Limbic-predominant Age-related TDP-43 Encephalopathy Research Articles

Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer’s disease, suspected-LATE and frontotemporal dementia

BackgroundThe locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer’s disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.MethodsSeventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.ResultsWe found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.ConclusionsThe alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although "pure" LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and/or age-related tau astrogliopathy (ARTAG). The patterns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions ("synergies") between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets.

Neuropathologic changes at age 90+ related to sleep duration 19 to 40 years earlier: The 90+ Study.

We investigated the association between sleep duration and neuropathologic changes 19 to 40 years later in oldest-old (age 90+) participants of The 90+ Study. Participants self-reported sleep duration and underwent neuropathologic evaluation. We categorized sleep duration as<7, 7 to 8=reference,>8hours and dichotomized neuropathologic changes as present/absent. We estimated odds ratio (OR) and 95% confidence intervals (CI) using logistic regression. In 264 participants, mean age at sleep self-report was 69 years, mean age at autopsy was 98 years, and mean interval between sleep self-report and autopsy was 29 years (range: 19-40). Those reporting>8hours of sleep had lower likelihood of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) inclusions (OR=0.18; CI=0.04-0.82) and amyloid beta deposits (OR=0.34; 95% CI=0.12-0.94). Long self-reported sleep is associated with lower odds of neurodegenerative neuropathologic changes 19 to 40 years later in the oldest-old, suggesting a potential role of sleep in accumulation of dementia-related neuropathologies. Association of self-reported sleep with non-Alzheimer's disease neuropathologic changes has not been explored. Whether sleep duration is related to dementia neuropathologic changes decades later is unclear. Long self-reported sleep is associated with lower odds of Alzheimer's disease neuropathologic change 19 to 40 years later in the oldest-old. Long self-reported sleep is associated with lower odds of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change 19 to 40 years later in the oldest-old.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation

Limbic predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE-NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the “LATE-NC network”. Ex-vivo diffusion MRI and detailed neuropathological data were collected on 184 community-based older adults. Linear regression revealed an independent association of higher LATE-NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE-NC stage with weaker integration and segregation in the LATE-NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE-NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.

Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer’s Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

Chronic traumatic encephalopathy neuropathologic change in former Australian rugby players.

We applied the 2021 consensus criteria for both chronic traumatic encephalopathy neuropathological change and traumatic encephalopathy syndrome in a small case series of six former elite-level Australian rugby code players. Neuropathological assessment of these cases was carried out at the Sydney and Victorian Brain Banks. Clinical data were collected via clinical interviews and health questionnaires completed by the participants and/or their next of kin, and neuropsychological testing was conducted with participants who were capable of completing this testing. All cases exhibited progressive cognitive impairment during life. Chronic traumatic encephalopathy neuropathological change was identified in four out of the six cases. However, coexisting neuropathologies were common, with limbic-predominant age-related TDP-43 encephalopathy and ageing-related tau astrogliopathy seen in all cases, intermediate or high Alzheimer's disease neuropathological change seen in four cases and hippocampal sclerosis seen in two of the six cases. The presence of multiple neuropathologies in these cases complicates clinical diagnostic efforts for traumatic encephalopathy syndrome. It will be important for further clinicopathological studies on larger groups to report all neuropathological comorbidities found in cases diagnosed with either chronic traumatic encephalopathy neuropathological change and/or traumatic encephalopathy syndrome.

Neuropathologic Burden and Dementia in Nonagenarians and Centenarians: Comparison of 2 Community-Based Cohorts

The aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially from those seen in younger-old adults. Autopsied participants from The 90+ Study and Adult Changes in Thought (ACT) Study community-based cohort studies were evaluated for dementia-associated neuropathologic changes. Associations between neuropathologic variables and dementia were assessed using logistic or linear regression, and the weighted population attributable fraction (PAF) per type of neuropathologic change was estimated. The 90+ Study participants (n = 414) were older (mean age at death = 97.7 years) and had higher amyloid/tau burden than ACT <90 (n = 418) (mean age at death = 83.5 years) and ACT 90+ (n = 401) (mean age at death = 94.2 years) participants. The ACT 90+ cohort had significantly higher rates of limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), microvascular brain injury (μVBI), and total neuropathologic burden. Independent associations between individual neuropathologic lesions and odds of dementia were similar between all 3 groups, with the exception of μVBI, which was associated with increased dementia risk in the ACT <90 group only (odds ratio 1.5, 95% CI 1.2-1.8, p < 0.001). Weighted PAF scores indicated that eliminating μVBI, although more prevalent in ACT 90+ participants, would have little effect on dementia. Conversely, eliminating μVBI in ACT <90 could theoretically reduce dementia at a similar rate to that of AD neuropathologic change (weighted PAF = 6.1%, 95% CI 3.8-8.4, p = 0.001). Furthermore, reducing LATE-NC in The 90+ Study could potentially reduce dementia to a greater degree (weighted PAF = 5.1%, 95% CI 3.0-7.3, p = 0.001) than either ACT cohort (weighted PAFs = 1.69, 95% CI 0.4-2.7). Our results suggest that specific neuropathologic features may differ in their effect on dementia among nonagenarians and centenarians from cohorts with different selection criteria and study design. Furthermore, microvascular lesions seem to have a more significant effect on dementia in younger compared with older participants. The results from this study demonstrate that different populations may require distinct dementia interventions, underscoring the need for disease-specific biomarkers.

Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains

The aggregation, mislocalization, and phosphorylation of TDP-43 are pathologic hallmarks of several neurodegenerative diseases and provide a defining criterion for the neuropathologic diagnosis of Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). LATE neuropathologic changes (LATE-NC) are often comorbid with other neurodegenerative pathologies including Alzheimer’s disease neuropathologic changes (ADNC). We examined whether TDP-43 regulated cryptic exons accumulate in the hippocampus of neuropathologically confirmed LATE-NC cases. We found that several cryptic RNAs are robustly expressed in LATE-NC cases with or without comorbid ADNC and correlate with pTDP-43 abundance; however, the accumulation of cryptic RNAs is more robust in LATE-NC with comorbid ADNC. Additionally, cryptic RNAs can robustly distinguish LATE-NC from healthy controls and AD cases. These findings expand our current understanding and provide novel potential biomarkers for LATE pathogenesis.

The influence of limbic-predominant age-related TDP-43 encephalopathy on argyrophilic grain disease: A voxel-based morphometry analysis of pathologically confirmed cases

BackgroundThe influence of limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathological change (LATE-NC) on structural alterations in argyrophilic grain disease (AGD) have not been documented. This study aimed to investigate the morphological impact of LATE-NC on AGD through voxel-based morphometry (VBM) technique. Materials and methodsFifteen individuals with pathologically verified AGD, comprising 6 with LATE-NC (comorbid AGD [cAGD]) and 9 without LATE-NC (pure AGD [pAGD]), along with 10 healthy controls (HC) were enrolled. Whole-brain 3D-T1-weighted images were captured and preprocessed utilizing the Computational Anatomy Toolbox 12. VBM was employed to compare gray matter volume among (i) pAGD and HC, (ii) cAGD and HC, and (iii) pAGD and cAGD. ResultsIn comparison to HC, the pAGD group exhibited slightly asymmetric gray matter volume loss, particularly in the ambient gyrus, amygdala, hippocampus, anterior cingulate gyrus, and insula. Alternatively, the cAGD group exhibited greater gray matter volume loss, with a predominant focus on the inferolateral regions encompassing the ambient gyrus, amygdala, hippocampus, and the inferior temporal area, including the anterior temporal pole. The atrophy of the bilateral anterior temporal pole and right inferior temporal gyrus persisted when contrasting the pAGD and cAGD groups. ConclusionComorbidity with LATE-NC is linked to different atrophic distribution, particularly affecting the inferolateral regions in AGD. Consequently, the consideration of comorbid LATE-NC is crucial in individuals with AGD exhibiting more widespread temporal atrophy.

Pathologic correlates of aging-related tau astrogliopathy: ARTAG is associated with LATE-NC and cerebrovascular pathologies, but not with ADNC

Age-related tau astrogliopathy (ARTAG) is detectable in the brains of over one-third of autopsied persons beyond age 80, but the pathoetiology of ARTAG is poorly understood. Insights can be gained by analyzing risk factors and comorbid pathologies. Here we addressed the question of which prevalent co-pathologies are observed with increased frequency in brains with ARTAG. The study sample was the National Alzheimer's Coordinating Center (NACC) data set, derived from multiple Alzheimer's disease research centers (ADRCs) in the United States. Data from persons with unusual conditions (e.g. frontotemporal dementia) were excluded leaving 504 individual autopsied research participants, clustering from 20 different ADRCs, autopsied since 2020; ARTAG was reported in 222 (44.0%) of included participants. As has been shown previously, ARTAG was increasingly frequent with older age and in males. The presence and severity of other common subtypes of pathology that were previously linked to dementia were analyzed, stratifying for the presence of ARTAG. In logistical regression-based statistical models that included age and sex as covariates, ARTAG was relatively more likely to be found in brains with limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and in brains with comorbid cerebrovascular pathology (arteriolosclerosis and/or brain infarcts). However, ARTAG was not associated with severe Alzheimer's disease neuropathologic change (ADNC), or primary age-related tauopathy (PART). In a subset analysis of 167 participants with neurocognitive testing data, there was a marginal trend for ARTAG pathology to be associated with cognitive impairment as assessed with MMSE scores (P = 0.07, adjusting for age, sex, interval between final clinic visit and death, and ADNC severity). A limitation of the study was that there were missing data about ARTAG pathologies, with incomplete operationalization of ARTAG according to anatomic region and pathologic subtypes (e.g., thorn-shaped or granular-fuzzy astrocytes). In summary, ARTAG was not associated with ADNC, whereas prior observations about ARTAG occurring with increased frequency in aging, males, and brains with LATE-NC were replicated. It remains to be determined whether the increased frequency of ARTAG in brains with comorbid cerebrovascular pathology is related to local infarctions or neuroinflammatory signaling, or with some other set of correlated factors including blood-brain barrier dysfunction.

Clinicopathological feature of limbic-predominant age-related TDP-43 encephalopathy (LATE) in Lewy body disease and Alzheimer’s disease: Research Introduction

Clinicopathological feature of limbic-predominant age-related TDP-43 encephalopathy (LATE) in Lewy body disease and Alzheimer’s disease: Research Introduction

Cognitive symptoms progress with limbic-predominant age-related TDP-43 encephalopathy stage and co-occurrence with Alzheimer disease.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a neuropathologic entity characterized by transactive response DNA-binding protein of 43-kDa (TDP-43)-immunoreactive inclusions that originate in the amygdala and then progress to the hippocampi and middle frontal gyrus. LATE-NC may mimic Alzheimer disease clinically and often co-occurs with Alzheimer disease neuropathologic change (ADNC). This report focuses on the cognitive effects of isolated and concomitant LATE-NC and ADNC. Cognitive/neuropsychological, neuropathologic, genetic, and demographic variables were analyzed in 28 control, 31 isolated LATE-NC, 244 isolated ADNC, and 172 concurrent LATE-NC/ADNC subjects from the National Alzheimer's Coordinating Center. Cases with LATE-NC and ADNC were significantly older than controls; cases with ADNC had a significantly higher proportion of cases with at least one APOE ε4 allele. Both LATE-NC and ADNC exhibited deleterious effects on overall cognition proportional to their neuropathological stages; concurrent LATE-NC/ADNC exhibited the worst overall cognitive effect. Multivariate logistic regression analysis determined an independent risk of cognitive impairment for progressive LATE-NC stages (OR 1.66; p = 0.0256) and ADNC levels (OR 3.41; p < 0.0001). These data add to the existing knowledge on the clinical consequences of LATE-NC pathology and the growing literature on the effects of multiple concurrent neurodegenerative pathologies.

Novel quantitative method for characterization of hippocampal sclerosis and its association with other neuropathologies and cognitive deficits

AbstractBackgroundHippocampal sclerosis of aging (HS) is characterized by neuronal loss and astrogliosis in subiculum and/or CA1 subfield of hippocampus. Using a novel quantitative approach, we studied the prevalence and localization of HS pathology in a well‐characterized oldest‐old cohort and examined its association with other neuropathologic changes and cognitive impairment.MethodsWe studied 409 consecutive autopsied participants of The 90+ Study with longitudinal assessments. In those with HS by traditional method (presence/absence), we used digitized hematoxylin and eosin and luxol fast blue hippocampal slides for further quantitative analysis. Using QuPath, we measured the length of each hippocampal subfield partitioned into three subregions (Figure1). We then calculated the proportion affected by HS for each subregion. Both traditional (presence/absence) and quantitative (subfield‐specific proportions) measures were used to study the relationship between HS and other neuropathologic changes and cognitive outcomes using regression models adjusted for sex, age at death, and education with all neuropathologic changes as covariates.ResultsHS was present in 11% of participants and was always focal, mostly affecting CA1 (89%), followed by subiculum (27%). Overlapping CA1/subiculum pathology was seen in 16% (Figure2). Left‐sided HS was more frequent (75%) than right‐sided (18%). Bilateral cases were the least frequent (7%). HS presence (traditional measure) was only associated with Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (OR = 3.45, p&lt;0.001). Quantitative measures revealed that HS proportion in subiculum and CA1 was associated with arteriolosclerosis (t36 = 4.11, p = 0.001) and LATE (t35 = 2.98, p = 0.005). HS proportion in subiculum alone was inversely associated with microvascular lesions (t41 = ‐3.16, p = 0.003) (Table1). HS proportion in subiculum and CA1 was associated with dementia at death and impairment of memory, language, calculation, and orientation. HS proportion in subiculum was additionally associated with impaired executive function. HS traditional measure was only associated with impaired orientation (Table1).ConclusionBased on our novel quantitative analysis, HS pathology was always focal, mostly unilateral, and associated with dementia and impairment in major cognitive domains. We found associations between HS and vascular pathologies that were not detected using traditional measure. The associations of HS with dementia and impaired memory, language, and calculation, identified with our quantitative method, were not detected using traditional measure.

Plasma TDP‐43 Levels are Associated with Neuroimaging Measures of Temporal Lobe Structure

AbstractBackgroundTar DNA binding protein of 43kDa (TDP‐43) proteinopathy is a pathological hallmark of limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), with or without comorbid Alzheimer’s disease neuropathologic change (AD‐NC). At present, the diagnosis of LATE neuropathologic change (LATE‐NC) can only be made at autopsy. There is thus an urgent need for a clinical biomarker for LATE and a blood‐based method would be optimal for clinical and economic reasons. Here, we assessed the relationship between plasma TDP‐43 levels with imaging measures of neurodegeneration (volume and cortical thickness).MethodParticipants were 72 nondemented older adults (47 women, age range 60‐94 years). Immunoassays for TDP‐43, phosphorylated threonine‐181 tau (p‐tau181), total tau (t‐tau), amyloid beta‐42 (Aß42), and amyloid beta‐40 (Aß40) were quantified (pg/mL) in duplicate for each participant using the Quanterix Simoa HD‐X instrument. Neuroimaging was conducted using a 3 Tesla MRI Siemens Prisma scanner with a 64‐channel head coil. A T1‐weighted MPRAGE sequence with 1 cubic mm voxels covering the entire brain was acquired. FreeSurfer software was used to estimate intracranial volume (ICV) and volumes of the entorhinal cortex (ERC), amygdala, and subiculum of the hippocampus, regions known to harbor TDP‐43 pathology in early stages of LATE‐NC. Multivariate linear regression models controlling for age, sex, and ICV were conducted in SPSS using plasma TDP‐43 as the predictor and volumetric or cortical thickness measurements as dependent variables.ResultThere was a negative association between plasma TDP‐43 concentration and ERC volume, a relationship that remained significant after controlling for plasma markers of AD‐NC (the Aß42/Aß40 ratio, p‐tau181/Aß40 ratio or t‐tau/Aß40 ratio). Results from subsequent exploratory analyses indicated a negative association between TDP‐43 and cortical thickness in the inferior temporal lobe, a finding which also remained significant after controlling for AD‐NC plasma biomarkers.ConclusionHigh plasma TDP‐43 levels were associated with in vivo imaging measures of neurodegeneration in multiple temporal lobe structures. Plasma TDP‐43 assays may prove useful in clinical trials seeking to enroll individuals at risk for LATE‐NC.

Rate of clinical progression in mixed Limbic‐Predominant Age‐Related TDP‐43 Encephalopathy (LATE) and Alzheimer disease

AbstractBackgroundLimbic predominant age‐related encephalopathy neuropathologic change (LATE‐NC) is associated with amnestic type dementia. LATE‐NC frequently coexists with Alzheimer disease neuropathologic change (ADNC). It is unclear whether LATE and Alzheimer disease neuropathologic change interact or independently affect clinical disease progression.MethodsData was from 80 autopsied participants with TDP‐43 immunohistochemical studies from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention. We used linear mixed effects models to estimate associations of ADNC and LATE‐NC with rate of progression of Clinical Dementia Rating Sum of Boxes (CDR‐SB) and investigated whether co‐occurrence of these two pathologies would modify these trends.ResultsParticipants in our sample were 42% female with mean age at death of 77.8 years (SD 9.6). Neuropathologic diagnoses were low/intermediate ADNC in 20 (25%), high ADNC in 29 (36%), LATE‐NC in 8 (10%), and LATE‐NC + high ADNC in 23 (29%) participants. Clinical progression of cognitive impairment was faster in participants with high ADNC than in those LATE‐NC (Slopes:1.82 units/year [95% CI: 0.93‐2.71] vs 1.33 units/year [95% CI: 0.29‐2.38]) (Figure). Co‐occurrence of LATE‐NC + high ADNC predicted similar progression than high ADNC alone (Slope: 1.83 units/year [95% CI: ‐0.45 – 4.12]) demonstrating interaction (p = 0.013) between LATE‐NC and high ADNC.ConclusionLATE‐NC and ADNC are independently associated with clinical progression of cognitive impairment. Co‐occurrence of LATE‐NC and high ADNC is expected to have similar clinical progression than ADNC alone. Research is ongoing to examine differences among these groups using T1‐weighted volumetric imaging and CSF glial activation biomarkers.

A novel fluid biomarker for TDP‐43 loss of function

AbstractBackgroundTDP‐43 nuclear clearance and cytoplasmic aggregation occur in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis‐frontotemporal dementia (ALS‐FTD), Alzheimer’s disease (AD), and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). Nuclear clearance of TDP‐43 leads to its failure to repress splicing of nonconserved cryptic exons. This loss of TDP‐43 splicing repression is well‐documented in postmortem tissues, but there is currently no method of detecting TDP‐43 dysfunction in living patients. As some cryptic exons are spliced in‐frame and translated into proteins carrying novel epitopes, we hypothesize that these “cryptic peptides” may be found in patient CSF as biomarkers of TDP‐43 dysfunction.MethodWe generated novel monoclonal antibodies against several TDP‐43 cryptic exon targets and then developed a sandwich ELISA using the Meso Scale Discovery (MSD) platform, which we validated in cells deficient in TDP‐43 for the cryptic exon target in HDGFL2. We then screened CSF samples of C9ORF72‐mutation carriers with or at risk of ALS‐FTD and control individuals for the presence of this cryptic peptide.ResultThe MSD signal for cryptic HDGFL2 was elevated in CSF of C9ORF72‐mutation carriers with ALS (n = 5, mean = 1601) compared to those of controls (n = 5, mean = ‐64.10; p&lt;0.013), so we examined a larger cohort of C9ORF72‐mutation carriers. In symptomatic individuals (n = 27), cryptic peptide levels showed a correlation nearing significance with symptom duration (r = ‐0.368, p = 0.059), suggesting that levels of the cryptic peptide tend to be higher during the earlier symptomatic phase. We also found elevated cryptic peptide levels in CSF of several pre‐symptomatic individuals. To clarify cryptic peptide dynamics during disease progression, we began to assess longitudinal CSF samples and found that in 82.35% (14/17) of symptomatic individuals, levels of the cryptic peptide decreased with disease progression.ConclusionOur findings indicate that loss of TDP‐43 splicing repression occurs early in disease progression in ALS‐FTD, even pre‐symptomatically, and that detection of HDGFL2’s cryptic neoepitope may facilitate earlier diagnosis of TDP‐43‐related diseases. Further efforts linking the presence of cryptic HGDFL2 to TDP‐43 co‐pathology in AD may help expand biomarker development in AD. Additionally, evaluating dynamics of these biomarkers could provide a way of measuring target engagement for new therapeutics aimed at restoring TDP‐43 function.

Development of TDP‐43 immunotherapy blocking transmission of seeding‐competent species from ALS/FTD

AbstractBackgroundAccumulation of pathological transactive response DNA binding protein 43 (TDP‐43) into intracellular inclusions underlies frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP), amyotrophic lateral sclerosis (ALS) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). TDP‐43 pathology is present as a co‐pathology in other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and chronic traumatic encephalopathy (CTE). Multiple mechanisms contribute to spreading of TDP‐43 pathology including transmission across synaptic terminals, exosomes and release of misfolded TDP‐43 from dying neurons. In fact, cerebrospinal fluid (CSF) obtained from ALS/FTLD‐TDP patients contains seeding‐competent TDP‐43 species. Therefore, antibody‐mediated clearance of pathological TDP‐43 represents an attractive therapeutic strategy. Our approach is to develop a TDP‐43‐specific immunotherapy that exploits Fcγ receptor‐mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP‐43 function.MethodHigh affinity monoclonal antibodies (mAbs) were generated against various regions of TDP‐43 using AC Immune’s SupraAntigen® platform and evaluated in mechanistic assays in vitro and in vivo models of TDP‐43 proteinopathies. A real‐time quaking‐induced conversion (RT‐QuIC) assay was established using patient’s CSF to evaluate the inhibitory properties of the lead therapeutic mAb on the seeding mechanism. Studies to evaluate the pharmacology and safety of the antibody were carried out in non‐human primates.ResultTargeting the C‐terminal domain of TDP‐43 but not the RNA recognition motifs reduced TDP‐43 pathology and prevented neuronal loss in vivo. This rescue was dependent on Fcγ receptor‐mediated immune complex uptake by microglia. The latter also promoted phagocytic capacity of ALS patient‐derived microglia. Importantly, the antibody efficiently neutralized seeding‐competent pathological TDP‐43 species in CSF from ALS patients. These beneficial effects were achieved while preserving physiological TDP‐43 function demonstrating safety of targeting TDP‐43 by immunotherapy. Modelling from non‐clinical pharmacokinetic studies of the antibody predicted a half‐life supporting target saturation in humans when administered monthly.ConclusionOur studies confirm the presence of extracellular seeding‐competent TDP‐43 species in the CSF of patients with ALS/FTLD‐TDP patients, providing an explanation for the spread of pathology including the non‐contiguous pattern of clinical manifestations observed in ALS. In addition, the binding and inhibitory properties of our lead therapeutic mAb in multiple patho‐mechanistic assays support clinical development in TDP‐43‐driven neurodegenerative diseases.

In severe ADNC, hippocampi with comorbid LATE-NC and hippocampal sclerosis have substantially more astrocytosis than those with LATE-NC or hippocampal sclerosis alone.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-A) pathologies are found together at autopsy in ∼20% of elderly demented persons. Although astrocytosis is known to occur in neurodegenerative diseases, it is currently unknown how the severity of astrocytosis is correlated with the common combinations of pathologies in aging brains. To address this knowledge gap, we analyzed a convenience sample of autopsied subjects from the University of Kentucky Alzheimer's Disease Research Center community-based autopsy cohort. The subjects were stratified into 5 groups (n = 51 total): pure ADNC, ADNC + LATE-NC, ADNC + HS-A, ADNC + LATE-NC + HS-A, and low-pathology controls. Following GFAP immunostaining and digital slide scanning with a ScanScope, we measured GFAP-immunoreactive astrocytosis. The severities of GFAP-immunoreactive astrocytosis in hippocampal subfield CA1 and subiculum were compared between groups. The group with ADNC + LATE-NC + HS-A had the most astrocytosis as operationalized by either any GFAP+ or strong GFAP+ immunoreactivity in both CA1 and subiculum. In comparison to that pathologic combination, ADNC + HS or ADNC + LATE-NC alone showed lower astrocytosis. Pure ADNC had only marginally increased astrocytosis in CA1 and subiculum, in comparison to low-pathology controls. We conclude that there appeared to be pathogenetic synergy such that ADNC + LATE-NC + HS-A cases had relatively high levels of astrocytosis in the hippocampal formation.

57 Clinical Utility of Neuropsychological Evaluation in the Differential Diagnosis Between Late-Onset Primary Progressive Aphasia Semantic Variant (PPA-SV) Versus Limbic Predominant Age-Related TDP-43 Encephalopathy (LATE): A Case Report

Objective:Primary progressive aphasia semantic variant (PPA-SV) is an atypical dementia subtype on the frontotemporal dementia (FTD) spectrum. PPA-SV is clinically defined by naming and semantic deficits, with progressive language decline that generalizes to other domains over time. Typically, it presents as an early-onset dementia with TDP-43 pathology, but 33-46% of PPA-SV cases display initial onset after age 65 with potentially different clinical features. Limbic Predominant Age-Related TDP-43 Encephalopathy (LATE), a more recently discovered neurodegenerative entity, is defined by an older age of onset, hippocampal sclerosis/atrophy, and TDP-43 pathology with a gradually progressive amnestic profile that expands to other cognitive deficits over time. The authors present a case report with overlapping features and suspected TDP-43 neuropathology ante-mortem for two reasons: first, to highlight the need for clinical criteria to formally diagnose LATE, and second, to address a gap in the literature on the possible clinical differences of late-onset PPA-SV.Participants and Methods:The authors present a case of a 78-year-old Indian bilingual man (English dominant) with 18 years of education, noncontributory medical history, and gradually progressive cognitive complaints reported over the past few years who was seen for outpatient neuropsychological evaluation. Prior workup was notable for negative amyloid PET scan, negative p-tau 217 blood test, and abnormal brain MRI revealing marked bilateral hippocampal atrophy with ex vacuo ventriculomegaly and minimal cerebrovascular disease. He scored 23/30 on prior MMSE, was diagnosed with amnestic MCI, prescribed Namenda and Exelon, and complained of minor memory and word-finding difficulties with reportedly intact IADLs and no signs of NPH.Results:Neuropsychological testing revealed a profound dysnomia (RBANS Naming raw score = 1/10), and he provided 0 words on two semantic fluency tasks but 15 words on letter fluency. Receptive vocabulary score was also impaired (PPVT-4, &lt;1st %). Memory performance also demonstrated rapid forgetting of information (RBANS List Recall raw = 0/10, Story Recall raw = 0/12) with no benefit to recognition cues (RBANS List Recognition raw = 12/20), but slightly better visual memory recall, albeit still impaired (RBANS Figure Recall raw = 4/20). Grooved pegboard scores were significantly worse with right-hand than left-hand. Irregular word reading (NAART = 16th %ile) was significantly below expectations and thought to reflect more of a surface dyslexia rather than a cultural confounder given that he has lived in the US for over 50 years and his occupational and educational history was completed in English.Conclusions:Results support the clinical utility of neuropsychological evaluation in the differential diagnosis to support a predominant clinical syndrome of PPA-SV despite overlapping features with LATE and suspected TDP-43 pathology. This case report highlights the diagnostic issue with the lack of literature describing the typical clinical progression or suggested diagnostic criteria of LATE. These findings also indicate that late-onset PPA-SV may include greater memory deficits earlier in the course, but this may also be a clinical masquerade that is more reflective of the extent of language deficits. Further research on late-onset manifestations of PPA-SV and LATE consensus clinical guidelines is advised.

Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals. Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART). In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART. Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups. Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.