Citations

ObjectiveThis study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD).MethodsPatients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story‐tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow‐up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow‐up period of 5 years.ResultsOf 180 patients free of parkinsonism or dementia, 156 provided follow‐up information. After a mean follow‐up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia‐first (n = 16) and parkinsonism‐first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism‐first with normal cognition converters (n = 17).InterpretationAutomated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530–543

Abstract OBJECTIVE We sought to define the mechanisms by which purines regulate DNA repair and therapy response. METHODS Phosphoproteomics was used to identify GTP-dependent (de)phosphorylation events after radiation (RT) and antibodies generated against novel sites. Animal models of glioblastoma (GBM) and normal tissues were used to assess DNA repair and treatment responses in vivo. RESULTS Pharmacogenomic inhibition of GTP (but not ATP) synthesis sensitized GBM cells to RT by inhibiting the activity of non-homologous end joining, but not homologous recombination. We found a GTP-dependent RT-induced dephosphorylation event on Abl interactor 1 (Abi-1) serine 323 (S323) using phosphoproteomics. We generated a new antibody for p-Abi-1 (S323), validated its specificity, and confirmed that RT causes a GTP-dependent dephosphorylation of Abi-1 (S323). Knockout of Abi-1 slowed RT-induced double-strand break (DSB) repair, and this was rescued by re-expression of dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D). Abi-1 canonically binds to G protein Rac1. Expression of constitutively active Rac1 promoted but dominant negative Rac1 blocked the dephosphorylation of Abi-1 (S323) and DSB repair. Knock-down or inhibition of protein phosphatase 5 reversed the GTP- and Rac1-mediated dephosphorylation of Abi-1 and DSB repair. In GBM PDX samples, p-Abi-1 (S323) levels negatively correlated with Rac1 activity and predicted favorable efficacy of genotoxic treatments. In orthotopic GBM mouse models, inhibiting Rac1 enhanced RT responses and suppressed Abi-1 (S323) dephosphorylation. Abi-1 knockout enhanced efficacy of genotoxic treatments and could be rescued by Abi-1 S323A (but not Abi-1 S323D) re-expression. This regulation is generalizable beyond brain cancer, as GTP supplementation promoted DNA repair and p-Abi1 (S323) dephosphorylation in non-malignant cells and protected mice from RT-mediated gastrointestinal injury and bleomycin-induced pulmonary fibrosis. CONCLUSION The GTP-Rac1-PP5-Abi-1 signaling axis links metabolism and DNA repair. Disrupting this pathway can overcome GBM resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues.

Abstract H3K27M-mutant diffuse midline glioma (DMG) patients have no proven effective therapies beyond radiation. ONC201, a mitochondrial protease ClpP agonist, has recently demonstrated efficacy in these patients, but the mechanism behind this remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue samples from patients treated in two completed multi-site clinical studies (n=71). Patients treated with ONC201 monotherapy following initial radiation but prior to recurrence (n=35) demonstrated a median overall survival of 21.7 months and a median progression-free survival of 12.2 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. Similar survival benefits were observed using in utero electroporation and orthotopic mouse models of H3K27M-DMG (median 107 versus 77 days [p=0.02] and median 97 versus 141 days [p=0.004], respectively). Integrated transcriptomic and metabolomic analysis of ONC201-treated H3K27M-DMG cells revealed downregulation of TCA cycle, glycolysis, and pyruvate metabolism genes, most notably oxoglutarate dehydrogenase (OGDH), and concomitant changes in levels of associated metabolites including ɑ-ketoglutarate (ɑ-KG). Interestingly, L-2-hydroxyglutarate (L-2HG), a known inhibitor of the Jumonji C domain family of histone lysine demethylases, was also increased. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuro-glial differentiation genes. Genetic knockdown of OGDH recapitulated ONC201-mediated increases in H3K27me3. In contrast, genetic knockdown of ClpP or lactate dehydrogenase A or overexpression of L-2-hydroxyglutarate dehydrogenase (L-2HGDH), but not D-2HGDH, abrogated ONC201-mediated increases in H3K27me3, demonstrating that ONC201 induces the production of L-2HG in H3K27M-DMG cells leading to increased H3K27me3. Overall, our data demonstrates the efficacy of ONC201 in H3K27M-mutant DMG and supports ONC201 as the first monotherapy to improve outcomes in patients with H3K27M-mutant DMG for whom few therapeutic options currently exist. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction.

ABSTRACT How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes nonhomologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard-of-care genotoxic treatments. The GTP–Rac1–PP5–Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in nonmalignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment. SIGNIFICANCE: A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues. This article is featured in Selected Articles from This Issue, p. 5

Abstract Introduction In this pilot study, we explored sleep biomarker risk probabilities for different neurodegenerative disorder (NDD) phenotypes across a spectrum of NDD patients, compared with controls. Methods We analyzed a cohort of patients with different NDD phenotypes who underwent in-home recordings with Sleep Profiler, including Lewy body disease (LBD=20), Alzheimer’s disease dementia (AD=29), and isolated REM sleep behavior disorder (iRBD=19). Controls with an MMSE>28 (CG=61) and patients with Parkinson disease (PD=16) and mild-cognitive-impairment (MCI=41) also participated. We developed a machine-learning classifier that assigned NDD probabilities for LBD, AD, iRBD, and CG. The input variables included: time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha. Probabilities >50% were assigned “likely”, and for CG>=50% and a NDD group probability 20-50%, the assignment was normal “plus”. Probability assignments were then made for the NDD and CG groups, then further applied to the PD and MCI patient groups. Results The CG group participants were assigned Normal-Likely=74%, Normal+AD=11%, Normal+iRBD=5%, iRBD-Likely=5%, and AD-Likely=5%. LBD patient distributions were LBD-Likely=70%, iRBD-Likely=5%, AD-Likely=5%, Normal+LBD=5%, Normal+iRBD=5%, Normal+AD=5%, and Normal-Likely=5%. AD group distributions were AD-Likely=71%, LBD-Likely=4%, Normal+AD=14%, Normal+iRBD=4%, Normal-Likely=7%. iRBD patients were characterized with iRBD-Likely=37%, LBD-Likely=5%, AD-Likely=5%, Normal+iRBD=27%, Normal-Likely=26%. PD patients were assigned iRBD-Likely=29%, LBD-likely=14%, AD-Likely=14%, Normal+iRBD=21%, Normal+AD=7%, Normal-Likely=14%. MCI distributions were AD-Likely=45%, LBD-Likely=8%, iRBD-Likely=5%, Normal+AD=21%, Normal-Likely=13%. Conclusions For LBD, AD and CG groups, correct risk assignments were >70% while gross misclassifications were <10%. Classification patterns for PD, MCI and iRBD were disbursed in a manner consistent with the range of severities expected in each group.

Abstract Introduction Atypical N3 sleep (AN3=delta waves with limited theta and sigma) has been associated with ICU delirium and sepsis and averaged 25% of sleep time in Japanese ICU patients. We were interested in exploring whether AN3 might be a marker of cerebral dysfunction in ambulatory patients across a range of neurodegenerative disorders, including those with a dementia diagnosis. Methods After ethics review and with informed consent, patients with Lewy body disease (DLB/PDD: n=20,male=90%,age=70 + 6.2), Alzheimers disease dementia (AD: n=29,male=79%,age=75 + 6.7), Parkinson disease (PD: n=16,male=69%,age=67 + 8.7), mild cognitive impairment (MCI: n=41,male=63%,age=70 + 8.5), isolated REM sleep behavior disorder (iRBD: n=19,male=74%,age=64 + 9.6) and a control group (CG: n=61,male=47%,age=65 + 8.3) were studied with the Sleep Profiler and auto-detected AN3 computed. Between-group comparisons were assessed with Mann-Whitney U and Chi-square tests. Results The mean percentages of sleep time with AN3 were significantly greater in DLB/PDD (8 + 12.3) vs. PD (4 + 10.8), AD (2 + 3.7), MCI (2 + 2.3), iRBD (1 + 1.6), and CG (1 + 2.4)(all p<0.02). The proportions of records with abnormal AN3 (>5% of sleep time) were significantly greater in those with DLB/PDD=35% vs. MCI=10%, iRBD=5% and CG=5% (all p<0.05), but not AD=17% and PD=13%. Conclusions Further investigations are needed to determine if abnormal AN3 may be a biomarker that distinguishes patients with Lewy body spectrum diseases from alternative pathologies and/or could be helpful in monitoring the side effects of CNS-acting medications

Abstract Introduction Symptoms associated with autonomic nervous system dysfunction are common to patients with neurodegenerative disorders (NDD) resulting from the accumulation of α-synuclein in the neurons and glial cells. In this study we investigate whether a novel biomarker, the autonomic activation index, can discriminate these potentially affected NDD groups. Methods After ethics review and with informed consent, patients with Lewy body disease (DLB/PDD: n=20%), Alzheimer’s disease dementia (AD: n=27), Parkinson disease (PD: n=14), mild cognitive impairment (MCI: n=37), isolated REM sleep behavior disorder (iRBD: n=15) and a control group (CG: n=58) were studied with the Sleep Profiler. AAI was based on a 6 BPM increase in pulse rate compared to the previous/subsequent 10th second. Between-group comparisons were assessed with Mann-Whitney U and Chi-square tests. Results The AAI values for the DLB/PDD patients were decreased compared to the AD, MCI (both p<0.03), and CG (p<0.0005), while the PD was less than AD and MCI (both < 0.05) and CG (p<0.002). The proportions of cases with abnormal AAI values (<10 events/h) was greatest in DLB/PDD patients, and greater than in ADem (p<0.02), MCI (p<0.02) and CG (p<0.0001), while AAI in PD and iRBD was greater than in CG (p<0.007 and 0.05 respectively). Conclusions These findings suggest that the AAI can be used to objectively confirm subjective complaints of autonomic dysfunction symptoms in patients with synucleinopathies. Longitudinal studies are needed determine factors that influence changes in the AAI.

Abstract Introduction In 2015, Lee et al. observed sleeping position influenced the efficiency of glymphatic clearance in rats. In 2018, Levendowski et al. reported supine sleep was independently associated with neurodegenerative disorders (NDD)(odds ratio=3.7). This update further evaluates the comparative frequency of the supine sleep position across a spectrum of cognitive impairment, including patients diagnosed with a Parkinsonian spectrum disorder (PSD), Alzheimer’s disease dementia (AD) and mild cognitive impairment (MCI), compared with a control group (CG) of patients without a known cognitive disorder. Methods After ethics review and with informed consent, a control group (CG: n=170), PSD (n=36), AD (n=29) and MCI group (n=41) were studied in-home with the Sleep Profiler; 89% across two-nights. Between-group comparisons were assessed with Mann-Whitney U and Chi-square tests. Results The hours of supine sleep were greater in PSD=3.0 + 1.9, AD=3.2 + 2.0 and MCI=3.0 + 2.0 vs. CG=1.9 + 1.8 (all p<0.002). The proportion of patients with >2 hours of supine sleep were PSD=69%, AD=69% and MCI=59% vs. CG=39%, with odds ratios of PSD=3.6, AD=3.5 and MCI=2.2 (all p<0.001). Conclusions Here we provide further evidence for a relatively strong association between supine sleep and neurodegenerative disease including PSD, AD and MCI cohorts. The nature of this association remains unclear from cross sectional study designs. Future prospective studies should test if there is a causal link between supine sleep and subsequent development of neurodegeneration.