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\"James D. Watson, the Nobel laureate whose pioneering work helped unlock the mystery of DNA's structure, charts the greatest scientific journey of our time, from the discovery of the double helix to today's controversies to what the future may hold. [This edition has been] updated to include new findings in gene editing, epigenetics, agricultural chemistry, as well as two entirely new chapters on personal genomics and cancer research\"--Provided by publisher.

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2 ) to show that loss of TDP-43 splicing repression occurs in ALS–FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS–FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS–FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials. This study identifies a fluid biomarker of TDP-43 dysfunction, a central pathological feature of the ALS–FTD disease spectrum, and demonstrates that such loss of TDP-43 splicing repression occurs presymptomatically.

To determine the mechanisms of speech intelligibility impairment due to neurologic impairments, intelligibility decline was modeled as a function of co-occurring changes in the articulatory, resonatory, phonatory, and respiratory subsystems. Sixty-six individuals diagnosed with amyotrophic lateral sclerosis (ALS) were studied longitudinally. The disease-related changes in articulatory, resonatory, phonatory, and respiratory subsystems were quantified using multiple instrumental measures, which were subjected to a principal component analysis and mixed effects models to derive a set of speech subsystem predictors. A stepwise approach was used to select the best set of subsystem predictors to model the overall decline in intelligibility. Intelligibility was modeled as a function of five predictors that corresponded to velocities of lip and jaw movements (articulatory), number of syllable repetitions in the alternating motion rate task (articulatory), nasal airflow (resonatory), maximum fundamental frequency (phonatory), and speech pauses (respiratory). The model accounted for 95.6% of the variance in intelligibility, among which the articulatory predictors showed the most substantial independent contribution (57.7%). Articulatory impairments characterized by reduced velocities of lip and jaw movements and resonatory impairments characterized by increased nasal airflow served as the subsystem predictors of the longitudinal decline of speech intelligibility in ALS. Declines in maximum performance tasks such as the alternating motion rate preceded declines in intelligibility, thus serving as early predictors of bulbar dysfunction. Following the rapid decline in speech intelligibility, a precipitous decline in maximum performance tasks subsequently occurred.

Although speech declines rapidly in some individuals with amyotrophic lateral sclerosis (ALS), longitudinal changes in speech have rarely been characterized. The study objectives were to model the rate of decline in speaking rate and speech intelligibility as a function of disease onset site, sex, and age at onset in 166 individuals with ALS; and estimate time to speech loss from symptom onset. We also examined the association between clinical (speaking rate/intelligibility) measures and patient-reported measures of ALS progression (ALSFRS-R). Speech measures declined faster in the bulbar-onset group than in the spinal-onset group. The rate of decline was not significantly affected by sex and age. Functional speech was still maintained at 60 months since disease onset for most patients with spinal onset. However, the time to speech loss was 23 months based on speaking rate < 120 (w/m) and 32 months based on speech intelligibility < 85% in individuals with ALS-bulbar onset. Speech measures were more responsive to functional decline than were the patient-reported measures. The findings of this study will inform future work directed toward improving speech prognosis in ALS, which is critical for determining the appropriate timing of interventions, providing appropriate counseling for patients, and evaluating functional changes during clinical trials.

Accelerometer-based digital measures offer a scalable and low-burden means of quantifying physical function, but existing processing algorithms may not quantify pathological gait correctly. In people living with amyotrophic lateral sclerosis (ALS), where gait patterns are slow, variable, and asymmetric, validated tools to quantify mobility are urgently needed. We proposed a step-counting algorithm designed for ankle-worn accelerometers that leverage wavelet-based decomposition to quantify heel strikes under heterogeneous gait patterns. We validated this method using five datasets comprising healthy individuals and those with ALS in controlled and semi-controlled activities, and we performed clinical validation in a free-living cohort of 305 people with ALS. We tested our method for accuracy in detecting steps and recognizing walking activity. Reference labels used for analytical validation were obtained from annotated studies or video-based ground truth. Step counting accuracy was assessed using Bland–Altman analysis while clinical validity was evaluated by comparing step counts to gross motor functioning on the ALS Functional Rating Scale-Revised (ALSFRS-R). Walking recognition was robust across walking conditions and body types; sensitivity ranged from 0.94 to 0.98, and specificity exceeded 0.95 across all evaluated datasets. The mean step counting bias was minimal (e.g., 0.44 steps), and the 95% limits of agreement were narrow (LoA = [−5.90, 5.40]) relative to reference standards, including video-annotated ground truth. Clinical validation indicated substantial differences between groups with various levels of gait impairment, e.g., participants who reported “walks with assist” on the ALSFRS-R accumulated a mean of 1283 (95% CI 1063, 1503) steps/day, while those reporting “normal” walking covered 3984 (95% CI 3537, 4432) steps/day. Our study covered analytical and clinical validation of a step-counting method developed for ankle-worn accelerometers and demonstrated its applicability to pathological gait. The method provides accurate quantification of walking activity in controlled and free-living environments, supporting its use as a digital endpoint in ALS research.

The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system.

Little is known about the characteristics of the workforce providing home-based medical care for traditional (fee-for-service) Medicare beneficiaries. We found that the number of participating home care providers in traditional Medicare increased from about 14,100 in 2012 to around 16,600 in 2016. Approximately 4,000 providers joined or reentered that workforce annually, and 3,000 stopped or paused participation. The number of home visits that most participants provided each year remained below 200. Only 0.7 percent of physicians in Medicare provided fifty or more home visits annually, with little change over the course of five years. In contrast, the number of home-visiting nurse practitioners almost doubled, and the average number of home visits they made increased each year. Despite generally low overall participation of traditional Medicare providers in home-based care, the workforce has seen modest but steady growth, driven primarily by increasing nurse practitioner participation. Additional stimuli may be necessary to ensure workforce adequacy and stability.

Objective The amyotrophic lateral sclerosis (ALS) trial outcome measures are clinic based. Active and passive smartphone data can provide important longitudinal information about ALS progression outside the clinic. Methods We used Beiwe, a research platform for smartphone‐based digital phenotyping, to collect active (self‐report ALSFRS‐R surveys and speech recordings) and passive (phone sensors and logs) data from patients with ALS for approximately 24 weeks. In clinics, at baseline and every 3 months, we collected vital capacity, ALSFRS‐R, and ALS‐CBS at enrollment, week 12, and week 24. We also collected ALSFRS‐R by telephone at week 6. Results Baseline in‐clinic ALSFRS‐R and smartphone self‐report correlation was 0.93 (P < 0.001). ALSFRS‐R slopes were equivalent and within‐subject standard deviation was smaller for smartphone‐based self‐report (0.26 vs. 0.56). Use of Beiwe afforded weekly collection of speech samples amenable to a variety of analyses, and we found mean pause time to increase by 0.02 sec per month across the sample. Interpretation Smartphone‐based digital phenotyping in people with ALS is feasible and informative. Self‐administered smartphone ALSFRS‐R scores correlate highly with clinic‐based ALSFRS‐R scores, have low variability, and could be used in clinical trials. More research is required to fully analyze speech recordings and passive data, and to identify optimal digital markers for use in future ALS clinical trials.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA-binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these ‘like-C9’ brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum.

Background Digital health technologies (DHTs) can quantify movements in daily routines but rely heavily on participant adherence over prolonged wear times. Methods We analyzed accelerometry data from wrist-worn devices during short at-home episodes of prescribed exercises performed by 329 individuals living with amyotrophic lateral sclerosis (ALS) in a longitudinal study. We developed an automated and interpretable signal processing method to estimate four metrics describing exercise repetitions, i.e., their count, duration, intensity, and similarity. We examined their associations with time elapsed from enrollment and ALS Functional Rating Scale-Revised (ALSFRS-R) using linear mixed effect models. We also compared them with previously validated free-living metrics that require substantial sensor wear-time. Finally, we studied how many repetitions are sufficient to determine participants’ upper limb functioning. Results Three out of four exercise metrics (all but count) demonstrated significant association with ALSFRS-R outcomes. The duration of exercise repetitions increased, while intensity and similarity of movement decreased over time (all p -value < 0.001), indicating longer but less vigorous and less consistent upper limb movements over time. Exercise intensity was determined as the most robust exercise-based predictor of changes in upper limb function, and it was comparable to free-living metrics, which required at 21 h of sensor wear time (R-squared 0.899 vs. 0.860, respectively). Sensitivity analysis indicated that as few as five exercise repetitions were sufficient to yield statistically significant associations with ALSFRS-R. Conclusions These results suggest that prescribed exercise can effectively quantify upper limb function and track longitudinal decline comparably to free-living observation. The proposed method may serve as an alternative that decreases participation burden, increases study adherence, and extends diagnostic accessibility.