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Plant cover and biochemical composition are essential parameters for evaluating cover crop management. Destructive sampling or estimates with aerial imagery require substantial labor, time, expertise, or instrumentation cost. Using low‐cost consumer and mobile phone cameras to estimate plant canopy coverage and biochemical composition could broaden the use of high‐throughput technologies in research and crop management. Here, we estimated canopy development, tissue nitrogen, and biomass of medium red clover (Trifolium pratense L.), a perennial forage legume and common cover crop, using red‐green‐blue (RGB) indices collected with standard settings in non‐standardized field conditions. Pixels were classified as plant or background using combinations of four RGB indices with both unsupervised machine learning and preset thresholds. The excess green minus red (ExGR) index with a preset threshold of zero was the best index and threshold combination. It correctly identified pixels as plant or background 86.25% of the time. This combination also provided accurate estimates of crop growth and quality: Canopy coverage correlated with red clover biomass (R2 = 0.554, root mean square error [RMSE] = 219.29 kg ha−1), and ExGR index values of vegetation pixels were highly correlated with clover nitrogen content (R2 = 0.573, RMSE = 3.5 g kg−1) and carbon:nitrogen ratio (R2 = 0.574, RMSE = 1.29 g g−1). Data collection were simple to implement and stable across imaging conditions. Pending testing across different sensors, sites, and crop species, this method contributes to a growing and open set of decision support tools for agricultural research and management. Core Ideas: Cover crop managemet has a need for robust sensing methods using low‐cost, readily available indices.Multiple red‐green‐blue (RGB) indices were compared to track the growth and nitrogen concentration of a forage cover crop.The top‐performing index (ExGR) correlated with cover crop biomass, N content, and carbon:nitrogen ratio (R2 > 0.55).These results are useful for cover crop management if embedded in regional systems for annual sampling of biomass and model parameterization. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Associations of cerebellar atrophy with specific neuropathologies in Alzheimer's disease and related dementias (ADRD) have not been systematically analyzed. This study examined cerebellar gray matter volume across major pathological subtypes of ADRD. METHODS: Cerebellar gray matter volume was examined using voxel‐based morphometry in 309 autopsy‐proven ADRD cases and 80 healthy controls. ADRD subtypes included AD, mixed Lewy body disease and AD (LBD‐AD), and frontotemporal lobar degeneration (FTLD). Clinical function was assessed using the Clinical Dementia Rating (CDR) scale. RESULTS: Distinct patterns of cerebellar atrophy were observed in all ADRD subtypes. Significant cerebellar gray matter changes appeared in the early stages of most subtypes and the very early stages of AD, LBD‐AD, FTLD‐TDP type A, and progressive supranuclear palsy. Cortical atrophy positively predicted cerebellar atrophy across all subtypes. DISCUSSION: Our findings establish pathology‐specific profiles of cerebellar atrophy in ADRD and propose cerebellar neuroimaging as a non‐invasive biomarker for differential diagnosis and disease monitoring. Highlights: Cerebellar atrophy was examined in 309 patients with autopsy‐proven neurodegeneration.Distinct patterns of cerebellar atrophy are found in all pathological subtypes of Alzheimer's disease and related dementias (ADRD).Cerebellar atrophy is seen in early‐stage (Clinical Dementia Rating [CDR] ≤1) AD, Lewy body dementia (LBD), frontotemporal lobar degeneration with tau‐positive inclusion (FTLD‐tau), and FTLD‐transactive response DNA binding protein (FTLD‐TDP).Cortical atrophy positively predicts cerebellar atrophy across all neuropathologies. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) represent the two ends of a clinical continuum or exist as distinct syndromic entities with specific pathologic/prognostic correlates. We aimed to characterize the main clinical features along the spectrum of progressive non‐fluent speech‐language disorders (nf‐SLD) and explore the existence of data‐driven symptom clusters with etiological/prognostic value. Method: We included 98 participants presenting with progressive motor speech impairment and/or agrammatism, of which 43 had an autopsy‐confirmed neuropathological diagnosis. Speech pathologists rated motor speech features indicative of dysarthria and AOS. Quantitative measures of expressive/receptive agrammatism were obtained and compared with healthy controls. Baseline and longitudinal disease severity was assessed with the Clinical Dementia Rating sum‐of‐boxes (CDR‐SB). We explored the clustering tendency of the data to form robust symptom clusters and used principal component analysis to extract data‐driven clinical components. The longitudinal CDR‐SB change was estimated with linear mixed‐effects models. Result: Ninety‐one participants fitted previously reported clinical profiles (69 AOS+agrammatism, 18 PPAOS and 4 PAA), while 7 remained unclassifiable and were characterized by nonfluent speech and dysarthria in the absence of apraxia of speech or agrammatism. None of the baseline clinical features discriminated between FTLD subgroups. The Hopkins statistic ruled out the existence of syndromic clusters in the whole sample. Three data‐driven components explained 71% of the variance ([i]severity‐agrammatism, [ii]AOS, and [iii]dysarthria). The component characterized by prominent dysarthria was more specific to patients with Progressive Supranuclear Palsy while the component characterized by severity‐agrammatism predicted a faster CDR‐SB increase. Conclusion: Our results suggest that nf‐SLD represents a clinical continuum. Splitting this continuum into different clinical phenotypes based on its major clinical features does not improve clinical‐pathological correlations, stressing the need for new clinical and biological markers. The term nf‐SLD could be used to group together these speech‐language phenotypes strongly associated with FTLD. [ABSTRACT FROM AUTHOR]

Background: The presence of multiple pathologies is the rule and not the exception in Alzheimer's disease (AD). The goal of this study was to assess whether 18F fluorodeoxyglucose (FDG) PET can provide information about the presence of non‐AD pathologies in autopsy‐proven AD patients. Method: Our cohort included 55 patients with antemortem FDG‐PET and autopsy‐proven intermediate/high ADNC from the UCSF Neurodegenerative Diseases Brain Bank. All patients underwent FDG‐PET. Standardized uptake value ratio (SUVR) images were computed using the pons as reference region. W‐maps (adjusted Z‐score maps) were created, comparing each patient to a group of 187 controls (age range: 20‐96, 40% males). Voxel‐wise correlations were computed to verify the unique contribution of each neuropathology to cerebral hypometabolism, while controlling for age, sex, time between FDG‐PET scan and death, scanner type, Thal and Braak staging, and the presence of all other co‐pathologies. Associations between SUVR values in specific region of interests (ROIs) were also assessed. The ROIs included were the following: Landau AD ROI for AD pathology, Cingulate Island Sign (CIS) for Lewy body disease, Inferior/Medial Temporal Lobe (IMT) and IMT/Frontal Supraorbital (IMT/FSO) ratios for limbic‐predominant age‐related TDP43 encephalopathy neuropathologic change (LATE‐NC). Result: Mean age was 63.8 ± 10.5, mean time between FDG and death was 6.2 ± 2.8, and mean MMSE was 21.1 ± 7.1 at the time of PET (Table 1). Group averaged W‐map showed the typical temporo‐parietal AD pattern; hypometabolism in these regions was associated with higher Thal phase and Braak stage (Figure 1). Lewy body disease (LBD), argyrophilic grain disease (AGD), aging‐related tau astrogliopathy (ARTAG), cerebral amyloid angiopathy (CAA) and vascular brain injury (VBI) were associated with hypometabolism in small discrete regional clusters (Figure 2). The Landau AD ROI was associated with both Thal (rs = ‐0.325, p =.015) and Braak stages (rs = ‐0.447, p<.001). The CIS sign was not associated with the presence of LBD (t(53) = 1.01, p = 0.319). Both the IMT (t(53) = ‐2.25, p =.028) and IMT/FSO (t(53) = ‐3.40, p =.001) ratios were associated with the presence of LATE‐NC. Conclusion: Co‐pathologies make a relatively small contribution to hypometabolism in patients with intermediate‐high ADNC. Novel biomarkers are needed for precise detection of co‐pathologies. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The development of biomarkers for Alzheimer's disease (AD) has allowed researchers to increase sample homogeneity and test candidate treatments earlier in the disease. The integration of biomarker "screening" criteria should be met with a parallel implementation of standardized methods to disclose biomarker testing results to research participants; however, the extent to which protocolized disclosure occurs in trials is unknown. METHODS: We reviewed the literature to identify prodromal AD trials published in the past 10 years. From these, we quantified the frequency of biomarker disclosure reporting and the depth of descriptions provided. RESULTS: Of 30 published trials using positron emission tomography or cerebrospinal fluid‐based amyloid positivity as an eligibility criterion, only one mentioned disclosure, with no details on methods. DISCUSSION: Possible reasons for and implications of this information gap are discussed. Recommendations are provided for trialists considering biomarker screening as part of intervention trials focused on prodromal AD. HIGHLIGHTS: Few prodromal Alzheimer's disease (AD) trial papers discuss biomarker disclosure.Disclosure has implications for participants, family members, and trial success.Disclosure must be consistently integrated and reported in prodromal AD trials.Best practice guidelines and training resources for disclosure are needed. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) represents a collection of neurocognitive syndromes with frontotemporal lobar degeneration (FTLD) neuropathology, and is associated with significant clinical, pathological, and genetic heterogeneity. We trained a deep neural network (DNN) classifier to differentiate behavioral‐variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and non‐fluent variant (nfvPPA) patients using MRI scans drawn from two multi‐site neuroimaging consortiums. Methods: BvFTD (N = 173), nfvPPA (N = 63), and svPPA (N = 41) patients with T1‐MRI were extracted from the FTLD Neuroimaging Initiative (FTLDNI) and the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) databases. MRI data were preprocessed with FreeSurfer, with cortical thickness, cortical volume, and subcortical volumes extracted. Cortical measures were parcellated into 360 patches (i.e., ROIs) according to the HCP‐MMP1 atlas. Both the patch‐based cortical thickness and volume features were harmonized to control confounding effects of sex, age, total intracranial volume (TIV), cohort, and scanner. Multi‐type features were parallelly fed into a multi‐layer‐perceptron (MLP)‐based classifier. Weighted cross‐entropy loss function was used to account for unbalanced sample sizes across FTD subtypes. 10‐fold nested cross‐validation was used to evaluate the robustness of the classification model, with data split into 80/10/10 of training/validation/test data sets. Results: Visual evaluation z‐scores of cortical features among FTLDNI and ALLFTD groups revealed site‐specific differences significantly reduced by feature harmonization, especially for volume (Figure 1). The balanced accuracy of the ensembled DNN classifier of each FTD subtype on test sets across all ten folds reached 0.76 ± 0.09 for bvFTD, 0.79 ± 0.07 for nfvPPA, and 0.88 ± 0.07 for svPPA (Figure 2). Figure 3 shows confusion matrices for classification performance in the test set across ten cross‐validation folds. Conclusion: We developed a deep‐learning‐based framework to classify three FTD subtypes: bvFTD, nfvPPA, and svPPA. The combination of feature harmonization and parallel multi‐type feature embedding framework showed promising differentiation power. This work can be used to recognize at‐risk populations for early and precise diagnosis, to aid intervention planning. Future studies will compare classification based on different input features and use visualization methods to identify the most discriminative regions and explore their clinical relevance. [ABSTRACT FROM AUTHOR]

Background: TMEM106B, a lysosomal trafficking protein, is an important genetic susceptibility risk factor for frontotemporal lobar degeneration (FTLD). In GRN mutation carriers, minor allele homozygosity in the TMEM106B rs1990622 SNP modulates the risk of FTLD. TMEM106B is often the main component of amyloid fibrils in FTLD with TDP43 aggregates. TMEM106B has been quantified in human brain specimens, but its role as a fluid biomarker is unknown. Here, we investigate the clinical value of CSF TMEM106B in FTLD. Methods: CSF TMEM106B was quantified with SOMAmer proteomics (v3.0, SomaLogic®) in an original cohort of C9orf72, GRN and MAPT symptomatic and asymptomatic mutation carriers and family non‐carrier controls, recruited through ALLFTD (n = 182), and a validation cohort of sporadic neuropathology‐confirmed FTLD‐tau and FTLD‐TDP43, clinically‐diagnosed progressive supranuclear palsy – Richardson syndrome (PSP‐RS) and age‐matched controls (n = 96). CSF TMEM106B was correlated with disease severity, measured by the Frontotemporal Lobar Degeneration module global scores (CDR+NACC/FTLD); brain volume, measured with Bayesian linear mixed‐effect modeling, using age, sex and total‐intracranial volume‐corrected permutations with threshold‐free cluster enhancement; and CSF neurofilament light chain (NfL) measured with Simoa. TMEM106B SOMAmer specificity was validated in cell culture overexpression systems and human brain specimens with high TMEM106B burden. Results: In both cohorts, there were no differences in CSF TMEM106B by sex, phenotype or neuropathological diagnosis, except for lower levels in PSP‐RS compared to controls (‐0.31 Log2‐fold change, p < 0.001). CSF TMEM106B did not correlate with age. Regardless of disease‐causing mutation, lower CSF TMEM106B was associated with worse disease severity (Figure 1 and 2). CSF TMEM106B was lower in homozygous TMEM106B rs1990622 protective allelein C9orf2 and MAPT, but not in GRN mutation carriers (Figures 3). CSF TMEM106B showed a trend for inverse correlation with NfL in the whole sample (r = ‐0.135, p = 0.052), and correlated positively with left frontal volume in symptomatic FTLD mutation gene carriers (p < 0.05). Conclusion: CSF TMEM106B is quantifiable in CSF in vivo. CSF TMEM106B levels are affected by an interaction of disease severity and FTLD and TMEM106B genotypes. Further work is needed to determine its value as a clinical biomarker. [ABSTRACT FROM AUTHOR]

Background: Patients with a history of repetitive head impacts (RHI) risk progressive memory loss and executive dysfunction consistent with traumatic encephalopathy syndrome (TES). TES is a clinical phenotype sensitive but non‐specific to underlying chronic traumatic encephalopathy (CTE). Cognitive symptoms overlap with Alzheimer's disease (AD), and features of AD pathology like beta‐amyloid (Aβ) plaques often co‐occur with CTE. We investigated whether Alzheimer's neuropathological changes influences cognition, brain volume, and plasma biomarkers in patients with RHI or TES. Methods: We studied 154 patients who underwent Aβ‐PET, including 33 with RHI/TES (age 61.5±11.5, 100% male, 11/33 Aβ[+]), 62 with AD and no prior RHI (age 67.1±10.2, 48% male, 62/62 Aβ[+]), and 59 healthy controls without RHI (HC; age 73.0±6.2, 40% male, 0/59 Aβ[+]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (regions of interest: frontal, temporal, parietal, occipital, hippocampus) and provided plasma samples analyzed for GFAP and NfL. Patients with RHI/TES were stratified as Aβ[+] or Aβ[‐] and compared to each other and with AD and HC groups (ANCOVA adjusting for age and sex). Results: Cognitively, Aβ[+] RHI/TES performed worse than Aβ[‐] RHI/TES on visuospatial (p =.04, d = 0.86) and memory testing (p =.07, d = 0.74). Comparing brain volume, Aβ[+] RHI/TES, but not Aβ[‐] RHI/TES, had lower parietal volume than HC (p =.003, d = 1.3). Conversely, Aβ[‐] RHI/TES had lower hippocampal volume than patients with AD (p =.03, d = 0.77). Comparing plasma biomarkers, Aβ[+] RHI/TES had higher plasma GFAP than HC (p =.01, d = 0.88) and similar GFAP levels to patients with AD (p =.26, d = 0.38). Conversely, Aβ[‐] RHI/TES had higher NfL than HC (p =.004, d = 0.93) and a trend towards higher plasma NfL than Aβ[+] RHI/TES (p =.11; d = 0.61). Conclusions: Patients with RHI/TES and positive Aβ‐PET have cognitive, brain volume, and plasma biomarker changes that more closely align to patients with AD than patients with Aβ[‐] RHI/TES. Visuospatial impairment and associated parietal atrophy may suggest the presence of AD pathology in participants with RHI. The suggestion of greater neuronal injury in patients with Aβ[‐] RHI/TES warrants further evaluation in supporting a diagnosis of TES due to suspected underlying CTE. Measuring these biomarkers in patients with RHI/TES could guide precise clinical management. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Sleep–wake disturbances are a prominent feature of Alzheimer's disease (AD). Atypical (non‐amnestic) AD syndromes have different patterns of cortical vulnerability to AD. We hypothesized that atypical AD also shows differential vulnerability in subcortical nuclei that will manifest as different patterns of sleep dysfunction. METHODS: Overnight electroencephalography monitoring was performed on 48 subjects, including 15 amnestic, 19 atypical AD, and 14 controls. AD was defined based on neuropathological or biomarker confirmation. We compared sleep architecture by visual scoring and spectral power analysis in each group. RESULTS: Overall, AD cases showed increased sleep fragmentation and N1 sleep compared to controls. Compared to atypical AD groups, typical AD showed worse N3 sleep dysfunction and relatively preserved rapid eye movement (REM) sleep. DISCUSSION: Results suggest differing effects of amnestic and atypical AD variants on slow wave versus REM sleep, respectively, corroborating the hypothesis of differential selective vulnerability patterns of the subcortical nuclei within variants. Optimal symptomatic treatment for sleep dysfunction in clinical phenotypes may differ. Highlights: Alzheimer's disease (AD) variants show distinct patterns of sleep impairment.Amnestic/typical AD has worse N3 slow wave sleep (SWS) impairment compared to atypical AD.Atypical AD shows more rapid eye movement deficits than typical AD.Selective vulnerability patterns in subcortical areas may underlie sleep differences.Relatively preserved SWS may explain better memory scores in atypical versus typical AD. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal lobar degeneration (FTLD) is associated with diverse clinical phenotypes underlain by multiple disease pathologies and genetic mutations. As such, traditional structural MRI analyses lack sensitivity and specificity for discriminating FTLD syndromes. Here, we use data‐driven methods to extract a concise set of MRI‐derived shape morphometric features and examine the discriminatory capability of their unique combinations in four FTLD clinical phenotypes. Method: 190 patients with sporadic or familial FTLD spectrum disorders (i.e., behavioral variant (bvFTD, n = 107), non‐fluent variant primary progressive aphasia (nfvPPA, n = 27), semantic variant primary progressive aphasia (svPPA, n = 12) and progressive supranuclear palsy (PSP, n = 44)) and 27 controls without pathogenic mutations from the ALLFTD cohort were evaluated. MRI data were preprocessed with FreeSurfer software and four cortical measures were extracted and indexed to a normalized surface atlas: cortical thickness (CT), surface area (SA), surface curvature (SC) and jacobian white matter surface metric distortion (JW). For all phenotypes, each shape feature was contrasted with controls using linear models adjusted for age and gender. Principal component analysis (PCA) was then applied to each individual structural measure and the discriminatory power based on individual and combined measures was assessed using logistic regression and 10‐fold cross‐validation. Result: Figure 1 displays FDR‐corrected T‐scores of differences from controls in each morphometric feature in bvFTD. Results reveal complementary patterns of CT, SA, SC and JW for each phenotype, with greatest differences observed in CT across groups. In Figure 2, we display the features derived from the PCA, weighted by eigenvector coefficients, in bvFTD. In Figures 3‐6, receiver operating characteristic curves for individual and combined measures alongside areas under the curve (AUCs) are shown for each phenotype. In bvFTD, nfvPPA and PSP, the superior model included CT and SC at AUCs of 88.3, 87, and 78.6, respectively. For svPPA, the superior model included CT, SC and JW at an AUC of 85.6. Conclusion: Integrating additional MRI‐derived surface morphometric features improved classification performance in all FTLD phenotypes. The principal component analysis‐based approach indicated distinct brain regions contribute to discrimination for each shape feature, suggesting they may reflect unique aspects of neurodegeneration across groups. [ABSTRACT FROM AUTHOR]

Background: Mutations in microtubule‐associated protein tau (MAPT), granulin (GRN), and hexanucleotide expansion repeat in the open reading frame of chromosome 9 (C9orf72) are found in 60% of familial frontotemporal dementia (FTD) cases. The current study aims to delineate brain regions with reduced glucose metabolism in patients with genetic FTD in comparison with cognitively normal controls. Methods: (18)F‐ fluorodeoxyglucose (FDG)‐positron emission tomography (PET) images were retrospectively obtained from 17 genetic FTD patients. All patients were symptomatic at the time of imaging, and the autopsy was available for 13. Pittsburgh compound B (PiB) amyloid PET scans were done for 13 patients (Table 1). FDG‐PET was collected at Lawrence Berkeley National Laboratory on a PET or PET‐CT scanner as six 5‐min frames acquired 30 min post tracer injection. Standard Uptake Value Ratio (SUVR) images were created for each patient using pons as a reference region. W‐score (age‐adjusted Z‐score) maps were created for each patient's FDG SUVR using a group of neurologically unimpaired controls (N=74, Mean age 65+16, 41 female) as reference. Result: On review of single‐subject w‐maps, all patients with MAPT mutation showed hypometabolism in the anteromedial temporal lobes with 66% showing anterolateral temporal hypometabolism and 33% in the frontal and dorsolateral parietal lobes. Hypometabolism in temporal lobes was seen in all GRN patients and 75% had frontal and parietal hypometabolism in an asymmetric pattern. 80% of theC9orf72 patients had hypometabolism in anteromedial temporal and orbitofrontal regions. 60% showed hypometabolism in dorsolateral prefrontal, medial frontal, and anterolateral temporal lobes. Posterior temporal, posterior cingulate, parietal lobe, cerebellum, insula, thalamus, and caudate were hypometabolic in less than 40% of the C9orf72 patients (Figure 1). On group‐level analysis, compared to controls, patients with C9orf72 showed hypometabolism in the frontotemporal regions, cerebellum and thalamus. Hypometabolism in the frontotemporal and parietal regions was seen with GRN mutation. MAPT mutation carriers showed frontal and anteromedial temporal hypometabolism (Figure 2). Conclusion: Hypometabolism in the posterior regions and cerebellum is more suggestive of C9orf72 repeat expansion. An asymmetric pattern of hypometabolism was seen in all GRN mutation carriers. MAPT mutation resulted in a greater degree of hypometabolism in the anterior medial temporal lobes. [ABSTRACT FROM AUTHOR]

A biologic is a therapeutic agent with biological activity that is administered to achieve an enhanced regenerative or reparative effect. The use of biologics has progressively become a core component of contemporary periodontal practice. However, some questions remain about their safety, indications, and effectiveness in specific clinical scenarios. Given their availability for routine clinical use and the existing amount of related evidence, the goal of this American Academy of Periodontology (AAP) best evidence consensus (BEC) was to provide a state‐of‐the‐art, evidence‐based perspective on the therapeutic application of autologous blood‐derived products (ABPs), enamel matrix derivative (EMD), recombinant human platelet‐derived growth factor BB (rhPDGF‐BB), and recombinant human bone morphogenetic protein 2 (rhBMP‐2). A panel of experts with extensive knowledge on the science and clinical application of biologics was convened. Three systematic reviews covering the areas of periodontal plastic surgery, treatment of infrabony defects, and alveolar ridge preservation/reconstruction and implant site development were conducted a priori and provided the foundation for the deliberations. The expert panel debated the merits of published data and exchanged experiential information to formulate evidence‐based consensus statements and recommendations for clinical practice and future research. Based on an analysis of the current evidence and expert opinion, the panel concluded that the appropriate use of biologics in periodontal practice is generally safe and provides added benefits to conventional treatment approaches. However, therapeutic benefits and risks range based on the specific biologics used as well as patient‐related local and systemic factors. Given the limited evidence available for some indications (e.g., gingival augmentation therapy, alveolar ridge preservation/reconstruction, and implant site development), future clinical studies that can expand the knowledge base on the clinical use of biologics in periodontal practice are warranted. [ABSTRACT FROM AUTHOR]

Background: Among prominent unmet needs of the Alzheimer's disease and related dementia (ADRD) research community is the ability to leverage opportunities to improve the assessments of persons with and at risk for ADRD. This vision can be realized by providing the tools and infrastructure to transform dementia assessment using remote sensing and digital technologies, pervasive computing, and wireless communications, all in concert with high dimensional data analytics. The Collaborative Aging Research using Technology (CART) initiative (carthome.org), a non‐proprietary, sharable end‐to‐end system for capturing and handling diverse kinds of digital data has been developed. The CART technology platform offers the opportunity to bring new assessment methodology and data types to NIA Alzheimer's Disease Research Centers (ADRC) and related centers and transform the clinical research enterprise. Herein we report on progress in capturing digital data across multiple ADRC's. Method: Participants were recruited from affiliated studies at five NIA ADRC's (Digital Technology Core at Oregon Health & Science University, Minority Aging Research Study at Rush University, Cognitive Empowerment Program at Emory University and Georgia Institute of Technology, ALLFTD study at University of California San Francisco, and a pilot study of Mexican Americans at University of Texas Health Science Center at San Antonio). Field technicians at each center installed the CART technology platform in the home of each participant. Result: A total of 195 research participants have been enrolled across the 5 centers and followed for a median of 19 months (range 1‐46). A summary of the center cohorts is provided in the table. The flexibility of the platform and its components has allowed it to successfully be adapted for research in each of these studies with diverse cohorts, use cases, and research aims. Attrition due to technology concerns has been very low (0.5%). Conclusion: Digital biomarker and related data can be readily captured across diverse cohorts, research teams, and settings using a common platform. The largely passive, continuous, and objective data generated with this approach promises to improve the opportunity to create more quantitative and ecologically valid measurements for ADRD phenotypes within the ADRD research community and related research settings. [ABSTRACT FROM AUTHOR]

Background: We examined the associations of white matter hyperintensities (WMH), amyloid‐PET, and tau‐PET with multi‐domain cognitive performance in symptomatic patients on the Alzheimer’s disease (AD) continuum. Method: 119 amyloid‐PET‐positive patients diagnosed with MCI or AD dementia underwent 3‐Tesla structural MRI, 18F‐flortaucipir (tau)‐PET,11C‐PIB (amyloid)‐PET, and neuropsychological assessment. Standardized uptake value ratio (SUVR) flortaucipir‐ and PIB‐PET images were created using tracer‐specific reference regions and warped to template space. Patients were split based on availability of FLAIR‐MRI (Figure 1). The exploratory sample (n=50; no FLAIR) was used to run voxelwise models to identify regions where flortaucipir‐ and PIB‐PET were associated with episodic memory, executive, language, semantic memory, and visuospatial composite scores. In the validation sample (n=69), WMH were segmented from FLAIR and T1‐MRIs using a two‐step supervised algorithm. Linear regression models assessed the independent contributions of global WMH volume (corrected for intracranial volume and log‐transformed) and cognitive domain‐specific regional PET‐SUVR (derived in the exploratory sample) to each cognitive domain. Result: The two samples had comparable demographics and clinical characteristics, with relatively young age (mean ∼65.5) and moderate impairment (mean MMSE ∼ 22, Table 1). In the exploratory sample, cognitive scores were associated with regional flortaucipir‐SUVR patterns (Figure 2); PIB‐SUVR was not robustly associated with cognition. In the validation sample, global WMH volume was inversely correlated with global PIB‐SUVR (r=‐.25, p=.04) but not global cortical flortaucipir‐SUVR (r=‐.18, p=.15). Older age predicted lower cortical flortaucipir‐SUVR (r=‐.70, p<.001) and greater WMH volume (r=.46, p<.001). Female sex was specifically associated with greater cortical flortaucipir‐SUVR (d=0.64, p=.01; psdsps Conclusion: In patients at the early clinical stages of AD, tau‐PET and global WMH volume were not associated with each other, but independently contributed to cognitive impairment. These findings emphasize the clinical relevance of cerebrovascular injury in the context of AD pathology, even in younger patients. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), cognitive symptoms have varying associations with tau, amyloid and neurodegeneration. Patients with early‐onset AD (EOAD, age<65) have more non‐amnestic symptoms, greater AD pathological burden, and less co‐pathologies than late‐onset AD (LOAD, age≥65). It is unknown whether the association between cognitive symptoms and Alzheimer's disease biomarkers differs with age, and this has implications for clinical trials. The goal of this study was (1) to evaluate the association between domain‐specific cognitive performance and PET‐based pathology in AD, and (2) to compare whether theses associations differ in EOAD versus LOAD. Method: Amyloid‐positive patients meeting criteria for mild cognitive impairment or AD dementia (Total n=71; EOAD n=33, mean age 58±4, MMSE 20±7, 61% female; LOAD n=38, mean age 74±6, MMSE 24±5, 45% female) underwent neuropsychological testing, 18F‐flortaucipir (FTP‐PET), 11C‐PIB‐PET (PIB‐PET), and a subset underwent 18F‐fluorodeoxyglucose‐PET (FDG‐PET, n=57). Composite scores were calculated for episodic memory, semantic memory, language, executive function and visuospatial domains. Voxelwise regressions (thresholded at uncorrected p<0.001 voxel‐level, FWE p<0.05 cluster‐level) evaluated PET/cognition correlations, and EOAD versus LOAD differences were tested with a PET*group interaction. Mediation analyses assessed direct and FDG‐PET‐mediated associations between FTP‐PET and cognitive performance in regions‐of‐interest based on the voxelwise regressions. Results: FTP‐PET and FDG‐PET (lesser extent), but not PIB‐PET, showed significant domain‐specific voxelwise associations with cognitive performance that aligned with known brain‐behavior relationships (episodic memory/medial temporal lobe, semantic memory/anterior temporal, language/perisylvian, executive/frontal, visuospatial/occipital) (Figures 1‐3). There were no significant interactions between age and PET correlations across all modalities. Mediation analysis revealed that FDG‐PET mediated the relationship between FTP‐PET and cognition in all domains except episodic memory (Table 1). FTP‐PET also had a direct effect on executive function (p<0.001) and visuospatial (p=0.02) performance. Conclusion: In AD, cognitive performance correlated with tau and neurodegeneration, but not amyloid, in similar patterns across the age spectrum. The relationship between tau and cognition was in part mediated by glucose metabolism. These findings provide support for inclusion of EOAD patients in clinical trials, for tau PET as a biomarker that captures molecular specificity and aligns with clinical performance, and for the shared potential of disease‐modifying therapies across the AD age spectrum. [ABSTRACT FROM AUTHOR]

Background: Education level is a well established modifiable risk factor for dementia prevention. Aiming to improve cognitive reserve and reduce dementia risk in vulnerable populations in Brazil, we created a literacy training program targeting low educated and illiterate adults. In this study, we intend to analyze how executive functioning and cognitive heterogeneity may interfere in the program's effectiveness. Method: 130 adults attending classes for adult education were screened and 108 met inclusion criteria. The group was divided into control (regular classes, n = 51) and intervention (regular classes + program targeting literacy training) (n = 57). In addition to answering clinical and education history questions, all the subjects underwent an extensive neuropsychological assessment at baseline and at follow up (after six months of intervention), measuring global cognition, executive functioning (EF), memory and language. Result: 77 subjects completed all the assessments at the end of the study. Mean age (years) was 59.0 (±9.17), mean education level (years) 2 (±2.18), 79.2% women and 89.6% Blacks. No significant differences were found between control and intervention groups improvement on reading abilities (reading accuracy of isolated words) at follow up. Considering abandonment reasons of formal education in childhood, subjects with childhood history of learning disability (CHLD) had less improvement on reading abilities at follow‐up. The CHLD group also showed poorer performance on a composite score of EF tasks at baseline (F = 3.814, p = 0.021). EF level at baseline correlated with reading abilities at baseline (Spearman's rho = 0.659, p<0.001) and follow‐up (Spearman's rho = 0.703, p<0.001). Conclusion: Both control and intervention groups showed improvement on reading abilities, regardless of specific literacy training. EF seems to have an impact on reading skills progress. Subjects with CHLD currently display poorer EF and show very little improvement of reading skills, which might indicate an undiagnosed neurodevelopmental disorder (e.g. ADHD, dyslexia, dyscalculia): an uncared condition still harming cognitive reserve improvement to this day. Thus, there is greater risk of developing dementia. Inclusive learning environments must also be considered for low educated populations. [ABSTRACT FROM AUTHOR]

Background: The role of education is a well established protective factor regarding dementia but not much is known as to the effect of literacy acquisition in adults. Therefore, our study aims to determine whether adults enrolled in late‐life literacy programs will improve memory and cognitive reserve and the role of socioeconomic status in learning. Method: 108 illiterate adults were enrolled and 77 completed the assessments. For SES, only participants living in Belo Horizonte with a verifiable address were included (68). The intervention group had 34 participants that received intensive literacy training, while the 34 controls attended regular classes for six months. SES was based on the Quality of Urban Living Index (QULI) of 2016 created by the municipal council and the Municipal Human Development Index (MHDI) of 2010 made by Atlas Brasil. The instruments used were Rodrigues et al, 2015 list of words and pseudowords to assess reading and Beta III matrix reasoning for non‐verbal reasoning. Result: Participants lived in 14 different regions of Belo Horizonte, 32 in areas with a low QULI and 36 within a high QULI. When using the HDI classification, 29 had medium MHDI, 25 had high MHDI and 14 very‐high MHDI. In regards to reading, people from low QULI areas went from reading on average 20.86 to 22.26 words and 4.21 to 5.13 pseudowords. Participants from high QULI regions went from an average of 22.14 to 25.08 words and 5.56 pseudowords to 6.86. One‐way ANOVA showed a significant effect of MHDI on post‐test Beta III scores, F (2, 37.5) = 3.64, p = 0.03. Post Hoc comparisons using Games‐Howell test indicated that the average score in high MHDI (M = 6.24, SD = 2.26) were significantly better than those with medium MHDI (M = 4.63, SD = 2.14), but no significant difference was found between high and very high or very high to medium MHDI. Conclusion: Participants from all groups improved during the assessments. However, it was also possible to see that SES has a role to play in the extent of this improvement. [ABSTRACT FROM AUTHOR]

Background: Formal education acquired early in life protects against dementia, but whether acquiring education later in life can decrease dementia risk is less clear. Episodic memory impairment is one of the first symptoms of Alzheimer's Disease. Therefore, we aimed to identify whether a late life literacy training delivered to illiterate adults could improve episodic memory as a mechanism of cognitive reserve enhancement, eventually contributing to prevent dementia in this population. Methods: We ran a clinical trial with 108 illiterate adults cognitively healthy allocated into two groups at baseline: the intervention group (n = 57) that attended classes focused on learning how to read and write and the control group (n = 51), that attended regular classes (not focused on literacy training), for 6 months. We used the Free and Cued Selective Reminding (FCSRT) test to evaluate the episodic memory. Participants also underwent a thorough neuropsychological investigation and rsfMRI. The primary outcome measure was defined as the change in the free recall sum‐of attempts scores of the FCSRT. We used linear mixed effect models to calculate the change over time and between the intervention and control groups controlling for age and sex. ClinicalTrials.gov Identifier: NCT04473235 Results: Seventy seven participants completed the study. The control group had 38 participants aged 58.5 ±8.5 years, being 78.9 women and 92.1 Blacks. The intervention group had 39 participants aged 59.6 ±9.7 years, 79.5 women and 87.1 Blacks, with no significant differences in demographics between groups. Participants improved their episodic memory over time (FCSRT free recall sum of attempts: F = 21.5, p<0.001, FCSRT delayed recall: F = 27.1, p<0.001 and FCSRT efficacy: F = 26.2, p<0.001, but with no difference between the control and the intervention groups. The rsfMRI measurements are under analysis. Conclusion: Attending a late life literacy program in adulthood improved episodic memory, regardless of whether the intervention was focused on learning how to read and write or just attending regular classes. The results shed light into a possible low cost tool to increase cognitive reserve through improving episodic memory, eventually preventing dementia in vulnerable populations. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life's Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD. Method: 243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD. Result: Mutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913) Conclusion: Better cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD. [ABSTRACT FROM AUTHOR]

Background: Asian Americans and Canadians (ASACs) are the fastest growing minority group in the U.S. and Canada. However, ASACs are under‐sampled in Alzheimer's disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer's Disease (ACAD), the first large dementia genetics cohort currently focuses on Chinese, Korean, and Vietnamese, launched in 2021 to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and diverse cultural and scientific training backgrounds: both are critical in leading AD and CBPR research. Method: The ACAD pilot study has 7 recruiting sites (5 US and 2 Canadian), a coordinating site, and an analysis site. ACAD piloted a comprehensive study protocol including community outreach and recruitment strategies, the data collection packet (DCP), pre‐screening and sample collection procedures, and a centralized data management system in English, Chinese (Mandarin and Cantonese), Korean, and Vietnamese. To ensure the protocol consistency, ACAD implemented a training curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment in collaboration with community partners, clinics, and nursing homes that serve Asian communities. Result: As of December 2022, ACAD's pilot study has consented 606 participants, 527 participants have complete DCP data submitted to REDCap (448 Chinese, 54 Korean, and 25 Vietnamese), and more than 1,500 people have expressed interests in ACAD. The majority 66.2%)women. The age range of the sample is 60‐93 years. 47.3% have college or graduate level education. 451 participants provided a saliva (274) or a blood (177) sample. Feedback in pilot indicates a need to adapt the Early Life Enrichment inventory further to apply to wartime deprivation conditions for this population, as well as more cultural tailored neuropsychological tests. Conclusion: ACAD has learned valuable experience in interactions with ASACs and shown the feasibility of recruiting ASACs in clinical research. With an expansion plan and in collaboration with other AD research focuses on minority, insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD. [ABSTRACT FROM AUTHOR]

Background: Smartphone‐based cognitive and motor tests enable frequent remote assessments in observational research studies and clinical trials, limiting travel burden and increasing access to research for underrepresented groups. One such smartphone tool is the ALLFTD Mobile App, which was designed to capture the clinical features of neurodegenerative diseases via a battery of cognitive, speech, and motor tasks. In this study, we focus on recruiting a demographically diverse normative sample. We have partnered with the UCSF Brain Health Registry (BHR) to recruit 1,000 cognitively healthy participants across the lifespan. Here we describe the study design and initial feasibility results. Methods: We designed an automated workflow in which participants never interact with the study team except for troubleshooting. BHR participants without reported cognitive impairment were contacted by email to participate in this study (n = 668). Interested participants downloaded the app onto their smartphone and completed in‐app electronic consent. They were asked to complete three ∼30‐minute sessions of cognitive, motor and speech measures over two weeks. Adherence was determined by evaluating the completion rate of app tasks. In a subset who completed a user experience questionnaire (n = 116), responses were quantified using descriptive statistics. Results: The current enrollment rate is 23.20% (155/668) of contacted participants. Average age is 62 (SD = 8.2, range = 25‐84). Average adherence is 76%. Participants reported a range of perceived task difficulty: 38% indicated tasks were "very easy" or "somewhat easy", 26% indicated they were "neutral," 36% found the tasks "somewhat difficult," and none reported them to be "very difficult." The time commitment was reported to be acceptable by 97% of participants, and 20% were willing to complete additional tasks. Over half (59%) of participants indicated that they preferred using a smartphone to complete cognitive assessments over traditional pen‐and‐paper measures. Conclusions: Our preliminary results demonstrate the feasibility and acceptability of recruiting participants, including older adults, through a registry and conducting remote smartphone testing via a fully automated workflow that is highly scalable. Future analysis will study the effects of demographic factors on feasibility and investigate the reliability and validity of the app measures in this sample. [ABSTRACT FROM AUTHOR]

Background: Asian American and Canadian (ASAC) populations have long been under‐represented in Alzheimer's disease (AD) research. The Asian Cohort for Alzheimer's Disease (ACAD) is the first large US and Canada cohort to study genetic and non‐genetic AD risk factors specifically for older ASAC persons. The University of California San Francisco (UCSF) is one of ACAD's largest recruitment sites for Chinese American participants. Method: The UCSF ACAD team has adopted a collaborative multifaceted approach to outreach, recruitment, and data collection including a) recruitment from community partners, social media platforms, clinic referrals, CARE (a research recruitment registry for Asian Americans, Native Hawaiians, and Pacific Islanders), and other ongoing studies (e.g., UCSF's Alzheimer's Disease Research Center); b) coordination of multilingual and culturally appropriate outreach events with multiple San Francisco Bay Area community organizations that serve the Chinese American community; c) pilot of ACAD's data collection packet and procedures in two testing modes (in‐person, on‐line) and three spoken languages (Cantonese, English, Mandarin). Result: As of January 2023, UCSF has enrolled 121 participants, 116 (95.87%) of whom have completed their visits since we began enrollment in July 2021. Out of the 116 participants, 80 (68.97%) were co‐enrolled with other ongoing studies, 21 (18.10%) were recruited from outreach events in the community, and 15 (12.93%) participated in ACAD through CARE registry, clinic referrals, or social media platforms. The age of our cohort ranges from 60‐90 years (m = 70.45 years). Most of the participants were females (72.4%) and had a college or graduate level education (68.97%). Approximately 50% of the participants completed the study in Mandarin, 32.76% in English, and 17.24% in Cantonese. Nearly two‐thirds of the participants completed their visits virtually. Consensus diagnoses were fully reviewed on 106 participants, including 61 cognitively normal controls, 16 with subjective cognitive complaints, 23 with mild cognitive impairments, and 6 with AD diagnosis. Conclusion: ACAD aims to enhance the representation of ASAC communities in AD research. The use of culturally and linguistically tailored approaches has and will continue to assist us in outreach, recruitment, and data collection efforts as we aim to expand our sample size and collect longitudinal data. [ABSTRACT FROM AUTHOR]

Background: There has been a rise in remote cognitive testing for neurodegenerative diseases. The ALLFTD Mobile App is designed to capture clinical features of frontotemporal dementia (FTD) through repeated remote assessment on smartphones. This is a departure from traditional neuropsychological practice in which a single examiner‐led assessment occurs in a controlled setting. When participants complete tasks on their own, those with greater disease severity may be more variable in their performance for a variety of reasons (e.g. greater distractibility, less engagement). Here we study whether intraindividual cognitive variability (IIV) is associated with older age and increasing disease severity. Method: Participants were 279 (mean age = 54.9) healthy controls and participants with sporadic FTD or from familial FTD kindreds with a range of disease severities based on FTLD Clinical Dementia Rating scale (CDR®+NACC‐FTLD Global) scores: 0 (n = 132), 0.5 (n = 54), and ≥1 (n = 47). Participants completed three cognitive tasks at least two times across twelve days. Measures included an adaptive memory task and gamified versions of Flanker and Go/no‐go tasks. IIV was operationalized as the standard deviation in performance on each task. Regression analyses investigated the relationship of IIV with CDR®+NACC‐FTLD group, and with age in those without symptoms. Education and gender were included as covariates in all analyses. Result: Greater disease severity (CDR®+NACC‐FTLD) was associated with greater variability on Flanker (p<.001) and Go/No‐go (p =.02) tasks; a positive but non‐significant association was seen with memory testing (p =.16). Post‐hoc comparisons found that those with CDR®+NACC‐FTLD of 0.5 had significantly more IIV on the Flanker task (훃 =.39, p =.004) than those with CDR®+NACC‐FTLD's of 0. Moreover, those with a CDR®+NACC‐FTLD ≥1 had significantly greater IIV on the Flanker (훃 =.85, p<.001) and Go/No‐go tasks (훃 =.51, p =.007) than those with a CDR®+NACC‐FTLD of 0. In those without symptoms (CDR®+NACC‐FTLD = 0), age was associated with increased IIV on the Flanker (훃 =.27, p<.001) and Go/no‐go (훃 =.23, p<.001) tasks. Conclusion: Increased IIV, particularly on processing speed/executive functioning tasks, was associated with greater age and greater functional impairment, even in the mildest stages. Future investigations exploring predictors of IIV and the prognostic value of IIV are warranted. [ABSTRACT FROM AUTHOR]

Background: The ALLFTD (ARTFL‐LEFFTDS Longitudinal Frontemporal Lobar Degeneration) study is an NIH‐funded effort to prepare for clinical trials in sporadic (s‐FTLD) and familial (f‐FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. ALLFTD represents the merger and continuation of two prior studies: Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Methods: ALLFTD recruits participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD‐ALS, CBS or PSP), with strong family histories of FTLD, or known FTLD‐associated genetic variants within the family. 26 sites in North America enroll participants for clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants; participants are requested to return annually for follow‐up evaluation. All participants are genotyped for dementia‐associated mutations. Participants also enroll in the FTD Disorders Registry for follow‐up surveys. A subset of participants undergo remote assessment via the ALLFTD app. Visits conducted under ARTFL and LEFFTDS are included in the ALLFTD dataset. Results: ALLFTD has been successful in developing methods to conduct remote or hybrid visits and in actively evaluating participants. Since ALLFTD began in January 2020, 1034 participants (736 new; 298 previously enrolled in ARTFL or LEFFTDS) have been evaluated in the longitudinal arm; an additional 119 participants have been participated in a shortened, biofluid‐focused visit. 349 have returned for follow‐up visits. Including prior participants, the ALLFTD dataset contains 3871 visits from 2343 individuals. 1277 people have sporadic syndromes; 1045 were enrolled as familial. Among s‐FTLD, bvFTD is the most common phenotype (32.8%) followed by PSP (15.9%). 61.4% of f‐FTLD participants were clinically normal at first visit; bvFTD is the most common syndrome in symptomatic f‐FTLD (40%). 477 are confirmed carriers of FTLD‐associated genetic mutations. MRIs were obtained for 2594 visits; 3492 visits have associated blood biospecimens banked; 978 visits have associated CSF samples. Conclusions: The ALLFTD consortium is actively evaluating participants across North America to better characterize FTLD syndromes and support the planning and development of FTLD clinical trials. Longitudinal datasets including clinical, genetic, and imaging data are available by request. [ABSTRACT FROM AUTHOR]

Background: Memory impairment is generally considered minimal to absent in those with behavioral variant frontotemporal dementia (bvFTD). We sought to assess the frequencies of subjective and objective memory impairment in individuals with mild bvFTD according to consensus criteria. Method: Assessments were performed in mildly symptomatic bvFTD [defined by global FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD) = 1] mutation carriers (Familial) and non‐mutation carriers (Sporadic) who are participants in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD, www.allftd.org) study. Mutation carriers had a pathogenic mutation in the MAPT, GRN or C9orf72 gene. The presence of subjective memory impairment was defined by a rating >0 on the memory domain of the CDR®+NACC FTLD. Evidence of objective memory impairment was based on performance across 7 memory measures, which include the National Alzheimer's Coordinating Center Uniform Data Set Version 3 – Craft Story Immediate Recall (CSImm) and Delayed Recall (CSDel), Benson Figure Delayed Recall (BenDel), and the California Verbal Learning Test – Learning (CVLearn), Immediate Recall (CVImm), Delayed Recall (CVDel), and Recognition (CVRecog). Performance was considered abnormal for z‐scores ≤ ‐1.5. Result: Data from 38 Familial (mean age 60±8 years, 61% male), and 109 Sporadic (mean age 63±7 years, 70% male) participants were analyzed. Memory ratings >0 on the CDR®+NACC FTLD were common for both Familial (84%) and Sporadic (88%). The frequencies of abnormal performance in the Familial vs Sporadic groups, respectively, per memory measure were: CSImm 43.8% vs 45.9%, p = 0.83; CSDel 46.9% vs 52.6%, p = 0.58; BenDel 29.4% vs 46.4%, p = 0.08; CVLearn 54.8% vs 39.8, p = 0.14; CVImm 64.5% vs 50%, p = 0.16, CVDel 80.6% vs 55.1%, p = 0.01, and CVRecog 51.6 vs 49%, p = 0.80. The frequencies of abnormal performance did not differ (all p>0.05) between Familial and Sporadic for ≥2 tests (79.3% vs 67.7%), ≥4 tests (55.2% vs 44.1%) and ≥6 tests (34.5% vs 31.2%). Conclusion: These data suggest that among those with a mild global severity of bvFTD features: 1) subjective and objective memory impairment are relatively frequent, and 2) the frequency of impairment across memory measures is largely similar between familial and sporadic bvFTD. The presence of memory impairment should not preclude a diagnosis of bvFTD. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is a leading cause of dementia in individuals under age 65. Due to limitations in access to in‐person evaluations, there is an urgent need to examine remote, accessible, and low‐burden assessment techniques for FTD. Unobtrusive monitoring of at‐home computer use in older adults has shown that those with mild cognitive impairment (MCI) have significant declines in computer use over time. To extend these findings, we characterized daily trajectories in smartphone battery percentage, a proxy of smartphone use, and examined relationships with clinical indicators of disease severity in FTD. Method: Participants included 250 adults enrolled in the ALLFTD Mobile App study (mean age = 53.9 [SD = 14.9]; 59% women; 94% White). To assess clinical disease severity, all participants completed the FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD), a brief neuropsychological battery, the Neuropsychiatric Inventory Questionnaire (NPI‐Q), and brain MRI. The ALLFTD Mobile App was installed onto participants' smartphones for remote, passive, continuous monitoring of smartphone use (average days of monitoring = 82 [range = 7‐541]). Battery percentage was collected every 15 minutes. Linear mixed effects models examined linear, quadratic, and cubic effects of time of day (i.e., hour; modeled as person‐specific random effects) and their interactions with each measure of disease severity on battery percentage. Models covaried for age. Result: 57% of participants were clinically normal, 21% had MCI, and 22% had dementia. CDR®+NACC FTLD Global score interacted with hour such that participants with MCI and dementia had flatter battery curves (i.e., less change in battery percentage throughout the day – a proxy of less smartphone use) than clinically normal participants (ps<0.001). Additional models showed that worse memory (hour3 x memory score: 훃 = 0.59, p<0.001) and executive functioning (hour3 x executive score: 훃 = 0.64, p<0.001), more neuropsychiatric symptoms (hour3 x NPI‐Q: 훃 = ‐0.22, p = 0.004), and smaller gray matter volumes (controlling for intracranial volume; hour3 x volume: 훃 = 0.49, p<0.001) were also statistically significantly related to less battery usage throughout the day. Conclusion: These findings are proof‐of‐concept that passively acquired smartphone data, specifically battery usage, can provide insights about disease progression in FTD. Results support future research focusing on the development of passively collected digital metrics sensitive to clinical declines in neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Background: Pathogenic mutations in the MAPT (tau) gene cause familial frontotemporal lobar degeneration (f‐FTLD). No disease‐modifying treatments exist. Tau therapeutics being tested in other tauopathies may be suitable candidates, but the small number of identified mutation carriers prohibits traditional clinical trial designs from achieving adequate power. Platform trial designs permit multiple therapies to be tested in parallel and improve power by sharing placebo groups across treatment arms. We evaluate whether a platform design could improve the likelihood of identifying an effective treatment for MAPT mutation carriers. Method: ALLFTD and GENFI observational data were used to simulate MAPT prevention and early symptomatic clinical trials (CDR®+NACC‐FTLD≤1). Only presymptomatic participants (CDR®+NACC‐FTLD = 0) within 2.5 years of expected symptom onset based on disease progression models (DPM) were included. First, we evaluated the time and sample size required to test five treatments using a platform design compared to sequential randomized control trials. Platform designs assumed a max of three treatment arms at any time, with new arms enrolling upon completion of prior arms. Each arm randomized 60 mutations carriers 3:1 treatment to placebo, with a placebo group shared across arms. Minimum follow up was 1.5 years with common close. Sequential trials assumed 90 participants allocated 1:1 treatment to placebo, with three‐month intervals between trials. Using a platform design, we compared a novel method for testing therapeutic effects using DPMs to account for differential rates of expected progression compared to traditional mixed models for repeated measures (MMRM) tests controlling for baseline CDR®+NACC‐FTLD. Result: Five treatments could be tested in a platform design using 300 participants (75% treated) over five years, compared to 450 participants (50% treated) over 13 years using traditional, sequential trials. Platform trial simulations indicated that with 80% power, DPM‐based analytic approach could detect a 25% treatment effect, whereas traditional MMRM could only detect a 40% effect. Conclusion: Platform designs combined with DPM‐based analyses provide a path to testing more treatments with fewer participants. Adequately powered MAPT platform trials are feasible but require a global clinical trial infrastructure. [ABSTRACT FROM AUTHOR]

Background: Given the rarity of genetic frontotemporal dementia (FTD), researchers across the world have come together to form the FTD Prevention Initiative (FPI) in an effort to improve prevention trials design. As this initiative begins to bring together large‐scale data from worldwide cohort series, including ALLFTD in North America and GENFI in Europe and Canada, it is critical for FPI to quantify the level of relatedness between all participants. Here we provide the most recent update to these ongoing analyses. Methods: Genome‐wide SNP genotyping data from 1,684 ALLFTD and 568 GENFI participants was used to perform lineage analyses using PLINK. Briefly, QC was performed similarly in all datasets to remove individuals with low call rate and filter autosomal SNPs for missingness, frequency, and deviation from Hardy‐Weinberg equilibrium. Genetic ancestry was inferred by projecting genotyped samples into the principal components of the 1000 Genomes reference panel, using R package bigsnpr. Overlapping ALLFTD and GENFI genotyping data was then used, in a two‐stage approach, to calculate pairwise identity‐by‐descent (IBD) estimates and KING coefficients, followed by family‐network identification and pedigree reconstruction using PRIMUS. Results: First, we calculated IBD estimates among all participants by restricting pairs to those with estimates>0.1875 (up to second‐degree relatives). Overall, we identified a total of 292 second‐degree family networks, including 168 ALLFTD and 120 GENFI families, mostly associated with pathogenic variants in the 3 major FTD‐causing genes. We also identified 4 family networks with participants enrolled in both the ALLFTD and GENFI series, as well as several multi‐site families within the ALLFTD consortium. This first, overall approach allowed us to predict close relationships even between individuals with different ancestral backgrounds, including at least 4 confirmed admixed families. More distant relationships were also detected within ALLFTD and GENFI by performing ancestry‐based analysis among participants with estimated European ancestry, using the KING‐robust algorithm. Conclusions: These lineage analyses allowed us to identify, otherwise unknown, close (and distant) relatives from different study sites, as well as within the ALLFTD and GENFI series. This dataset will be a crucial resource to increase statistical accuracy and power in upcoming collaborative FPI studies. [ABSTRACT FROM AUTHOR]

Background: The ALLFTD Consortium aims to characterize preclinical and prodromal stage of familial Frontotemporal Lobar Degeneration (f‐FTLD) to prepare for clinical trials in FTLD. Method: We prospectively followed 320 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD with a mutation in MAPT (n = 106), GRN (n = 74), or C9orf72 (n = 140), and describe the ratings on the eight domains of CDR® plus NACC FTLD (FTLD‐CDR) in those who phenoconverted to Mild Behavioral and/or Cognitive Impairment (MBCI). MBCI was diagnosed by the proposed research criteria for MBCI‐FTD (Barker MS, et al. Brain 2022). Participants who were diagnosed as MBCI but returned to asymptomatic at the following visit were excluded from the FTLD‐CDR assessment. ANOVA was used to compare continuous variables, and chi‐square test was used to compare categorical variables across the groups. Result: Thirty‐six participants (15 MAPT, 9 GRN, 12 C9orf72) developed MBCI during follow‐up visits, 13 participants (5 MAPT, 3 GRN, 5 C9orf72) were diagnosed as MBCI but were characterized as asymptomatic at the following visit, and 271 participants stayed asymptomatic. Percentage of male in MBCI participants was 50% (MAPT 60%, GRN 33%, C9orf72 50%, p = 0.45). Age at phenoconversion to MBCI was 53.6±13.0 years old, the youngest in MAPT and the oldest in GRN participants (MAPT 44.3±8.3, GRN 63.1±11.3, C9orf72 56.4±10.8, p<0.001). Abnormal rating on each of the eight CDR® plus NACC FTLD domains at the initial visit of MBCI phenoconversion were observed in: "Memory" 36% (MAPT 33%, GRN 33%, C9orf72 44%, p = 0.95); "Orientation" 8% (MAPT 7%, GRN 8%, C9orf72 11%, p = 0.93); "Judgment/Problem Solving" 44% (MAPT 47%, GRN 50%, C9orf72 33%, p = 0.73); "Community Affairs" 22% (MAPT 27%, GRN 17%, C9orf72 22%, p = 0.82); "Home/Hobbies" 25% (MAPT 40%, GRN 8%, C9orf72 22%, p = 0.16); "Personal Care" 0%; "Behavior/Comportment/Personality" 44% (MAPT 60%, GRN 42%, C9orf72 22%, p = 0.19); "Language" 31% (MAPT 13%, GRN 50%, C9orf72 33%, p = 0.12). Conclusion: The three most common FTLD‐CDR domains initially disturbed in the prodromal stage of fFTLD were "Behavior/Comportment/Personality", "Judgment/Problem Solving", and "Memory", while "Orientation" was intact in the majority of the individuals. Memory impairment without disorientation was seen in one‐third of the prodromal fFTLD participants. [ABSTRACT FROM AUTHOR]

Background: Diverse ethnic ancestry and adverse social health determinants are increasingly recognized to impact dementia on multiple dimensions: genetically and environmentally determined risk, clinical presentation, detection, and the utility of cognitive testing and management. Most evidence originates from ethnically diverse cohorts in North America, with little representation of other world regions. We aimed to assess dementia clinical and neuroimaging phenotype in individuals of Middle Eastern and Northern African (MENA) descent, a population severely underrepresented in brain health research. Methods: The Alzheimer's and atypical dementias in Israelis of diverse ancestry and disparate social health determinants (ADIDAS) project started on January 1st, 2022, and will prospectively recruit 200 individuals aged 40‐80 years reporting a new cognitive decline. The ADIDAS protocol includes APOE genotyping, structured assessment of early‐to‐late life social determinants, Israeli neighbourhood disadvantage index, medical history, vascular risk factors, cognitive testing, plasma Alzheimer's biomarkers (Aβ40, Aβ42, total‐tau, p‐tau181, and NfL), and brain MRI. Ancestry was defined using participants and paternal country of birth. Countries were grouped into MENA, European, or neither, as defined by the World Bank. The project aims to assess the relationship between ethnic ancestry and associated social health determinants as predictors of brain neurodegeneration evident on neuroimaging and plasma biomarkers. Preliminary Results: As of January 1st, 2023, the ADIDAS cohort recruited 51 participants (55% female, mean age 65.8±8.4 years) of MENA (n = 24), European (n = 23), and neither (n = 3) ancestry. A preliminary comparison of MENA and European groups reveals MENA in our cohort are on average younger (63.87±8.9 vs. 68.3±8.2 years), have fewer years of schooling(11.7±2.5 vs. 16.2±3.4 years), and more likely to obtain only elementary or vocational education (75% vs. 13%). MENA were more likely to score poor results on cognitive testing‐ MMSE (21.6±4.9 vs. 24.8±5.5), receive a higher clinical dementia rating sum of boxes (3.4±2.5 vs. 1.45±1.4), and a lower carriage rate of apoE4 allele (11% vs. 30%). Conclusion: Preliminary non‐matched comparison suggests MENA with early‐stage cognitive impairment have a different social, cognitive, and genetic risk profile than individuals of European ancestry. Results of plasma biomarkers profile and MRI‐related structural changes will be shared at AAIC2023. [ABSTRACT FROM AUTHOR]

Background: Agitation is a behavioral syndrome involving increased motor activity, restlessness, aggressiveness and emotional distress. Its has a 30% prevalence across multiple types of dementia and is associated with negative outcomes, including reduced quality of life, caregiver distress, and mortality. Pharmacological treatment risks serious side effects, including mortality. Understanding brain network topology could provide insights into novel treatment methods. Method: Participants comprised 600 subjects from 3 existing databases: the Alzheimer's Disease Neuroimaging Initiative (ADNI), Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD) and the Mesulam Center for Cognitive Neurology and Alzheimer's Disease at Northwestern University. Participants were clinically diagnosed with either behavioral variant frontotemporal dementia (bvFTD), mild cognitive impairment (MCI), dementia of the Alzeheimer type (DAT) or cognitively normal (CN). The Neuropsychiatric Inventory Questionnaire (NPI‐Q) caregiver rating was used to determine whether individuals were agitated or not. Morphometric similarity networks (MSNs) were generated from Freesurfer statistics calculated from T1‐weighted MRIs. 7 surface‐based cortical metrics (e.g. gray matter volume, surface area) were calculated for each of 360 parcels. Pairwise inter‐parcel Pearson correlations of feature vectors were calculated to produce a morphometric similarity matrix for each individual. We calculated sub‐matrices for salience (SN) cognitive control (CCN) and default mode networks (DMN). Brain Connectivity Toolbox calculated transitivity and global efficiency of each network. Metrics were calculated at different thresholds to ensure the results were not threshold‐dependent. We calculated 2 (Agitation present/absent) x 4 (Diagnosis) repeated measures ANCOVAS for transitivity and global efficiency for each network. Covariates were age, sex, race, database, education, ICV, CDR‐SB and days MRI‐NPI‐Q. Result: For the SN, people with Agitation had significantly lower global efficiency than people without Agitation (Figure 1). There were no significant effects of diagnosis or interaction. For the CCN, people with agitation had significantly lower transitivity than people without Agitation (Figure 2). There were no significant effect of diagnosis or interaction. Conclusion: Across different forms of dementia, Agitation is associated with reduced integration (global efficiency) of the salience network, and reduced segregation (transitivity) of the cognitive control network. Interventions that alter these topological network features may be effective in reducing agitation in dementia, regardless of clinical diagnosis. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal Dementia (FTD) patients are geographically dispersed and often have behavioral and/or motor deficits that limit access to in‐person clinical trials and research. To address these participation barriers, we investigated the feasibility of installing in‐home sensor technologies to remotely assess everyday functioning in FTD. Method: We aimed to recruit 20 FTD participants with a variety of clinical syndromes, including behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). We also aimed to enroll a study partner for each participant that lived in the same home to serve as a control. The Collaborative Aging Research Using Technology (CART) platform was installed in participants' homes to collect continuous data for up to two years, using motion sensors, physiological monitoring devices (e.g., scales, sleep sensors), electronic pillboxes, and wearable actigraphs. Computer use and driving patterns were also tracked. Technology was installed either via a study coordinator visit or remotely through video and written instructions, based on schedule and logistics. Participants were asked to complete a weekly Qualtrics survey about time away from home, visitors, and health changes. Result: Of the 159 UCSF participants available for recruitment through ALLFTD and other FTD projects, 28% (N = 45) met inclusion criteria. Of those 45, ten were ineligible due to advanced disease severity or relocation to an assisted living facility. A third (36%, N = 17) declined due to overwhelmed study partners (N = 3), declined any subproject participation (N = 7), sensitivity to participant's diagnosis (N = 2), or lack of response (N = 5). Two additional participants were recruited through UCLA's ALLFTD cohort. The platform has been installed in 19 homes (bvFTD: n = 10; PPA: n = 5; CBS/PSP: n = 4). Two homes discontinued due to death or relocation to assisted living facility. Mean data collection is 360 days (max = 527). Of 103 reported technological issues, 92% were resolved without additional home visits, either by phone or email. Participants completed 65% of weekly health questionnaires. Conclusions: Although there were some recruitment and retention challenges, these findings generally provide preliminary support for the feasibility and sustainability of conducting comprehensive in‐home passive data research in FTD. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal lobar degeneration (FTLD) due to familial mutations results in heterogenous clinical phenotypes for which there are no specific biomarkers. Here, we test whether subcortical deformation differs in FTLD genetic mutation carriers, and if deformation was uniquely related to cortical thickness. Method: 317 participants from ALLFTD with familial FTLD (C9orf72 (n = 139), GRN (n = 77), and MAPT (n = 101)) and 27 controls without mutations (NCC) were evaluated. MRI data underwent FreeSurfer processing to estimate cortical thickness (CT). High‐dimensional, large‐deformation diffeomorphic metric mapping was used to model surfaces of the caudate and putamen. Regression analyses investigated the effect of mutation on CT and subcortical surface deformation, after controlling for age, sex, and education. Finally, linear models were constructed in each mutation group to explore the association between areas of significant surface deformity and CT, corrected for age and multiple comparisons. Result: Figure 1 shows significant (corrected p<.05) T‐scores where mutation carrier groups differ in CT from NCC (red = greater atrophy in mutation). Figure 2 shows greater outward local deformation in the caudate body among C9 and MAPT compared to NCC. Significant relationships between deformation and CT (corrected p<.05) were observed in bilateral temporoparietal, frontal and cingulate cortex in both C9 and MAPT carriers. C9 and MAPT mutation carriers have greater outward deformation in postero‐lateral putamen. Deformation was associated with CT in C9 within the left temporal and prefrontal lobes, and in the right temporoparietal, occipital and cingulate cortices for MAPT (Figure 3). No significant deformation was observed in GRN compared to NCC. Conclusion: Familial FTLD mutations are associated with subtle subcortical shape variations that show unique relationships to cortical atrophy. [ABSTRACT FROM AUTHOR]

Background: Characterizing disease trajectories in frontotemporal lobar degeneration (FTLD) is essential to determine the optimal timing for initiating therapeutic interventions, and there is an urgent need for novel and sensitive disease biomarkers. Intrinsic connectivity network (ICN) mapping using task‐free fMRI is a promising biomarker which reveals early abnormalities even before symptomatic onset (Dopper et al. 2014; Lee et al. 2016). Yet, ICN trajectories from the presymptomatic to symptomatic stages in FTLD mutation carriers remain unclear. Method: In this cross‐sectional study, we used UCSF and ALLFTD Consortia data to study 129 carriers with variants in MAPT (presymptomatic/prodromal/symptomatic: 34/4/7), C9orf72 (30/9/12) and GRN (22/4/7). Using cross‐sectional data to construct ICN trajectories by genotype, we built separate generalized additive models for each genetic group to estimate non‐linear relationships between standardized connectivity changes and disease age across clinical stages. ICN connectivity was based on seed‐based analyses for networks associated with common clinical syndromes for each genetic group (i.e., salience and default mode [MAPT/C9orf72/GRN], corticobasal syndrome [MAPT/GRN], progressive supranuclear palsy syndrome [MAPT], sensorimotor and medial pulvinar‐related [C9orf72], and non‐fluent variant primary progressive aphasia (nfvPPA) syndrome networks [GRN]). We included 127 healthy controls as a reference to calculate ICN z‐scores for each carrier. Each carrier's disease age was defined as the difference between the carrier's chronological age and estimated age of onset based on multimodal measures of structural imaging, fluid biomarker and clinical assessments (Staffaroni et al. 2022). Result: In MAPT+, presymptomatic carriers showed declining salience network connectivity starting approximately 30 years before estimated onset, which plateaued about 20 years before onset. In C9orf72+, salience network hyperconnectivity emerged about 30 years before onset and declined throughout the presymptomatic and symptomatic stages. For GRN+, connectivity changes as a function of disease age were found within the salience and nfvPPA networks, with connectivity stable until around 10 years before estimated onset, followed by decline starting in the late presymptomatic phase and continuing through the prodromal and symptomatic stages. Conclusion: These findings demonstrate that FTLD genes show distinct ICN trajectories throughout the clinical spectrum. These results help pave the way for determining the optimal timing to initiate therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Presymptomatic frontotemporal lobar degeneration (FTLD) mutation carriers as young as their thirties display gray matter (GM) deficits and alterations in the specific neural networks targeted during the symptomatic phase (Lee et al. NeuroImage Clin 2017; Bertrand et al. JAMA Neurol 2018). These studies raise the question of a potential neurodevelopmental role of pathogenic mutations in FTLD, yet sufficient research in young adults is lacking. Method: Leveraging 3T MRI brain scans from UCSF and the ALLFTD Consortia, we studied structural and functional connectivity alterations in 31 presymptomatic mutation carriers [PreSxAll; 12 C9orf72,13 MAPT, 6 GRN, mean age: 25.2±3.9, range 18‐30 years] and 28 demographically‐matched healthy controls [HC; mean age: 26.5±3.1, range 18‐30 years]. We performed voxel‐based morphometry (VBM) to compare GM volume between HC and PreSxAll, and HC and each mutation carrier subgroup using ANCOVA (SPM12). VBM statistical results were thresholded at a height of p<0.001 uncorrected or p<0.05 familywise error corrected. We used seed‐based task‐free functional MRI (tf‐fMRI) analysis to examine salience network (SN) and default mode network (DMN) connectivity. Single‐subject connectivity maps were analyzed using ANCOVA in SPM for group comparisons and masked to the relevant network. Tf‐fMRI results were thresholded at a height of p<0.05 and extent of p<0.05. For all analyses, nuisance covariates included age, sex, education, handedness, scanner and TIV (GM only). Result: We found no significant GM differences between groups. PreSxAll showed regions of SN hyperconnectivity compared with HC, specifically in the bilateral insula, right superior frontal gyrus, bilateral midcingulate cortex, and the left cerebellum. Compared to controls, each mutation carrier subgroup featured SN hyperconnectivity within key network hubs, such as the insula and anterior cingulate cortex. The DMN showed no significant alterations for PreSxAll vs. HC. Scattered small clusters of DMN alterations were noted in subcortical regions and the cerebellum in presymptomatic C9orf72 and GRN. Conclusion: Despite the absence of GM deficits in young adult FTLD mutation carriers, tf‐fMRI detected SN alterations in these carriers compared with healthy controls. Future studies focused on other neuroimaging measures will further explore differences in young adult FTLD mutation carriers. [ABSTRACT FROM AUTHOR]

Background: Presymptomatic C9orf72 expansion carriers show regions of low local gyrification index (lGI) as early as their thirties (Caverzasi et al. JNNP 2019) and regions of gyrification decline have been reported (van Veenhuijzen et al. Ann Neurol 2022). These findings raise the question as to whether abnormal gyrification represents a neurodevelopmental difference or early neurodegeneration in frontotemporal lobar degeneration (FTLD) mutation carriers. Yet, previous studies focusing on young adults is lacking and no study has explored gyrification in the two other common FTLD mutations, GRN and MAPT. Here, we analyzed lGI in young adult presymptomatic FTLD mutation carriers. Method: LGI quantifies buried cortex within the sulcal folds compared to the visible cortex on the outer surface, with larger values indicating more folding (Schaer et al. IEEE trans med imaging 2008). Mean lGI values, as measured by a parcel‐wise analysis implemented in FreeSurfer v.6.0, were compared between 31 presymptomatic (preSx) carriers (12 C9orf72, 13 MAPT, 6 GRN, mean age: 25.2 ± 3.91 years) and 28 demographically‐matched healthy controls (HC: mean age: 25.6 ± 3.8 years). We used ANCOVA to compare all presymptomatic carriers combined (preSxAll) and HC to identify regions with significant lGI differences regressing age, sex, education, handedness, total intracranial volume and scanner type as nuisance covariates. Significant group differences were analyzed by Dunnett's post‐hoc tests between each mutation subgroup and HC (p<0.05). Result: Compared to HC, preSxAll had higher mean gyrification in the right caudal (F = 5.07, p = 0.03) and rostral anterior cingulate (F = 6.22, p = 0.17), and lower lGI in the left middle temporal gyrus (F = 4.22, p = 0.046). Within these regions, post‐hoc analyses showed that preSx GRN had greater gyrification in the right caudal anterior cingulate (t = 2.57, p = 0.039, 95% CI = [0.005, 0.248]) and preSx C9orf72 had lower lGI in the left middle temporal gyrus (t = ‐3.14, p = 0.009, 95% CI = [‐0.37, ‐0.04]) vs. HC. Conclusion: Young adult FTLD mutation carriers displayed higher gyrification in the right anterior cingulate and lower gyrification in the left middle temporal gyrus compared to HC. Future studies in children will confirm the extent to which these gyrification abnormalities represent neurodevelopmental differences. [ABSTRACT FROM AUTHOR]

Background: The pathophysiological mechanisms driving frontotemporal lobar degeneration (FTLD) disease progression and corresponding biomarkers that capture these changes are not fully understood. We leveraged high‐throughput proteomics to identify networks of co‐expressed CSF proteins and candidate biomarkers for prediction of disease progression in adults with autosomal dominant FTLD mutations. Method: 113 adults carrying autosomal dominant FTLD mutations (C9orf72/GRN/MAPT) and 38 noncarrier controls from the ALLFTD consortium completed baseline lumbar puncture and longitudinal neuropsychological testing. CSF was assayed for SOMAmer proteomics on SOMAscan® v3.0 (4,140 proteins). Network analysis identified weighted protein co‐expression modules, which were annotated via gene ontology and cell‐type enrichment analysis. Disease age estimates that capture proximity to symptom onset were derived from a Bayesian disease progression model incorporating genotype‐specific clinical (cognition, CDR®+NACC FTLD) and biomarker (brain volume, plasma NfL) information. At baseline, local‐weighted regression examined module z‐scores (based on mean/SD of module levels [first principal component] in noncarriers) in relation to disease age. Longitudinal linear mixed‐effects models examined global cognitive trajectories in relation to baseline module z‐scores, as well as individual proteins within prognostic modules. Result: Network analysis identified 32 CSF protein co‐expression modules (37 to 223 proteins/module). 16 modules showed mutation‐related deviations from noncarriers. Deviations in ion transport, neurodevelopmental, metabolic, and transcriptional modules occurred several decades before estimated symptom onset (disease age: ‐30 to ‐20 years) and persisted across disease age. Deviations in neuroinflammatory and ubiquitination/autophagy modules occurred ∼10 years before estimated symptom onset. Sharp deviations in RNA binding, protein phosphorylation, neurogenesis, synaptic function, and lysosomal modules occurred near symptom onset (disease age: ‐1 to 4 years). Baseline synaptic and neurogenesis modules were the strongest prognosticators of cognitive decline (module x time: bs>.10, ps<.05). Within these modules, individual proteins with stronger intramodular connectivity exhibited stronger associations with cognitive decline (e.g., synaptic/transmembrane module: r =.40, p = 2.85e‐6; e.g., EPHA5, LRRTM2). Conclusion: Large‐scale analysis of the CSF proteome reveals a biologically‐diverse landscape of protein networks associated with presymptomatic and symptomatic stages of autosomal dominant FTLD. Synaptic and neuron‐enriched protein networks exhibited prodromal deviations that forecasted incipient cognitive decline. 'Hub' proteins derived from these affected networks warrant further validation as candidate biomarkers for early FTLD disease progression. [ABSTRACT FROM AUTHOR]

Background: Aldehyde dehydrogenases (ALDH) are enzymes which oxidize toxic aldehydic species into carboxylates. ALDH4A1 is a mitochondrial, NAD+‐dependent, dimeric enzyme and oxidizes the toxic aldehyde glutamic‐g‐semialdehyde (GSA) to glutamate. ALDH4A1 lies at the nexus of proline and arginine metabolism, the TCA cycle, and mitochondrial health (Fig. 1). The substrate of ALDH4A1, GSA, inactivates vitamin B6 (Farrant et al., 2001), an essential cofactor for amino acid and neurotransmitter biosynthesis. Toxic aldehydes like 4‐hydroxynonenal (4‐HNE), are elevated in Alzheimer's Disease (AD) patients (Markesbery & Lovell, 1998) and promote amyloid‐b aggregation (Siegel et al., 2007). A recent genetic analysis identified a missense variant of ALDH4A1 as a risk factor for Late Onset Alzheimer's Disease (LOAD) (Wang et al., 2015). Our previous analysis found that ALDH4A1 is an essential enzyme with no common loss of function variants (Chen et al., 2021). Our work elucidates the contribution of ALDH4A1 to AD pathology. Method: Recombinant protein was characterized to determine changes in protein activity and stability. The AD risk factor mutation was knocked‐in to the endogenous locus of induced pluripotent cells to monitor mitochondrial health, metabolism, and AD biomarkers. Mouse embryonic fibroblasts that do not express ALDH4A1 were used to monitor protein stability in cellulo. Result: The AD associated variant of ALDH4A1 has decreased activity compared to wildtype (WT) (Fig. 2). ALDH4A1 can oxidize the toxic AD‐associated aldehyde 4‐HNE, and the variant has 50% of the activity of WT with 4‐HNE (Fig. 2). The variant enzyme is less stable in cellulo; variant ALDH4A1 is degraded within a few hours compared to WT that remains stable up to 24 hours. Knock‐in cells accumulate 25% more extracellular proline, and show a trend towards increased intracellular proline, indicating faulty proline metabolism in cells expressing the AD‐associated mutant ALDH4A1. Conclusion: ALDH4A1 oxidizes AD associated aldehydes (i.e., 4‐HNE) in addition to its known substrate. The AD‐associated variant of ALDH4A1 is less catalytically active and less stable than the WT enzyme. Cells expressing this variant have dysregulated proline metabolism. These data indicate that ALDH4A1 variants may contribute to AD through altered metabolism and increased aldehydic load from dysregulated protein activity and stability. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive composite scores offer a means of precisely measuring executive functioning (EF). Methods: We developed the Uniform Data Set v3.0 EF composite score (UDS3‐EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item‐response theory and applied nonlinear and linear demographic adjustments. The UDS3‐EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models. Results: Final model fit was good‐to‐excellent: comparative fit index = 0.99; root mean squared error of approximation = 0.057. UDS3‐EF scores differed across validation cohorts (controls > mild cognitive impairment > Alzheimer's disease‐dementia ≈ behavioral variant frontotemporal dementia; P < 0.001). The UDS3‐EF correlated most strongly with other EF tests (βs = 0.50 to 0.85, Ps < 0.001) and more with frontal, parietal, and temporal lobe gray matter volumes (βs = 0.18 to 0.33, Ps ≤ 0.004) than occipital gray matter (β = 0.12, P = 0.04). The total sample needed to detect a 40% reduction in UDS3‐EF change (n = 286) was ≈40% of the next best measure (F‐words; n = 714). Conclusions: The UDS3‐EF is well suited to quantify EF in research and clinical trials and offers psychometric and practical advantages over its component tests. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates. Objective: The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. Methods: Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation. Results: 29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%). Conclusions: Favorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation. [ABSTRACT FROM AUTHOR]

Background: Neurodegeneration caused by pathological protein aggregation in Alzheimer’s disease (AD) is reflected in cortical atrophy and glucose hypometabolism, measured with structural MRI and FDG‐PET, but how these disease processes relate to each other within and across brain networks remains unclear. We examine multimodal neuroimaging relationships within and between multiple large‐scale brain networks among CSF‐defined (i.e., amyloid, total tau, and p‐tau) “A/T/N” subgroups of AD. Method: Alzheimer’s Disease Neuroimaging Initiative subjects with CSF analysis, MRI and FDG‐PET: AD‐Continuum (A+(T or N ‐/+), N = 559), Suspected Non‐AD Pathologic Change (SNAP) (A‐(T or N+), N = 149), Normal (A‐T‐N‐, N = 179). T1‐MPRAGE scans underwent FreeSurfer processing to estimate cortical thickness, normalized 18FDG‐PET images were co‐registered and uptake values were projected onto corresponding cortical surface. Using a well‐validated atlas, MRI and FDG‐PET images were parcellated into 360 cortical “patches” corresponding to 12 cortical networks. Partial Pearson correlations were computed between the 360 patches of cortical thickness and FDG metabolism and displayed visually as heatmaps, organized by network. Bonferroni correction was used to account for multiple comparisons. Result: Limited significant correlations were seen in Normal subjects (Figure 1). Among SNAP subjects, positive within‐network correlations between atrophy and hypometabolism were found within the dorsal attention, frontoparietal and default‐mode networks (Figure 2). Across‐network relationships were also present with hypometabolism in the dorsal attention and frontoparietal networks associated with widespread cortical atrophy. In AD‐Continuum subjects, positive within‐network correlations between cortical atrophy and glucose hypometabolism were most frequent within the dorsal attention, default‐mode and posterior multimodal networks (Figure 3). Across‐network relationships were frequent with atrophy within the dorsal attention and default‐mode networks associated with widespread hypometabolism and hypometabolism within the dorsal attention, frontoparietal and default‐mode networks associated with widespread atrophy. Conclusion: These findings suggest that, in both SNAP and AD‐Continuum subjects, local and distant relationships between cortical atrophy and hypometabolism are common, especially within regions known to be impacted by AD neuropathology (e.g., frontoparietal and default‐mode networks). SNAP subjects show fewer across‐network correlations as compared to AD‐Continuum, supporting the conclusion that tau aggregation drives local neurodegeneration while the relationships between amyloid and neurodegeneration are less region‐specific. [ABSTRACT FROM AUTHOR]

Anaerobic potentially mineralizable nitrogen (PMN) combined with preplant nitrate test (PPNT) or pre‐sidedress nitrate test (PSNT) may improve corn (Zea mays L.) N management. Forty‐nine corn N response studies were conducted across the U.S. Midwest to evaluate the capacity of PPNT and PSNT to predict grain yield, N uptake, and economic optimal N rate (EONR) when adjusted by soil sampling depth, soil texture, temperature, PMN, and initial NH4–N from PMN analysis. Pre‐plant soil samples were obtained for PPNT (0‐ to 30‐, 30‐ to 60‐, 60‐ to 90‐cm depths) and PMN (0‐ to 30‐cm depth) before corn planting and N fertilization. In‐season soil samples were obtained at the V5 corn development stage for PSNT (0‐ to 30‐, 30‐ to 60‐cm depths) at 0 kg N ha−1 at‐planting rate and for PMN when 0 and 180 kg N ha−1 was applied at planting. Grain yield, N uptake, and EONR were best predicted when separating soils by texture or sites by annual growing degree‐days and including PMN and initial NH4–N with either NO3–N test. Using PSNT (mean R2 =.30)‐instead of PPNT (mean R2 =.19)‐based models normally increased predictability of corn agronomic variables by a mean of 11%. Including PMN and initial NH4–N with PPNT or PSNT only marginally improved predictability of grain yield, N uptake, and EONR (R2 increase ≤.33; mean R2 =.35). Therefore, including PMN with PPNT or PSNT is not suggested as a tool to improve N fertilizer management in the U.S. Midwest. [ABSTRACT FROM AUTHOR]

The mutation of K‐RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K‐RAS mutations. The reduced sensitivity of K‐RAS‐mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C‐RAF and with the reactivation of mitogen‐activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB‐283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD‐0325901) and selumetinib, in suppressing the proliferation of K‐RAS‐mutated non‐small‐cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B‐RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF‐dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K‐RAS‐mutated cells. This synergistic effect was also observed in several K‐RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho‐ERK blockade in enhancing the antitumor activity observed in the K‐RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K‐RAS‐mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K‐RAS mutations and other MAPK pathway aberrations. [ABSTRACT FROM AUTHOR]

The anaerobic potentially mineralizable N (PMN) test combined with the preplant (PPNT) and presidedress (PSNT) nitrate tests may improve corn (Zea mays L.) N fertilization predictions. Forty‐nine corn N response experiments (mostly corn following soybean [Glycine max (L.) Merr.]) were conducted in the U.S. Midwest from 2014–2016 to evaluate the ability of the PPNT and PSNT to predict corn relative yield (RY) and N fertilizer over‐ and under‐application rates when adjusted by PMN. Before planting and N fertilization, PPNT (0–30, 30–60, and 60–90 cm) and PMN (0–30 cm) samples were obtained. In‐season soil samples were obtained at the V5 development stage for PSNT (0–30, 30–60 cm) in all N rate treatments and PMN (0–30 cm) in only the 0 and 180 kg N ha−1 preplant N treatments. Increasing NO3–N sampling depths beyond 30 cm with or without PMN improved RY predictability marginally (R2 increase up to 0.20) and reduced over‐ and under‐application frequencies up to 14%. Including PMN (preplant only) with PPNT or PSNT improved RY predictability minimally (R2 increase up to 0.10) only for coarse‐ and medium‐textured soils, but N fertilizer over‐ and under‐application frequencies were not substantially reduced (≤12%). These marginal improvements in RY predictability and N fertilizer over‐ and under‐application frequencies, regardless of the variables used (e.g., fertilization, sampling depth, soil texture, and growing degree‐day categories), demonstrate that including PMN with soil NO3–N alone does not improve corn N fertilization need predictions enough to recommend their use. [ABSTRACT FROM AUTHOR]

Introduction: We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early‐onset versus late‐onset Alzheimer's disease (EOAD and LOAD). Methods: Plasma was analyzed using ultra‐sensitive immuno‐based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. Results: Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL‐6, IP‐10, IL‐10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. Disucssion: Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD. [ABSTRACT FROM AUTHOR]

The article discusses the American Academy of Periodontology's (AAP's) use of a best evidence consensus (BEC) model for defining periodontal phenotype modification therapy (PhMT) for purposes of dental restoration and orthodontic therapy. Topics, including gingival recession and phenotypes, peri-implantitis, disease classification, dental prostheses and keratinized mucosa, are discussed.

Nitrogen (N) loss from cropping systems has important environmental implications, including contamination of drinking water with nitrate. A 2‐yr study evaluated the effects of six N rate, source, and timing treatments, including a variable rate (VR) N treatment based on the N sufficiency index approach using remote sensing, and two irrigation rate treatments, including conventional and reduced rate, on nitrate leaching, residual soil nitrate, and plant N uptake for potato (Solanum tuberosum L. cv. Russet Burbank) production in 2016 and 2017 on a Hubbard loamy sand. Nitrate leaching losses measured with suction‐cup lysimeters varied between 2016 and 2017 with flow‐weighted mean nitrate N concentrations of 5.6 and 12.8 mg N L−1, respectively, and increased from 7.1 to 10.4 mg N L−1 as N rate increased from 45 to 270 kg N ha−1. Despite reductions in N rate of 22 and 44 kg N ha−1 in 2016 and 2017, respectively, for the VR N treatment, there was no significant difference in nitrate leaching compared with the existing N best management practices (BMPs). Reducing irrigation rate by 15% decreased nitrate leaching load by 17% through a reduction in percolation. Residual soil nitrate N in the top 60 cm across all treatments (7.9 mg N kg−1) suggests a risk for nitrate leaching during the nongrowing season, and plant N uptake did not explain yearly variation in nitrate leaching and residual soil nitrate. Although existing N BMPs are effective at controlling N losses, development of alternative practices is needed to further reduce the risk of groundwater contamination. [ABSTRACT FROM AUTHOR]

Introduction: We created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD. Methods: The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants. Results: The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non‐fluent/agrammatic variant primary progressive aphasia participants. Discussion: The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders. [ABSTRACT FROM AUTHOR]

Introduction: Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD). Methods: We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium. Results: The CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®‐SB) = 0. The CDR®‐SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®‐SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders. Discussion: The BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD. [ABSTRACT FROM AUTHOR]

Introduction: Familial frontotemporal lobar degeneration (f‐FTLD) due to autosomal dominant mutations is an important entity for developing treatments for FTLD. The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) longitudinal studies were designed to describe the natural history of f‐FTLD. Methods: We summarized recent publications from the ARTFL and LEFFTDS studies, along with other recent publications describing the natural history of f‐FTLD. Results: Published and emerging studies are producing data on all phases of f‐FTLD, including the asymptomatic and symptomatic phases of disease, as well as the transitional phase when symptoms are just beginning to develop. These data indicate that rates of change increase along with disease severity, which is consistent with commonly cited models of neurodegeneration, and that measurement of biomarkers may predict onset of symptoms. Discussion: Data from large multisite studies are producing important data on the natural history of f‐FTLD that will be critical for planning intervention trials. [ABSTRACT FROM AUTHOR]