
Authors: Pottier Cyril P , Lincoln Sarah J. , Boon Baayla D.C. , Wickland Daniel P. , Rothberg Darren M. , DeTure Michael , Ertekin‐Taner Nilufer , Graff‐Radford Neill R , Dickson Dennis W. , Murray Melissa E.
Published: December 2023

Background

PSEN1 mutations are the most common genetic cause for autosomal dominant forms of Alzheimer’s disease patients with an age at onset below 65 years (ADAD). Even though all PSEN1 mutations lead to an increased Aβ processing and production, there is a large variability in phenotypic presentation even in individuals with the same mutation. Splicing isoforms in AD genes are reported to be associated with the disease, however little is known about correlation between splicing pattern and phenotypic presentation (e.g. variable age onset). We hypothesized that cellular and transcriptomic alterations differ amongst patients with different phenotypic presentation. In a group of 8 ADAD with the same PSEN1 p.G206A mutation, we investigate the association between brain cell type proportion, gene expression, and splicing isoforms with age at onset, Aβ plaque type and severity of AD neuropathologic change.

Methods

Eight Hispanic ADAD cases with PSEN1 p.G206A mutation were identified in the Mayo Clinic brain bank housed in Jacksonville, FL. Standard (immuno)histochemical stains, including H&E and thioflavin S, were performed to evaluate AD neuropathologic change. We focused on distinct Aβ plaque types in an association cortex (inferior parietal gyrus) and primary cortex (motor). We carried‐out single‐nuclei short and long read RNA sequencing on both brain regions. We will stratify our transcriptomic analyses based on neuropathology and phenotypic presentation.

Results

We observed large variability in age at onset (median = 53 years; range: 42‐59 years). Furthermore, disease duration was reportedly variable (median = 10 years; range: 8‐17). All cases had a Braak tangle stage VI and Thal amyloid phase 5. Only 3 patients carried at least one APOE*ε4 risk allele, suggesting that its effect was minimal on ages at onset and death. Different plaque types were observed for short versus long survivors. In short survivors, plaques were predominantly fibrillar with an eosinophilic radial component, whereas in longer survivors predominantly cored plaques were observed.

Conclusion

Large phenotypic variability within patients with the same mutation is observed suggesting the involvement of yet to be discovered genetic modifiers. Understanding cellular transcriptomic events in ADAD is essential to future development of therapeutic approaches and development of biomarkers.
Differentiation of clinically diagnosed patients with aMCI and dementia from cognitively unimpaired older adults using plasma and serum p‐tau 181 and NfL
Authors: Jurasova Vanesa , Veverova Katerina , Angelucci Francesco , Katonova Alzbeta , Vyhnalek Martin , Andel Ross , Hort Jakub
Published: December 2023

Background

Blood‐based biomarkers give the possibility of having a less invasive, more acceptable to patients, and cost‐ and time‐efficient screening tool. Therefore, blood‐based biomarkers represent an ideal addition to cerebrospinal fluid (CSF) and neuroimaging biomarkers. Standard examination of neurocognitive disorders, such as lumbar punction or brain PET scan, cannot be performed within general practice. Given the high prevalence of these diseases, alternatives such as blood‐based biomarkers would represent a significant advance. The aim of this study was to investigate whether levels of p‐tau 181 and neurofilament light chain (NfL) in serum and plasma can differentiate cognitively unimpaired (CU) elderly individuals from individuals in the stage of aMCI and dementia.

Method

A total of 75 biomarker‐defined individuals from the Czech Brain Aging Study were recruited for the study, including the CU, individuals in the aMCI stage, and individuals in the stage of dementia syndrome with various etiology (AD, FTLD or LBD). Commercial ELISA kits were used for the assessment of standard biomarkers from CSF (Aß42, Aß40, pTau, tTau). Plasma and serum samples were analyzed using a Quanterix SR‐X analyzer with Simoa technology. Receiver operating characteristic analyses of the concentrations of p‐tau 181 and NfL in plasma and serum were performed using the R statistical software and GraphPad Prism.

Result

Plasma NfL, AUC 0.9861 (95% CI, 0.9439 to 1.000), and serum NfL with AUC 0.9583 (95% CI, 0.8774 to 1.000) differentiated aMCI and dementia from CU with high predictive accuracy. The results were significant for plasma p‐tau 181 too with AUC 0.7869 (95% CI, 0.6474 to 0.9265), along with serum p‐tau 181 with AUC 0.7623 (95% CI, 0.6292 to 0.8954).

Conclusion

Plasma and serum p‐tau 181 and NfL may be potentially useful and cost‐effective biomarkers for differentiating cognitively unimpaired elderly individuals from those at aMCI and dementia stages in general health care settings.
Longitudinal changes in blood flow, vessel pulsatility, and trans‐capillary pulse wave delay in small vessel disease and amyloid biomarker positive
Authors: Rivera‐Rivera Leonardo A. , Du Lianlian , Langhough Rebecca E , Jonaitis Erin M. , Betthauser Tobey J , Burghy Cory , Cody Karly Alex , Chin Nathaniel A. , Eisenmenger Laura B. , Johnson Sterling C , Johnson Kevin M.
Published: December 2023

Background

This work characterized longitudinal changes in cerebrovascular health in humans with and without presence of small vessel disease (SVD) and amyloid‐β using different neuroimaging techniques.

Method

Participants (n = 41) were biomarker characterized into three groups: amyloid and SVD negative (A‐V‐; “control”), SVD positive (A‐V+), and amyloid positive (A+V‐). All were cognitively unimpaired except two participants clinically diagnosed with MCI (A‐V+) and dementia (A+V‐) (Table 1). MRI:
Vascular imaging: Whole‐brain 4D‐Flow data were acquired to characterize cerebrovascular health. Two MRI time‐points were used to establish 4D‐Flow‐based longitudinal changes. Measurements were extracted from intracranial arteries and veins and included blood flow, vessel pulsatility index, and trans‐capillary pulse wave delay (TPWD). TPWD was defined as the time shift between arterial and venous cardiac waveforms. Structural imaging: TIV‐normalized WMH volumes were segmented from T2‐FLAIR images and used as surrogate for SVD. V+/‐ thresholds were determined from Gaussian Mixture Model on 930 participants. PET: Amyloid‐β burden was assessed using 11C‐PiB PET imaging. Amyloid positivity was established as mean cortical PiB DVR >1.16. Vascular changes were assessed using Kruskal‐Wallis followed by multiple comparisons (P<0.05 significance).

Result

After ∼4.5 years, middle cerebral arteries (MCAs) blood flow decreased significantly more in amyloid than SVD groups, while vessel pulsatility increased significantly more in amyloid compared to SVD (Fig.1). TPWD shortened significantly in SVD compared to amyloid and control groups. All groups showed a decreased in blood flow, increased in vessel pulsatility and shortening of TPWD with time. At the time of the last MRI visit, MCAs blood flow was somewhat higher in SVD compared to amyloid and control groups, but not significantly (Fig.2). Vessel pulsatility was similar between groups, yet slightly higher in SVD and amyloid groups. TPWD was significantly shorter in SVD compared to the amyloid group.

Conclusion

This work demonstrates the feasibility to measure longitudinal cerebrovascular changes using 4D‐Flow MRI in the context of SVD and AD biomarker positive groups. Preliminary results indicate 4D‐Flow‐based vascular markers can detect differences between SVD and amyloid groups both longitudinally and cross‐sectionally. Cerebrovascular changes in A+ suggest decreased metabolism and increased macro‐vessel stiffness, while findings in SVD positive supports stiffness of the micro‐circulation and capillaries.
Associations of GFAP, NfL, Aβ42/40, and pTau231 with global cognition in LEADS
Authors: Kostadinova Ralitsa V. , Hammers Dustin B. , Logan Paige E. , Manchella Mohit K. , Nemes Sára , Fagan Anne M. , Foroud Tatiana M. , Blennow Kaj , Zetterberg Henrik , Kramer Joel H. , Aisen Paul S. S , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Brad C. , Apostolova Liana G. , Dage Jeff L.
Published: December 2023

Background

Historically, Alzheimer’s disease (AD) biomarkers have been used to identify the presence of pathology and have been shown to change well ahead of symptom onset. While previous research has evaluated plasma pTau231 and its associations with cognition, little to none of this research has focused on early‐onset AD (EOAD) populations. Here we investigate how select plasma biomarkers are associated with global cognitive measures in early‐onset cognitive impairment.

Method

The current sample included 367 Longitudinal Early‐Onset AD Study (LEADS) participants (aged 41 to 65) categorized as amyloid PET‐positive EOAD, amyloid PET‐negative EOnonAD, or cognitively normal (CN). Each participant had baseline global cognitive (Mini‐Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA], Clinical Dementia Rating Scale sum of boxes [CDR‐SB], and ADAS‐Cog13) and plasma biomarker assessments (Simoa‐HDx N4PE kit: Aβ42/40, phosphorylated Tau [pTau231], Neurofilament light protein [NfL], and glial fibrillary acidic protein [GFAP]). Partial correlations were used to check for associations with cognitive performance controlling for age, sex, and years of education. Fisher r‐to‐z transformations were conducted to compare the performance across diagnostic groups.

Result

Partial correlations in the pooled sample showed moderate associations between cognition and plasma pTau231, GFAP and NfL (r = .42‐.50, p<.001) and weaker associations with Aβ42/40 (r = .25‐.33, p<.001). When split into diagnostic groups, the NfL and GFAP correlations were significant in both EOAD and EOnonAD, but not CN. The pTau231 correlations were significant only in EOAD. Aβ42/40 correlations were non‐significant within specific diagnostic groups. No differences were observed in the magnitude of the cognitive and biomarker associations between EOAD and EOnonAD samples (ps>.05).

Conclusion

As expected, the neurodegenerative biomarkers pTau231 and NfL showed stronger association with cognition compared to the marker for brain amyloidosis (Aβ42/40). The nonspecific markers for neurodegeneration (NfL) and brain astrogliosis (GFAP) showed associations in both EOAD and EOnonAD while the markers specific to AD were only significant in EOAD. Plasma biomarkers show great promise for AD diagnosis and monitoring.
Transcriptomic Profiling Across Age, APOE and Sex for Models of Alzheimer’s Disease at a Single Cell Resolution
Authors: Li Yaqiao , Hao Yanxia , Yoon Seo Yeon , Grone Brian , Ding Leonardo , Blumenfeld Jessica , Oskotsky Tomiko , Huang Yadong , Sirota Marina
Published: December 2023

Background

Advanced age, apolipoprotein E4(APOE4), and female sex are well‐established risk factors for Alzheimer’s Disease(AD). Almost two‐thirds of people with AD are women. The APOE4 genotype, the strongest genetic risk factor for AD, is associated with higher AD risk in women than in men between ages 55 to 70. We propose to study the interplay between these risk factors by analyzing single‐nucleus RNA‐sequencing(snRNA‐seq) data of the hippocampus of human APOE4 and APOE3 knock‐in(KI) female and male mice across age.

Methods

A sex‐balanced cohort of APOE3‐KI and APOE4‐KI homozygous mice were sacrificed at 6 (young), 12 (adult), and 18 (old) months of age(Figure1A). Single nuclei were prepared from the hippocampus from each mouse and sequenced. Demultiplexed fastq files were aligned to a custom reference genome mm10‐1.2.0, using Cellranger v2.0.1. Quality assurance, count normalization, clustering, cell type identification, and differentially expressed gene(DEG) analysis were performed using Seurat4.0.

Results

Our dataset consists of a total of 527,395 cells covering 27,153 genes. A total of 36 cell clusters were determined with six major brain cell types including astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, and excitatory and inhibitory neurons (Figure1B). We investigated the abundance of each cell type and found that cellular composition is consistent across ages, APOE genotypes, and sexes for all cell types except astrocytes. Astrocyte abundance is significantly higher in old females compared to old males(padj = 0.025, Tukey’s multiple comparison test) and in APOE4 young males compared to APOE3 young males (padj = 0.042)(Figure1C).

Sex and age stratified differential gene expression analysis comparing APOE4 versus APOE3 astrocytes reveals many shared DEGs between young and adult males but not with old males, while females have few consistent DEGs across the three age groups(Figure1D). We identified several DEGs associated with plasma membrane assembling and post‐synaptic transmission and signaling that are upregulated in APOE4 old females versus APOE3 old females while downregulated in APOE4 young females, young and adult male compared to their APOE3 counterparts.

Conclusion

We identify clear interplay between age, APOE genotype, and sex in mouse models of AD and investigate the interaction and convergence of these risk factors at a single cell resolution.
Single‐nuclei transcriptomic identifies type‐specific neuronal cell vulnerability and non‐neuronal molecular changes in Amnestic and Logopenic Variant Primary Progressive Aphasia Alzheimer’s disease
Authors: Pereira Felipe Luiz , Lew Caroline , Li Song Hua , Soloviev Alexander , Spina Salvatore , Seeley William W. , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Newell Kathy L , Ghetti Bernardino Francesco , Murray Melissa E. , Grinberg Lea T.
Published: December 2023

Background

Individuals with neuropathological criteria for Alzheimer’s disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1. In contrast, logopenic variant primary progressive aphasia (lvPPA) cases have a higher tau burden in the superior temporal gyrus (STG). Single‐cell technology enables investigations on the molecular basis of differential neuronal vulnerability in AD. Therefore, we investigated factors underlying selective vulnerability using brain samples from individuals with pure AD with different clinical manifestations.

Method

snRNA Sequencing using the Chromium Single Cell 3′ (10X Genomics, USA) on nuclei cells extracted from the CA1 sector and posterior STG of postmortem brain tissue of 24 individuals either meeting pathological criteria for AD (A3B3C3; 12 amnestic and eight lvPPA) and healthy controls (A≤1B≤1C≤1; n = 4) (Table 1, Fig. 1A/B). Bioinformatics analyses were conducted using Cell Ranger and R software. Comparisons between cell subpopulations were conducted with Wald statistical test, and p‐values < .05 were considered significant.

Result

After quality control, we recovered 98,180 nuclei with a mean of 2,130 genes per nuclei. Upon cross‐sample alignment and t‐stochastic neighborhood embedding clustering (Fig. 1C), we found 21 excitatory neuronal subpopulations (Exc‐sub) in CA1 and 26 in STG, and 22 and 27 inhibitory neuronal subpopulations (Inh‐sub) in CA1 and STG, respectively; 16 astrocytes subpopulations in both areas and 20 microglia subpopulations in CA1 and 17 in STG (Fig. 2). One STG Exc‐sub, expressing CUX2 and LAMP5 genes showed vulnerability in lvPPA patients. Also, one STG Inh‐sub, expressing the ADARB2 gene, showed vulnerability for all AD patients. Furthermore, two astrocytes subpopulations (one in both areas and one in STG) and three STG microglia subpopulations showed proportional composition changes comparing AD patients and HC.

Conclusion

Our preliminary study identified a vulnerable population of excitatory neurons related to lvPPA. We are conducting validation studies using quantitative pathology to confirm these results. Furthermore, analysis of a higher number of cases is ongoing and will continue to inform on factors associated with neuronal vulnerability.
Amyloid beta (1‐42) peptide suppression of macroscopic homomeric Kv1.2 and heteromeric Kv1.1/1.2 currents is calcium‐ and calcineurin‐dependent: Implications for Alzheimer’s disease
Authors: Jamshidi Dina , DeBoeuf Kristi , Farley Joseph
Published: December 2023

Background

The roles of Aβ in the pathogenesis of Alzheimer ’s disease (AD) include disruption of: 1) Ca2+ homeostasis, 2) synaptic communication, and 3) learning‐ and memory‐related synaptic plasticity and neuronal excitability mechanisms. Exactly how these abnormalities arise is incompletely understood. Our lab has focused on the involvement of voltage‐gated potassium channels (VGKCs) in several of these processes. VGKCs are activated during an action potential and regulate Ca2+ influx. Inhibition of VGKCs can lead to synapto‐ and neuro‐toxicity. Kv1.x family subunits can assemble as functional homomers or select heteromers; Kv1.1 is often co‐expressed with Kv1.2. We’ve previously found that: 1) Aβ peptides suppress both Kv1.1 and Kv1.2 homomeric channel activities, as well as Kv1.1/1.2 heteromeric activity, 2) Aβ suppression of Kv1.1 was partially (∼ 50%) dependent on intracellular calcium [Ca2+]i, being reduced by exposure of cells to the calcium chelator BAPTA‐AM, as well as by cyclosporine A (CsA), an inhibitor of PP2B/calcineurin (CaN). Here we asked if Aβ‐suppression of Kv1.2 and Kv1.1/1.2 currents was similarly dependent on [Ca2+]i, and CaN in the case of Kv1.2.

Methods

Stage V/VI Xenopus laevis oocytes from Ecocyte Bioscience (Austin, TX) were injected with Kv1.2 cRNA for homomeric expression. Heteromeric expression was produced by co‐injection of Kv1.1 and 1.2 cRNAs. Macroscopic currents were measured 2‐3 days later using TEVC.

Results

Bath application (1 μM) of Aβ(1‐42) produced significant suppression of Kv1.2 (46%, n = 10) and Kv1.1/1.2 (41%, n = 8), 30 min following Aβ application. These suppressions were significantly greater than those of DMSO‐exposed control cells: 2% for Kv1.2 (n = 15), p< .002; 11% (n = 7) for Kv1.1/1.2, p <.02. BAPTA‐AM treatment (n = 9; 50 μM for 1 hr, followed by 3X wash) greatly reduced Aβ‐suppression of Kv1.2 current (from 46% to 18%, p < .002). CsA exposure (n = 6, 10 μM for 12 hr) completely blocked Aβ suppression (from 46% to ‐4%, p < .0001). BAPTA‐AM (n = 5) also significantly attenuated suppression of Kv1.1/1.2 current (from 41% to 10%, p < .02).

Conclusion

Our results suggest that Aβ‐disruption of [Ca2+]i can lead to suppression of Kv1.1 and 1.2 activities through CaN activation, and thereby contribute to hyperexcitabilty phenotypes in AD.
Locus coeruleus MRI contrast is associated with Complement factor C3b in cerebrospinal fluid
Authors: Neumann Laura , Hayek Dayana , Sarkar Mousumi , Heinzinger Nils , Hämmerer Dorothea , Schneider Anja , Fließbach Klaus , Teipel Stefan , Spottke Annika , Brosseron Frederic , Jessen Frank , Düzel Emrah , Heneka Michael T. , Maass Anne , Betts Matthew
Published: December 2023

Background

Degeneration of the Locus coeruleus (LC) is associated with Alzheimer’s disease (AD) pathology and cognitive decline. Recent evidence from animal models indicates that this relationship may be mediated by neuroinflammation. Here we examined how LC MRI contrast is related to CSF biomarkers of neuroinflammation in humans.

Method

The LC as well as the Substantia nigra (SN) were visualized and segmented using neuromelanin‐sensitive T1‐weighted FLASH‐MRI images acquired at 3T and MRI contrast values were calculated as previously described (Betts et al., 2019b). A cohort of 65 participants with MRI contrast and CSF data from the DZNE longitudinal cognitive impairment and dementia (DELCODE) study (20 HC, 22 SCD, 16 MCI, 7 AD dementia; 53.8% female) were included in the analyses. We performed correlational analyses to test for associations between LC and SN contrast with a panel of 4 Principal Components (PC) created from a Principial Component Analysis on 16 individual inflammation‐related CSF biomarkers (Fig. 1). Both bivariate and partial correlation analyses were performed between PCs and MRI contrast values using sex, age, site and CSF levels of AD pathology, namely Aß42/40‐ratio and phosphorylated tau, as covariates (see Fig. 2).

Result

We found a significant positive association between LC MRI contrast and the inflammatory component PC4 including the proinflammatory complement factors C3 and C3b across the entire sample (r = 0.365, p = 0.003). Additional post‐hoc correlational analyses showed this association with LC MRI contrast was mainly due to a correlation with C3b (r = 0.349, p = 0.004). A significant positive association was still observed (r = 0.347, p = 0.008) in a subgroup of individuals comprising healthy older adults and individuals with a risk of AD dementia (HC, SCD and MCI) as shown in Fig. 2. In contrast, no significant associations between SN MRI contrast and any neurodegenerative or inflammatory measure were observed indicating effects were specific to the LC.

Conclusion

The results demonstrate LC MRI contrast is associated with complement factors in CSF, in particular complement factor C3b in healthy older adults and individuals with a risk of AD dementia. Further analyses are required to determine if elevated complement factors may predict degeneration of the LC and subsequent cognitive decline.
Exploring inflammation‐related protein expression and its relationship with TSPO PET in Alzheimer
Authors: Benedet Andrea Lessa , Antônio De Bastiani Marco , Brum Wagner Scheeren , Pola Ilaria , Rahmouni Nesrine , Tissot Cécile , Therriault Joseph , Pascoal Tharick A. , Blennow Kaj , Zetterberg Henrik , Zimmer Eduardo R , Ashton Nicholas J. , Rosa‐Neto Pedro
Published: December 2023

Background

Developing evidence highlight the importance of neuroinflammation in the progression of Alzheimer’s disease (AD) pathophysiology. It has been shown that inflammatory mechanisms affect both amyloid and tau deposition in the brain. However, given the complexity of the immune cascades and the unknown interactions between the peripheral and central nervous systems in the disease, it has been challenging to identify biomarkers that reflect a given inflammatory state in this context. Thus we aim here to further explore inflammation‐related proteins for potential biomarker utility in AD.

Method

Participants from the TRIAD cohort incorporating within the AD spectrum, and with available TSPO PET ([11C]PBR28) imaging data, had their cerebrospinal fluid (CSF) (n = 100) and plasma (n = 169) samples analyzed using Proximity Extension Assay (PEA) technology targeting 368 inflammation‐related proteins (Olink). LIMMA models evaluated the differential protein expression according to TSPO PET status (positivity attributed by 3 SD above the mean ROI‐SUVR of young participants), adjusting for age and brain amyloid load (PET). Associations were FDR corrected for multiple comparisons. Gene ontology (GO) was used for enrichment analysis on relevant results.

Result

Preliminary results identified several proteins that are in higher concentration in the CSF of TSPO positive in comparison with TSPO negative participants (Figure 1). The enrichment analysis (Figure 2) unveiled terms related with cytokine and chemokine signaling pathways as well as with the regulation of mitogen‐activated protein kinase (MAPK) cascade, which is an interesting finding given the frequently reported association between MAPK cascade and AD.

Conclusion

The initial assessment of the data revealed encouraging preliminary findings. However, more detailed analyses will be performed in both CSF and plasma to further investigate potential biomarkers and how they coverage between amyloid and tau deposition.
Home Cognitive Stimulation Activity in Thai Patients with Mild Cognitive Impairment and Mild Dementia
Authors: Rattanabannakit Chatchawan , Jinatongthai Wirarat , Thana‐Udom Kitikan , Senanarong Vorapun
Published: December 2023

Background

This study aims to investigate the characteristics of home cognitive stimulation activities for Thai patients with mild cognitive impairment (MCI) and mild dementia.

Method

A cross‐sectional, questionnaire‐based study was conducted on Thai patients with the diagnosis of MCI and mild dementia. Patients’ characteristics, ability to use IT device or telecommunication technology, and home cognitive stimulation activities were collected. All activities were divided and calculated into sub‐scores of cognitive, religion‐related, and physical activities according to its frequency.

Result

There were 157 patients with a mean age of 76.2±7.9 years, 65.6% were female. 46.5% were diagnosed with MCI, and 53.5% with mild dementia. 47.1% had a graduate or higher degree. The mean MoCA score was 20.8±4.7. 51% of patients were able to use IT devices (smartphones, tablets, or computers). Patients with MCI were able to use IT devices more than patients with mild dementia (79.5% vs. 26.2%, p<0.001). As many as 29.3% of them were able to use a teleconference technology such as video call or Zoom application. Among the 25 home cognitive stimulation activities collected (excluding watching television), only 7 activities that participants ≥30% rated as frequent (≥3 days per week) were doing chores (63.1%), working out (51.0%), listening to music (50.3%), praying (43.3%), reading (38.2%), cooking (33.1%), and texting via mobile (31.8%). The activities they engaged the least were playing cards, board games, doing crossword puzzles, and drawing (rated as frequent 0.6%). Compared with patients with mild dementia, patients with MCI exhibited higher scores in all sub‐scores (all p<0.01). The cognitive activity sub‐score had an inverse correlation with the patient’s age and geriatric depression scale (r = ‐0.340 and ‐0.171, both p<0.05). Patients who were able to use smart devices or video call/conference applications were found to be more likely to have higher scores in every activity sub‐scores (all p<0.01).

Conclusion

In this study, Thai patients had limited home activities, particularly those with dementia. However, about half of them were able to use IT devices, which may correlate with a higher cognitive activity score. Thai individuals with MCI or mild dementia may have room for improvement in the cognitive intervention delivered at home via teleconference.
Clinical value of CSF TMEM106B in familial and sporadic frontotemporal lobar degeneration
Authors: Rojas Julio C. , Cobigo Yann , Wise Amy B. , Li Jingyao , Loureiro Joseph , Worringer Katie , Heuer Hilary W. , Ljubenkov Peter A. , VandeVrede Lawren , Staffaroni Adam M. , Lago Argentina Lario , Ramos Eliana Marisa , Prudencio Mercedes , Marks Jordan M. , Cook Casey N. , Pernieel Jolien , Rademakers Rosa , Petrucelli Leonard , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. ,   ALLFTD
Published: December 2023

Background

TMEM106B, a lysosomal trafficking protein, is an important genetic susceptibility risk factor for frontotemporal lobar degeneration (FTLD). In GRN mutation carriers, minor allele homozygosity in the TMEM106B rs1990622 SNP modulates the risk of FTLD. TMEM106B is often the main component of amyloid fibrils in FTLD with TDP43 aggregates. TMEM106B has been quantified in human brain specimens, but its role as a fluid biomarker is unknown. Here, we investigate the clinical value of CSF TMEM106B in FTLD.

Methods

CSF TMEM106B was quantified with SOMAmer proteomics (v3.0, SomaLogic®) in an original cohort of C9orf72, GRN and MAPT symptomatic and asymptomatic mutation carriers and family non‐carrier controls, recruited through ALLFTD (n = 182), and a validation cohort of sporadic neuropathology‐confirmed FTLD‐tau and FTLD‐TDP43, clinically‐diagnosed progressive supranuclear palsy – Richardson syndrome (PSP‐RS) and age‐matched controls (n = 96). CSF TMEM106B was correlated with disease severity, measured by the Frontotemporal Lobar Degeneration module global scores (CDR+NACC/FTLD); brain volume, measured with Bayesian linear mixed‐effect modeling, using age, sex and total‐intracranial volume‐corrected permutations with threshold‐free cluster enhancement; and CSF neurofilament light chain (NfL) measured with Simoa. TMEM106B SOMAmer specificity was validated in cell culture overexpression systems and human brain specimens with high TMEM106B burden.

Results

In both cohorts, there were no differences in CSF TMEM106B by sex, phenotype or neuropathological diagnosis, except for lower levels in PSP‐RS compared to controls (‐0.31 Log2‐fold change, p < 0.001). CSF TMEM106B did not correlate with age. Regardless of disease‐causing mutation, lower CSF TMEM106B was associated with worse disease severity (Figure 1 and 2). CSF TMEM106B was lower in homozygous TMEM106B rs1990622 protective allelein C9orf2 and MAPT, but not in GRN mutation carriers (Figures 3). CSF TMEM106B showed a trend for inverse correlation with NfL in the whole sample (r = ‐0.135, p = 0.052), and correlated positively with left frontal volume in symptomatic FTLD mutation gene carriers (p < 0.05).

Conclusion

CSF TMEM106B is quantifiable in CSF in vivo. CSF TMEM106B levels are affected by an interaction of disease severity and FTLD and TMEM106B genotypes. Further work is needed to determine its value as a clinical biomarker.
Longitudinal associations of depression and diabetes with Alzheimer’s disease and related dementias risk among American Indian and Alaska Native people
Authors: Goins R. Turner
Published: December 2023

Background

Alzheimer’s disease and related dementias (ADRD) research worldwide indicate that it is more common in indigenous than in non‐indigenous populations. The increased risk for ADRD among indigenous people may be partially due to the population’s high rates of depression and diabetes. Thus, we examined the relationship of depression and diabetes, alone and together, with incident ADRD in a large sample of American Indian and Alaska Native people (AI/ANs).

Method

We used data from the Indian Health Service (IHS) Improving Health Care Delivery Data Project with a sample of 65,801 AI/ANs aged ≥ 45 years. The IHS Data Project includes data for a purposeful sample of AI/ANs who lived in 15 IHS service units, which are IHS geographic classifications located throughout the United States. We used Cox proportional hazard models to estimate associations between ADRD risk and baseline depression and diabetes.

Result

We found that 2.3% of our sample received an ADRD diagnosis during FY2010‐13. Compared to persons with neither depression nor diabetes, unadjusted models indicated that those who had both depression and diabetes had twice the risk of developing ADRD (Hazard Ratio (HR) = 2.02, 95% CI = 1.72‐2.37). The unadjusted risk among those with depression only was 77% higher (HR = 1.77, 95% CI = 1.50‐2.08). Adjusted analyses showed that the HR for those with depression and diabetes was 1.82 (95% CI = 1.53‐2.16) and those with depression only had a hazard ratio of 1.70 (95% CI = 1.44‐2.00) for ADRD. The association between depression and diabetes and depression only with ADRD risk was stronger for persons aged 45 to 64 years compared to persons aged ≥ 65 years. In the adjusted models, we did not find a relationship between only having diabetes and ADRD risk.

Conclusion

Our findings suggest that depression by itself and depression with diabetes increases the risk of ADRD in AI/ANs aged ≥ 45 years. In the future, ensuring clinical and behavioral services for AI/ANs include regular mental health screening and depression treatment might help decrease ADRD risk. Such efforts may also focus on middle‐aged persons.
Multi‐channel segmentation allows simultaneous estimation of classic tissue compartments, WMH and enlarged perivascular spaces
Authors: Gunter Jeffrey L. , Przybelski Scott A. , Sparrman Kohl Johnson , Cogswell Petrice M , Radford Jonathan Graff , Knopman David S. , Petersen Ronald C. , Vemuri Prashanthi , Jack Clifford R. , Persons Benjamin
Published: December 2023

Background

Large neuroimaging studies like ADNI‐4 now include T1‐weighted, T2‐weighted and FLAIR images at isotropic1mm resolution for investigation of both neurodegenerative and cerebrovascular disease. These three input types allow segmentation of GM, WM, DeepGM, WMH, and CSF compartments. Additionally, this supports automated assessment of enlarged perivascular spaces (PVS). Our objective was to propose a unified framework for segmentation of intracranial classes and PVS while reducing human effort.

Methods

FLAIR and T2‐weighted images are aligned to the T1‐weighted image.. Standard SPM12 unified segmentation using all three input images establishes deformations between subject and template space and bias field corrections. Extended tissue priors including deep GM are deformed into subject space. Adding mean intensities from high probability deep GM voxels as seeds and using the extended prior set, segmentation is re‐started, refining model parameters, deformations and bias‐field estimates. The procedure repeats, adding a WMH channel, resulting in a segmentation including GM, WM, CSF, deep GM, WMH and nuisance classes. Frangi filters are applied to the T1‐ and T2‐ weighted images. Filter response images are smoothed, averaged, masked and inserted in place of the CSF prior. Probability maps of vessel‐like shapes with CSF‐like contrast are estimated to identify PVS. Visual grading was also performed for comparison.

Results

The method was applied to 300 participants. Visual quality control found two instances of poor WMH over‐segmentation. Perivascular space maps were all visually reasonable. Standard segmentation classes were visibly superior to single T1‐based segmentation. Figures 1,2 present examples. Pearson correlations of PVS fractional volume with multiple human raters’ PVS counts in CSO/CR was over 0.7 in a subset of 125 participants (Figure 3).

Conclusion

Modern dementia protocols include high‐resolution T1‐weighted, T2‐weighted, and FLAIR images that can be used together as inputs to extend probabilistic segmentation adding deep grey and WMH classes with automated PVS assessment.
Defining research engagement with African American participants in Alzheimer’s disease research studies: A qualitative study
Authors: Romano Raymond R , Full Kelsie , Velez Marina , Williams Tasha , Cowley Pam , Cambronero Francis E , Jefferson Angela L.
Published: December 2023

Background

Diverse recruitment of racial and ethnic groups affected by Alzheimer’s disease (AD) into research is an important public health priority. Black/African American older adults are more likely to develop AD compared to White older adults; however, representation of Black/African American individuals in AD research studies is estimated to be as low as 2.5 percent. Improved engagement with underrepresented communities is essential to increasing representation. Here, we define a theory of research engagement from a grounded theory approach in collaboration with Black/African American participants enrolled in two ongoing Alzheimer’s disease cohort studies at Vanderbilt University Medical Center.

Method

Vanderbilt Memory and Aging Project and Tennessee Alzheimer’s Project participants (n = 18, 68±10 years) who self‐identify as Black or African American were invited to participate in focus groups on research engagement. Focus groups were hosted in a community location. Pre‐discussion, participants completed the Measuring Trust in Medical Researchers scale. Each session lasting 90 minutes was moderated by a trained staff member, audio‐recorded, and subsequently transcribed. Data were analyzed following methodology described by Strauss and Corbin (1990, 1998) and modified by Charmaz (2006). Open coding to identify themes was independently conducted by 3 team members, and codes were refined using an iterative process.

Result

The overall mean score of trust in medical research was 43.9±7.4 (range = 36‐59) suggesting a moderate amount of trust. Participants expressed inclusion in the process and experiencing benefits from research as motivators for research engagement. Participants voiced a desire to better understand inclusion and exclusion criteria and an interest in hearing about the cohort and previously used methods of recruitment. Some members communicated the importance of a welcoming and passionate environment as a driver for engagement.

Conclusion

Our initial work defining research engagement identified key concepts important to our local community. Working together with the community to define research engagement helps immerse participants in the research process. These concepts are well established in the literature, and lessons learned from our focus groups will help define a theory of engagement with local context that can be used to evaluate our future activities.