Citations

Patzelt et al. previously characterized dermal-binding autoantibodies using an indirect immunofluorescence (IIF) mosaic assay with cells transfected with p200-laminin β4, laminin-332 or collagen VII subunits among specimens showing a dermal pattern on IIF using salt-split skin (IIF-SSS) and IgG. This study expanded testing to include specimens with either a dermal or mixed pattern on IIF-SSS and demonstrated improved test sensitivity with modified testing methods.

Abstract Aims Glucagon-like peptide-1 receptor agonists (GLP-1RA) reduce cardiovascular risk in patients with Type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease and are recommended in guidelines. We evaluated the real-world effectiveness of GLP-1RA therapy on cardiovascular outcomes in patients with T2D after myocardial infarction (MI) or ischaemic stroke and examined trends and disparities. Methods and results Using nationwide Czech registry data (2015–24), we identified patients with incident nonfatal MI or ischaemic stroke and confirmed T2D. GLP-1RA users—initiating therapy within 12 months post-event—were propensity score matched to non-users. The primary outcome was major adverse cardiovascular events (MACE: nonfatal MI, nonfatal stroke, cardiovascular death); secondary outcomes included individual components and all-cause mortality. GLP-1RA therapy was initiated in only ∼2% of MI and stroke survivors with T2D. Among 126 845 MI survivors, 28 206 had T2D; the matched cohort comprised 2271 patients (401 GLP-1RA; median follow-up 35 months). GLP-1RA use was associated with lower risk of MACE (HR 0.7; 95% CI, 0.52–0.93), all-cause (HR 0.61; 95% CI, 0.47–0.80), and cardiovascular death (HR 0.54; 95% CI, 0.36–0.80). Among 177 115 stroke survivors, 73 750 had T2D; the matched cohort comprised 2235 patients (385 GLP-1RA; median follow-up 27 months). GLP-1RA use was associated with lower risk of MACE (HR 0.71; 95% CI, 0.54–0.94), all-cause (HR 0.59; 95% CI, 0.46–0.76), and cardiovascular death (HR 0.55; 95% CI, 0.37–0.81). Conclusion GLP-1RA therapy after MI or stroke in T2D was associated with substantially lower risks of MACE, cardiovascular, and all-cause death in real-world practice. Utilization remained low, particularly among women and older adults, underscoring the need for broader and more equitable implementation in secondary prevention.

Abstract Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. However, not all patients with t(11;14)(CCND1;IGH) respond to treatment, and some progress early after initial response. To investigate this, we examined 44 whole-genome and whole-exome sequencing data samples from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 patients with MM. The presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired prevenetoclax and postvenetoclax treatment samples, postvenetoclax progression was recurrently driven by the selection of genomic events in the BCL2/MCL1 and RAS pathways and of high-risk features (eg, loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.

Purpose: These consensus guidelines by the American Clinical Neurophysiology Society (ACNS) describe best practices for performing intraoperative Electrocorticography (ioECoG) using subdural or depth electrodes for adult and pediatric population. Methods: A group of ACNS members was convened to develop technical standards for performing ioECoG. PubMed searches were performed to identify pertinent peer-reviewed literature. Sections were assigned to individual authors based on expertise. Consensus was achieved during subsequent group discussions to develop evidence-based recommendations to the extent possible. Recommendations: Communication between the neurosurgical and the neurophysiology teams is essential in verifying and documenting the location of the contacts. Most authors recommend ioECoG recordings of at least 5 and up to 30 minutes in duration to allow for sufficient observation of interictal activity. The anesthesia should be adjusted to allow continuous EEG activity and to minimize the effect on the ioECoG recording during general anesthesia or awake surgery. The surgical procedure and technical report should separate ioECoG recordings to define the irritative zone from ioECoG findings during functional mapping. The neurophysiology physician’s physical presence in the operating room is required in the definition of the services. Conclusion: These consensus guidelines by the ACNS describe best practices for performing intraoperative ECoG based on published literature and expert consensus.

Abstract Background TMEM106B encodes a lysosomal protein and is a genetic susceptibility factor for frontotemporal lobar degeneration (FTLD). Aptamer‐based proteomics quantifies TMEM106B protein levels in CSF. The associations of CSF TMEM106B with measures of disease severity have not been previously evaluated, and the value of CSF TMEM106B as a clinical biomarker is unknown. Method CSF TMEM106B and NfL protein levels were quantified with aptamer‐based proteomics in participants from two independent cohorts: sporadic FTLD with neuropathology‐confirmed FTLD‐tau and FTLD‐TDP, clinically diagnosed PSP‐Richardson Syndrome, and controls (UCSF MAC, n = 95; mean age = 69 ± 6 yrs; 48% female) and familial FTLD comprised of presymptomatic and symptomatic FTLD mutation carriers with family non‐carrier controls (ALLFTD, n = 179; mean age = 49 ± 13 yrs; 53% female). The association between biomarkers and diverse measures of disease severity, including the CDR®+NACC‐FTLD and CDR®+NACC‐FTLD sum of boxes, were determined with linear regressions or mixed linear models. Associations with brain volumes were determined within the framework of voxel‐based morphometry. Result In both cohorts, at baseline, CSF TMEM106B did not differ by sex, age, FTLD phenotype, or CSF NfL. CSF TMEM106B was lower in cases with worse disease severity (Figure 1) and in participants with the protective TMEM106B rs1990622 G/G genotype, regardless of pathological diagnosis or FTLD‐causing mutation. Low CSF TMEM106B was associated with more severe longitudinal worsening in FTLD disease severity (Figure 2), basic and instrumental function, global cognition, executive function, and depression scores. These associations were weaker than those of NfL. Low CSF TMEM106B was associated with low brain volumes in frontal, parietal, and temporal regions (FWE‐corrected p < 0.05) (Figure 3A). CSF NfL negatively correlated (FWE‐corrected p < 0.05) with brain volumes in frontotemporal regions (Figure 3B). Conclusion CSF TMEM106B concentrations are influenced by the TMEM106B rs1990622 genotype, and correlate with disease severity and brain volume in both genetic and sporadic FTLD. Lower levels of CSF TMEM106B correlate with more severe disease and brain atrophy. Disease severity is more strongly associated with CSF NfL, while brain volumes are more strongly associated with CSF TMEM106B. CSF TMEM106B may have value as a biomarker of neurodegeneration in FTLD.

Abstract Background African Americans (AA) are twice as likely to develop dementia than non‐Hispanic Whites but remain underrepresented in Alzheimer's Disease (AD) research. Recent studies have identified AA specific risk factors for AD. Therefore, targeted biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study, we aimed to determine if genetic variants that show association with AD‐risk, plasma transcript or protein levels in AA, may serve as accurate and accessible AD biomarkers. Method In 189 clinically diagnosed AA AD cases and 183 AA cognitively unimpaired (CU) controls, we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants at these loci were tested for association with corresponding plasma transcripts and total tau protein levels previously measured in this cohort using a custom nanoString panel and Simoa assays, respectively. Utilizing phased haplotypes (SHAPEIT4) from target sequencing, we inferred local ancestry (RFMix v2) using five superpopulations from the 1000 Genomes Project as anchors. Subsequently, we tested the association of each ancestry specific allelic dosages with endophenotypes using Tractor. In receiver operating characteristic (ROC) analyses, the most significant e/pQTLs were added sequentially to a base model that included age and sex to identify e/pQTLs that improved the accuracy to correctly classify AD cases and CU controls. Result Of the 5,112 variants that were tested, 70 were nominally associated with AD‐risk and with plasma transcript or protein levels. Seven of these 70 variants also showed nominally significant associations of AD‐risk and transcript levels with either African or East Asian local ancestry. ROC analysis of age, sex, 33 e/pQTLs in APOE , SORL1 , TLR4 , EPHA1 , ABCA7 , CLU , and CR1 , and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE ‐ɛ4 dosage achieved 88.2% area under the curve to discriminate AD vs. CU, a 30.4% improvement over the base model that only included age and sex. Conclusion Plasma transcript levels and e/pQTLs are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.

Abstract Background The rare APOE3 ‐Christchurch ( APOE3Ch ) variant is associated with remarkable protective effects, delaying the age at onset of PSEN1 ‐E280A driven autosomal dominant Alzheimer's disease (AD). While much of the research on APOE3C h has focused on its role in AD, little is known about how this variant impacts APOE biology under non‐disease conditions. Using cortical organoids as a model system, we aim to investigate the fundamental mechanisms by which APOE3Ch alters APOE biology, including its effects on metabolism and cellular interactions, to better understand its unique properties and potential implications for broader applications. Method Cortical organoids were derived from the isogenic neurodegeneration iPSC line series, with either the APOE3 or APOE3Ch genotype. Single‐cell RNA sequencing (scRNA‐seq) was performed on three independent batches of 6‐month‐old cerebral organoids to identify pathways differentially regulated by APOE3Ch. To further investigate APOE lipidation and its effects on lipid metabolism, lipidomics analysis was conducted on 8‐month‐old cerebral organoids, offering additional insights into APOE3Ch ‐specific biological mechanisms. Validation was also carried out using iPSC‐derived astrocytes and neurons to confirm key findings. Result ScRNA‐seq revealed differences in cell populations and astrocyte subtypes between APOE3 and APOE3Ch organoids, with mitochondrial‐related pathways differentially regulated in APOE3Ch cerebral organoids. These findings were validated in iPSC‐derived astrocytes. APOE3Ch iPSC‐derived astrocytes exhibited increased APOE secretion compared to APOE3 . They also demonstrated enhanced mitochondrial function, as evidenced by increased spare respiratory capacity measured by Seahorse stress assays. Furthermore, APOE3Ch astrocytes showed reduced lipid droplet formation following oleic acid treatment. Lipidomics analysis of APOE3Ch cerebral organoids revealed decreased cholesterol ester levels, suggesting alterations in lipid metabolism. Conclusion Our findings provide novel insights into how the APOE3Ch variant alters APOE biology, revealing differences in mitochondrial function and lipid metabolism. The differential regulation of mitochondrial pathways in APOE3Ch cerebral organoids, along with the enhanced mitochondrial capacity and altered lipid metabolism observed in APOE3Ch astrocytes, highlights the unique properties of this variant. These results offer valuable mechanistic understanding that may inform future therapeutic strategies targeting APOE biology, particularly in the context of AD.

Abstract Background Recent technological advances have enhanced the precision of blood‐based multiplex proteomics and their application in Alzheimer's disease. However, these approaches remain underutilized in frontotemporal lobar degeneration (FTLD). Familial FTLD cohorts offer a unique opportunity to study presymptomatic periods of disease that cannot be studied in sporadic cases. We leveraged NUcleic acid Linked Immuno‐Sandwich Assay (NULISAseq) to identify blood‐detectable proteins that change prior to symptom onset in familial FTLD. Method 120 FTLD mutation carriers (40 C9orf72 , 40 GRN , 40 MAPT ) and 40 age and sex‐matched noncarrier controls from the ALLFTD Consortium completed blood draws and clinical assessment. Targeted plasma proteomics was performed via NUcleic acid Linked Immuno‐Sandwich Assay (NULISAseq; 132 proteins). Disease age estimates measuring predicted symptom onset were derived from a validated model incorporating FTLD gene‐specific clinical, neuroimaging, and biomarker data. Mass linear regression models identified disease age ‘thresholds’ where individual proteins significantly diverged between each mutation carrier group and controls. NULISAseq targets were validated against orthogonal assays, specifically Simoa (plasma) and SomaScan (cerebrospinal fluid [CSF]). Result Compared to controls, 14 plasma proteins significantly diverged ( p <.05) in C9orf72 , 24 in GRN , and 13 in MAPT . Beyond NEFL, 10 additional proteins significantly diverged in more than one mutation group, including markers of synaptic function (NPTX2, NPTXR) and vascular integrity (PGF) that deviated prior to estimated symptom onset (disease age range: ‐30 to 0). Proteins with gene‐specific signals included GFAP (increased in GRN at disease age ‐17), ENO2 (decreased in C9orf72 at disease age ‐7), and FLT1 (increased in MAPT at disease age ‐6). Plasma NULISA‐based NEFL and GFAP showed strong concordance when measured via plasma Simoa ( r s>0.88) and were among 38 targets with significant concordance when measured via CSF SomaScan ( r range: 0.16 to 0.75, p s<.05). Conclusion Alterations in plasma protein abundance are measurable in familial FTLD prior to predicted symptom onset. The validity and brain‐based relevance of blood‐detectable NULISA targets is bolstered by the observed convergence with plasma Simoa and CSF SomaScan. Replication of top hits in larger familial and sporadic FTLD sample sizes is warranted to determine generalizability and suitability for clinical trials.

Abstract Background The National Institute on Aging Alzheimer's Disease Family Based Study (NIA‐ AD FBS) is a multi‐site, longitudinal study aimed to be a data and bio sample resource for investigators worldwide. Since its inception in 2002 the FBS goal has been to promote greater cooperation and sharing of clinical and biological resources among researchers. Methods The focus of the Family Based Study (FBS) has been the recruitment of families with at least two affected individuals and a third first degree relative with or without dementia and willing to participate. Participants are from different ethnic backgrounds including Caucasian, African American and Hispanics. The FBS study is actively recruiting both late onset (LOAD) and early onset Alzheimer's Disease (EOAD) families as well as conducting follow up evaluations every two years, approximately. Uniform assessments are completed across all sites and include DNA, Plasma, PaXgene and PBMC samples collection and brain autopsies whenever possible. We conduct both in person and remote evaluations and use the services of a mobile phlebotomy company to collect bio samples. In addition, we’ve created a protocol for genetic testing on the proband for EOAD families where an additional sample is sent to a CLIA approved lab and after genetic counseling, the presence or not of AD related mutations is disclosed to the families. Results To date, this cohort has recruited 1,756 families and acquired data from 9,682 family members. Families are from Caucasian, African Americans and Hispanics ethnic groups. The cohort has longitudinal clinical data, cognitive assessment, family history and bio samples available for sharing. Genotype data includes APOE, GWAS, WES, WGS, brain methylation, RNA sequencing and biomarkers data. Conclusion The NIA‐LOAD FBS study is the largest collection of familial Alzheimer's Disease worldwide and many genetic studies of Alzheimer's disease (AD) have included cases and controls from this dataset. Over 140 publications have used data and/or samples from FBS to address the genetics of Alzheimer's Disease. The enriched resources provided by this cohort are invaluable to the scientific community.