A Nonsynonymous Substitution of Lhx3 Leads to Changes in Body Size in Dogs and Mice.

Lhx3 is a LIM-homeodomain transcription factor that affects body size in mammals by regulating the secretion of pituitary hormones. Akita, Shiba Inu, and Mame Shiba Inu dogs are Japanese native dog breeds that have different body sizes. To determine whether Lhx3 plays a role in the differing body sizes of these three dog breeds, we sequenced the Lhx3 gene in the three breeds, which led to the identification of an SNP in codon 280 (S280N) associated with body size. The allele frequency at this SNP differed significantly between the large Akita and the two kinds of smaller Shiba dogs. To validate the function of this SNP on body size, we introduced this change into the Lhx3 gene of mice. Homozygous mutant mice (S279N+/+) were found to have significantly increased body lengths and weights compared to heterozygous mutant (S279N+/-) and wild-type (S279N-/-) mice several weeks after weaning. These results demonstrate that a nonsynonymous substitution in Lhx3 plays an important role in regulating body size in mammals.

Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.

Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria.

BACKGROUND: Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. OBJECTIVE: The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. METHODS: Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. RESULTS: We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout). CONCLUSIONS: The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer's disease.

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain ( e.g., in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated in vitro - termed Strain A and Strain B - and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinson's Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.

Symptomatic progression of frontotemporal dementia with the TARDBP I383V variant.

We present a longitudinal description of a man with the TARDBP I383V variant of frontotemporal dementia (FTD). His progressive changes in behavior and language resulted in a diagnosis of the right temporal variant of FTD, also called the semantic behavioral variant (sbvFTD). We also present data from a small series of patients with the TARDBP I383V variant who were enrolled in a nationwide FTD research collaboration (ALLFTD). These data support slowly progressive loss of semantic function. While semantic dementia is infrequently considered genetic, the TARDBP I383V variant seems to be an exception. Longitudinal analyses in larger samples are warranted.

A Single-Center Experience with a Shear-Thinning Conformable Embolic.

The purpose of this study was to evaluate the technical success, effectiveness, and safety of transarterial embolization for acute bleeding management with a shear-thinning conformable embolic. This single-center retrospective study evaluated outcomes after embolization using Obsidio conformable embolic (OCE). Technical success was defined as performing transarterial embolization within the target vessel to complete stasis of antegrade flow. Treatment effectiveness was defined as cessation of bleeding for patients. Eleven patients underwent 11 embolization procedures. A total of 16 arteries were embolized. Indications for embolization were spontaneous tumor bleeding (6/11), hematuria (2/11), active duodenal bleeding (1/11), portal hypertensive bleeding (1/11), and rectus sheath hematoma (1/11). The technical success rate was 100%. The median vessel diameter was 2 mm (range, 1-3 mm). There were no adverse events or off-target embolization. OCE demonstrated technical success and treatment effectiveness with a short-term safety profile for transarterial embolization interventions.

C9orf72 repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis.

In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), the presence of secondary motor or cognitive-behavioral symptoms, respectively, is associated with shorter survival. However, factors influencing the risk and hazard of secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with amyotrophic lateral sclerosis (n=172) and behavioral-variant frontotemporal degeneration (n=69). Only individuals who had neuropathological confirmation of a TDP-43 proteinopathy at autopsy or had a C9orf72 repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether they were modified by the presence of a C9orf72 repeat expansion or initial clinical syndrome. Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [1.97-9.14]; p<0.001) and an increased hazard (HR= 4.77 [2.33-9.79], p<0.001) for developing secondary symptoms in C9orf72 expansion carriers compared to noncarriers. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary motor or cognitive-behavioral symptoms. These findings highlight the need for clinician vigilance to detect the onset of secondary motor symptoms and cognitive-behavioral in patients carrying a C9orf72 repeat expansion, regardless of initial clinical syndrome, and may warrant dual referrals between cognitive and neuromuscular clinics in these cases.

Magnetic-Resonance-Imaging-Guided Cryoablation for Solitary-Biopsy-Proven Renal Cell Carcinoma: A Tertiary Cancer Center Experience.

BACKGROUND: Our purpose is to evaluate the long-term oncologic efficacy and survival rates of MRI-guided cryoablation for patients with biopsy-proven cT1a renal cell carcinoma (RCC). MATERIALS AND METHODS: We retrospectively reviewed our renal ablation database between January 2007 and June 2021 and only included patients with solitary-biopsy-proven cT1a RCC (≤4 cm) who underwent MRI-guided cryoablation. We excluded patients with genetic syndromes, bilateral RCC, recurrent RCC or benign lesions, those without pathologically proven RCC lesions and patients who underwent radiofrequency ablation or CT-guided cryoablation. For each patient, we collected the following: age, sex, lesion size, right- or left-sided, pathology, ablation zone tumor recurrence, development of new tumor in the kidney other than ablation zone, development of metastatic disease, patient alive or not, date and cause of death. We used the Kaplan and Meier product limit estimator to estimate the survival outcomes. RESULTS: Twenty-nine patients (median age 70 years) met our inclusion criteria. Twenty-nine MRI-guided cryoablation procedures were performed for twenty-nine tumor lesions with a median size of 2.2 cm. A Clavien-Dindo grade III complication developed in one patient (3.4%). Clear cell RCC was the most reported histology (n = 19). The median follow up was 4.5 years. No tumor recurrence or metastatic disease developed in any of the patients. Two patients developed new renal lesions separate from the ablation zone. The 5- and 10-year OS were 72% and 55.6%, respectively. The 5- and 10-year DFS were 90.5% and the 5-year and 10-year LRFS, MFS and CSS were all 100%. CONCLUSIONS: MRI-guided cryoablation is a safe treatment with a low complication rate. Long-term follow-up data revealed long-standing oncologic control.

Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .

Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease and 5XFAD mice.

Approximately 22% of Alzheimer's disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbates AD pathology and related cognitive deficits, suggesting that seizures may be a targetable component of AD progression. Given that alterations in neuronal excitatory:inhibitory (E:I) balance occur in epilepsy, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients. We similarly hypothesized that in 5XFAD mice, the E:I imbalance would progress from an early stage (prodromal) to later symptomatic stages and be further exacerbated by pentylenetetrazol (PTZ) kindling. Post-mortem AD temporal cortical tissues from patients with or without seizure history were examined for changes in several markers of E:I balance, including levels of the inhibitory GABAA receptor, the sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2) and the excitatory NMDA and AMPA type glutamate receptors. We performed patch-clamp electrophysiological recordings from CA1 neurons in hippocampal slices and examined the same markers of E:I balance in prodromal 5XFAD mice. We next examined 5XFAD mice at chronic stages, after PTZ or control protocols, and in response to chronic mTORC1 inhibitor rapamycin, administered following kindled seizures, for markers of E:I balance. We found that AD patients with comorbid seizures had worsened cognitive and functional scores and decreased GABAA receptor subunit expression, as well as increased NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. Patch clamp recordings of prodromal 5XFAD CA1 neurons showed increased intrinsic excitability, along with decreased GABAergic inhibitory transmission and altered glutamatergic neurotransmission, indicating that E:I imbalance may occur in early disease stages. Furthermore, seizure induction in prodromal 5XFAD mice led to later dysregulation of NKCC1/KCC2 and a reduction in GluA2 AMPA glutamate receptor subunit expression, indicative of depolarizing GABA receptors and calcium permeable AMPA receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced amyloid-ß pathology and cognitive deficits, could also reverse elevations of the NKCC1/KCC2 ratio in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that targeting E:I balance, potentially with US Food and Drug Administration-approved mTOR inhibitors, hold therapeutic promise for AD patients with a seizure history.

Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease.

INTRODUCTION: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog). METHODS: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed ß-amyloid (Aß+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aß+ from Aß-. Survival analyses tested time to clinical dementia rating (global CDR) progression. RESULTS: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aß+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aß+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aß- individuals (HR = 3.11; p = 2.6e-09). DISCUSSION: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease. HIGHLIGHTS: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aß. Combining plasma p-tau181, GFAP, and NfL improved diagnostic accuracy for Aß status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aß/tau. Plasma NfL predicted longitudinal cognitive decline in both Aß+ and Aß- individuals.

Research Note: SOCS2 contributes to reduction of the third digit during development of the chicken forelimb.

The development of the avian wing pattern has been the subject of heated debate due to its special shape. The Suppressor of cytokine signaling 2 (SOCS2) gene encodes a negative regulator of growth hormone (GH) signaling and bone growth and is known to be strongly expressed in the third digit of chicken forelimbs. These observations suggest that SOCS2 might regulate the morphology of the avian wing, however, the function of SOCS2 in avian limb development remains unknown. Here, we reexamined SOCS2 expression in successive developmental stages of chicken limb development by in situ hybridization (ISH) and describe extended expression from the posterior of the stypolod to the third digit of the forelimbs. We used the RCAS avian retrovirus to overexpress SOCS2 in the developing chicken limb buds, which resulted in reduced or malformed chicken wings while hindlimbs developed normally. Transcriptome sequencing (mRNA-Seq) revealed changes in expression of genes known to be associated with growth and development in forelimbs with overexpressed SOCS2. This study highlights a pivotal role for SOCS2 during the development of the wing in the chicken and provides new insight into molecular mechanisms regulating avian limb development.

Greater white matter degeneration and lower structural connectivity in non-amnestic vs. amnestic Alzheimer's disease.

Introduction: Multimodal evidence indicates Alzheimer's disease (AD) is characterized by early white matter (WM) changes that precede overt cognitive impairment. WM changes have overwhelmingly been investigated in typical, amnestic mild cognitive impairment and AD; fewer studies have addressed WM change in atypical, non-amnestic syndromes. We hypothesized each non-amnestic AD syndrome would exhibit WM differences from amnestic and other non-amnestic syndromes. Materials and methods: Participants included 45 cognitively normal (CN) individuals; 41 amnestic AD patients; and 67 patients with non-amnestic AD syndromes including logopenic-variant primary progressive aphasia (lvPPA, n = 32), posterior cortical atrophy (PCA, n = 17), behavioral variant AD (bvAD, n = 10), and corticobasal syndrome (CBS, n = 8). All had T1-weighted MRI and 30-direction diffusion-weighted imaging (DWI). We performed whole-brain deterministic tractography between 148 cortical and subcortical regions; connection strength was quantified by tractwise mean generalized fractional anisotropy. Regression models assessed effects of group and phenotype as well as associations with grey matter volume. Topological analyses assessed differences in persistent homology (numbers of graph components and cycles). Additionally, we tested associations of topological metrics with global cognition, disease duration, and DWI microstructural metrics. Results: Both amnestic and non-amnestic patients exhibited lower WM connection strength than CN participants in corpus callosum, cingulum, and inferior and superior longitudinal fasciculi. Overall, non-amnestic patients had more WM disease than amnestic patients. LvPPA patients had left-lateralized WM degeneration; PCA patients had reductions in connections to bilateral posterior parietal, occipital, and temporal areas. Topological analysis showed the non-amnestic but not the amnestic group had more connected components than controls, indicating persistently lower connectivity. Longer disease duration and cognitive impairment were associated with more connected components and fewer cycles in individuals' brain graphs. Discussion: We have previously reported syndromic differences in GM degeneration and tau accumulation between AD syndromes; here we find corresponding differences in WM tracts connecting syndrome-specific epicenters. Determining the reasons for selective WM degeneration in non-amnestic AD is a research priority that will require integration of knowledge from neuroimaging, biomarker, autopsy, and functional genetic studies. Furthermore, longitudinal studies to determine the chronology of WM vs. GM degeneration will be key to assessing evidence for WM-mediated tau spread.

Cytoarchitectonic gradients of laminar degeneration in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e., periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; n=32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI, and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biologic variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways, and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was not related to the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau vs bvFTD-TDP ( p =0.039). In a structural model for long-range laminar connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio of mesocortex-to-isocortex SMI32-ir in bvFTD-tau vs bvFTD-TDP ( p =0.019), suggesting select long-projecting pathways may contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau vs bvFTD-TDP ( p =0.047), suggesting pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.

Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Automatic classification of AD pathology in FTD phenotypes using natural speech.

INTRODUCTION: Screening for Alzheimer's disease neuropathologic change (ADNC) in individuals with atypical presentations is challenging but essential for clinical management. We trained automatic speech-based classifiers to distinguish frontotemporal dementia (FTD) patients with ADNC from those with frontotemporal lobar degeneration (FTLD). METHODS: We trained automatic classifiers with 99 speech features from 1 minute speech samples of 179 participants (ADNC = 36, FTLD = 60, healthy controls [HC] = 89). Patients' pathology was assigned based on autopsy or cerebrospinal fluid analytes. Structural network-based magnetic resonance imaging analyses identified anatomical correlates of distinct speech features. RESULTS: Our classifier showed 0.88 ± $ \pm $ 0.03 area under the curve (AUC) for ADNC versus FTLD and 0.93 ± $ \pm $ 0.04 AUC for patients versus HC. Noun frequency and pause rate correlated with gray matter volume loss in the limbic and salience networks, respectively. DISCUSSION: Brief naturalistic speech samples can be used for screening FTD patients for underlying ADNC in vivo. This work supports the future development of digital assessment tools for FTD. HIGHLIGHTS: We trained machine learning classifiers for frontotemporal dementia patients using natural speech. We grouped participants by neuropathological diagnosis (autopsy) or cerebrospinal fluid biomarkers. Classifiers well distinguished underlying pathology (Alzheimer's disease vs. frontotemporal lobar degeneration) in patients. We identified important features through an explainable artificial intelligence approach. This work lays the groundwork for a speech-based neuropathology screening tool.

Disparities in Genetic Testing for Neurologic Disorders.

BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: Between 2015 and 2022, a total of 128,440 patients were seen in our outpatient neurology clinics and 2,540 patients underwent genetic evaluation. Black patients were less than half as likely as White patients to be evaluated (odds ratio [OR] 0.49, p < 0.001), and this disparity was similar after controlling for other demographic factors in multivariable analysis. Patients from the least wealthy quartile of zip codes were also less likely to be evaluated (OR 0.67, p < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.

Connecting dementia risk loci to the CSF proteome identifies pathophysiological leads for dementia.

Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia. We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins (proximity extension-based (PEA) immunoassays) in a deeply-phenotyped mixed-memory clinic cohort (n=502, mean age (sd) = 64.1 [8.7] years, 181 female [35.4%]), including patients with Alzheimer's disease (AD, n=213), dementia with Lewy bodies (DLB, n=50) and frontotemporal dementia (FTD, n=93), and controls (n=146). Validation was assessed in independent cohorts (n=99 PEA platform, n=198, MRM-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not. We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P=1.65e-08), ZCWPW1-PILRB (rs1476679, P=2.73e-32), CTSH-CTSH (rs3784539, P=2.88e-24) and HESX1-RETN (rs186108507, P=8.39e-08), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90e-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for frontotemporal dementia, either for the total sample as for analyses performed within FTD only. pQTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia.