Traumatic brain injury (TBI) significantly reduces the quality of life for millions of survivors worldwide, causing persistent brain tissue damage and cognitive impairments, with no established therapeutic interventions currently available. Slow-wave activity, a hallmark of deep sleep, has been implicated in recovery after TBI, but pharmacological approaches to enhance it lack specificity and scalability, complicating efforts to identify slow-wave activity as a direct mechanistic contributor and severely limiting clinical translation. To overcome these limitations, we developed a preclinical closed-loop auditory stimulation (CLAS) paradigm that targets sleep's slow waves, enabling highly specific and temporally precise enhancement of slow-wave activity. Therefore, we delivered 30-ms sound triggers targeting the up-phase of real-time detected slow-waves (upCLAS: TBI n = 8), or no sound stimulation (mockCLAS: non-TBI n = 8, TBI n = 7) during sleep to healthy controls (non-TBI) or brain injured (TBI) rats. Concomitantly, we assessed the ability of upCLAS-enhanced sleep to counteract brain tissue damage (primary outcome) and symptomatic sequelae (secondary outcome) of TBI. Bayesian analysis revealed that sound-mediated slow-wave activity enhancement: (1) reduces diffuse axonal injury, with TBI mockCLAS posterior estimates falling outside the 95% confidence intervals of both other groups, whereas the posterior distributions of TBI upCLAS and non-TBI groups largely overlapped (~13% posterior differences >0), consistent with a negligible effect size between groups; (2) decreases demyelination, with approximately 97% posterior differences >0 between TBI mockCLAS and TBI upCLAS groups, compared to approximately 60% between non-TBI and TBI upCLAS groups; and (3) preserves cognitive ability, with recognition indexes in the novel object recognition test significantly above chance level in non-TBI (*p = 0.031) and TBI upCLAS (*p = 0.026) groups, in contrast to mockCLAS-treated TBI rats (p = 0.156), presenting pronounced cognitive deficit. Furthermore, microglial response to brain injury was increased by deep sleep enhancement, with reduced ionized calcium-binding adaptor molecule 1+ area coverage in TBI upCLAS rats (*p = 0.0445) compared to non-TBI ones. These results unambiguously demonstrate slow-wave activity enhancement confers robust disease modification following TBI while overcoming major limitations of other preclinical approaches. Our findings constitute proof-of-concept that boosted sleep intensity mitigates histopathological and cognitive sequelae of brain trauma, suggesting that a clinically relevant, nonobtrusive, sleep-based therapy may represent a novel therapeutic intervention for TBI survivors. ANN NEUROL 2026.

The Parkinson's Progression Markers Initiative (PPMI) has remained at the vanguard of Parkinson's disease (PD) research through evolving recruitment strategies that mirror advances in PD biology. PPMI was initially focused on untreated, early-stage PD. Over time, it has expanded to include genetic cohorts, prodromal participants identified via olfactory testing and risk factor questionnaires targeting people with rapid eye movement (REM) sleep behavior disorder (RBD). Most recently, PPMI has focused on the biology underlying PD and sought to recruit individuals defined by neuronal alpha-synuclein disease (NSD) biomarkers. This evolution from clinical to biological enrollment demonstrates the feasibility of biomarker-driven cohort design and establishes a scalable model for early detection and prevention research in neurodegenerative disease. ANN NEUROL 2026.

The Path to Prevention (P2P) platform trial is a multicenter, multi-regimen, proof of concept, phase 2A, randomized clinical trial evaluating the safety and early efficacy of investigational products for the treatment of early-stage Neuronal Alpha-Synuclein disease (NSD) populations. The P2P trial is nested within the Parkinson's Progression Markers Initiative (PPMI), which means that its conceptualization, design, and implementation are based on learnings from the PPMI study. P2P will recruit eligible participants from the PPMI cohort. P2P will also leverage PPMI infrastructure including PPMI study sites and PPMI study cores including the site management, data management, biorepository, imaging, statistical, and data science cores for study execution. This paper reviews the conceptual design of P2P focusing on its relationship with PPMI to demonstrate how the connectivity between PPMI and P2P is essential for the success of the P2P study. P2P is an important step forward in clarifying the clinical trial design and regulatory path for interventions in the early-stage NSD population. ANN NEUROL 2026.

The Parkinson's Progression Marker Initiative (PPMI), sponsored by The Michael J. Fox Foundation for Parkinson's Research, is designed to develop disease biomarkers to accelerate Parkinson's disease (PD) therapeutics. During the past 15 years PPMI has acquired comprehensive clinical, imaging, biomarker and genetic data on thousands of participants that has guided clinical therapeutic studies for PD and related synucleinopathies. The study has established standardized strategies for acquisition and analysis of data and set a standard for data sharing and open-source publication. PPMI has by design consistently evolved to incorporate new knowledge and science. A key example is that PPMI data has enabled the transition from clinical to biologic definition of synucleinopathy. The study continues to expand our understanding of disease biology particularly in precise PD subsets in both in-clinic and a rapidly expanding remote participant cohort, using myPPMI, an online portal. This special issue reviews PPMI's continuing contribution to early detection, understanding disease biologic and staging, and innovative therapeutic strategies in PD and related synucleinopathies. ANN NEUROL 2026.

Immunohistochemically (IHC) measured transactive response DNA-binding protein 43 (TDP-43) inclusions are observed in Alzheimer's disease (AD) and are associated with medial temporal lobe atrophy. Accumulation of cryptic exons occurs in AD in response to TDP-43 pathology. We aimed to assess relationships between IHC and biochemically measured insoluble TDP-43 and cryptic exons and assess associations with hippocampal and amygdala volume loss and atrophy rates on magnetic resonance imaging (MRI). Eighty-one neuropathologically diagnosed AD cases were analyzed. For biochemistry, insoluble TDP-43 was quantified using a Meso-scale discovery (MSD) immunoassay. IHC-TDP burden was quantified with digital histopathology. Cryptic RNAs were assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Thirty-eight cases had serial brain MRI. Hippocampal and amygdala volumes were calculated using FreeSurfer. Regression models were used to investigate associations among IHC-TDP-43 status/burden, MSD-TDP status/levels, cryptic RNAs, and hippocampal and amygdala volumes and atrophy rates. IHC-TDP(+) cases exhibited elevated levels of MSD-TDP and cryptic RNAs (KCNQ2, STMN2, and UNC13A) and increased MSD-TDP levels were associated with increased cryptic RNA levels, in the hippocampus and amygdala. IHC-TDP(+) cases had smaller hippocampal and amygdala volumes compared to IHC-TDP(-) cases. MSD-TDP(+) cases had smaller hippocampal volumes and faster amygdala rates of atrophy compared with MSD-TDP(-) cases. Higher KCNQ2 and UNC13A levels were associated with smaller amygdala volumes. MSD-TDP level is a reliable surrogate for IHC-based TDP-43 status. Both TDP-43 and cryptic RNA levels are associated with reduced medial temporal volumes, suggesting cryptic exons may be playing a role in brain volume loss in AD. ANN NEUROL 2026.

Focal cortical dysplasia (FCD) is the most common cause of surgically treatable, drug-resistant epilepsy in children. Anxiety and depression are frequent comorbidities in epilepsy. This study examined whether FCD overlap with large-scale functional networks, the default mode network (DMN) and the limbic network, is associated with parent-reported anxiety or depressive symptoms. Sixty-nine patients with FCD-related epilepsy completed the Child Behavior Checklist (CBCL), among whom 56 finished the 6 to 18 years version of CBCL (CBCL6-18). FCD overlap (%) with Yeo 7-networks was calculated. General linear models tested FCDDMN or FCDlimbic overlap with CBCL Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM)-Anxiety Problems or DSM-Depressive Problems Scores controlling for age and gender. Fifty-six patients had preoperative CBCL6-18 (median age = 12.8 years, 55% male patients). FCDDMN overlap (B = 0.08, 95% confidence interval [CI] = 0.002-0.16, partial η2 = 0.086, p = 0.045) and female gender were associated with higher DSM-Depressive Problems T-scores. This lesion-network depressive-symptoms effect was stronger in an adolescent-only model (52% male patients): FCDDMN overlap (B = 0.19, 95% CI = 0.068-0.32, partial η2 = 0.37, p = 0.004). Network overlap was not associated with DSM-Anxiety Problems in any age group. FCDDMN overlap is associated with increased depressive symptoms, particularly for adolescents, whereas FCDlimbic overlap is not. These findings underscore the importance of lesion-network colocalization contributing to depression vulnerability in developmental epilepsy and highlight DMN colocalization involvement as a potential neurobiological marker of depressive risk. ANN NEUROL 2026.

We review the positive effects of several existing drugs from different classes, such as chemical chaperones, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), iron chelators, and cluster-Abelson tyrosine kinase inhibitors (c-Abl TKIs), in preclinical disease models and in available published human data following use of these drugs in individuals with common neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). A concept of combinatory neuroprotective therapy using a drug-repurposing approach is then discussed. Finally, we propose a strategy to design an ideal combination of drugs able to address multiple pathogenic processes involved in neurodegeneration to achieve clinically meaningful results. ANN NEUROL 2026 ANN NEUROL 2026;99:1099-1112.

For 25 years, The Michael J. Fox Foundation has made it our mission to harness the Parkinson's community's grit and generosity and turn it into tangible progress toward better treatments and cures. People and families living with Parkinson's, academic and industry researchers, treating physicians and allied health professionals, and regulators all have jumped in feet-first to get this job done. I am endlessly grateful for the vast wisdom and energy they have poured into our shared cause. This combined strength is nowhere more evident than in the Parkinson's Progression Markers Initiative (PPMI). Fifteen years in, two sets of experts — those who choose to be part of taking down Parkinson's and those who, like me, are here involuntarily — have formed a powerful partnership that is steadily dismantling the secrets of this complex disease. Quite frankly, there's nothing more rock-and-roll than PPMI: out of the gates a pioneering, bold, and astronomically expensive undertaking. “While there is no guarantee that validated biomarkers will result from PPMI,” we wrote in the 2010 press release announcing the study's launch, “their importance to therapeutic progress requires that we accept this risk.” Plenty of voices told us it would never work. Others underestimated the degree of difficulty, like the science reporter who patiently listened to us describing PPMI's ambitious goals, then wrapped up the conversation with a breezy “Call me when you find the biomarker!” That call didn't happen the next day, year, or decade. There were gaps — human-sized gaps — in our understanding of Parkinson's. But while we couldn't be certain when or even if the science would pan out, we were pretty sure we could motivate people with Parkinson's, those at risk, and control volunteers to join our study and be part of the solution they seek. Sure enough, the earliest participants to enroll in PPMI — those first 400 de novo patients and 200 age- and gender-matched controls — would eagerly blaze a path for tens of thousands to come. Scientists now had real-time access to deep, rich, and highly standardized clinical data and precious biosamples from a cohort that would come to span the entire continuum of Parkinson's risk, onset, and progression. Liberated from the challenge of assembling and funding small, ad hoc cohorts, they could turn their full attention to answering longstanding questions about the insidious biology of the human disease. Visit by visit, test by test, study participants helped us build an incredible data set. Researchers avidly leveraged it, with millions of data downloads powering thousands of individual studies worldwide. In addition, in 2023, the Foundation's CEO and co-founder Debi Brooks and founding Board member Nelle Fortenberry came to my home for an urgent meeting. Todd Sherer, chief mission officer, joined us remotely. Together, they shared the news that PPMI had done what it set out to do: validated a test to objectively and accurately detect Parkinson's biology in living people, even years before they had experienced a single symptom of the disease. Outside of milestone life events like my wedding or the births of my children, I'm not sure I have ever been so moved. I remember leaning forward to kiss Todd's forehead on my laptop screen. This was a game-changing moment for the field, not least for patients (myself included) who have had the singularly devastating experience of receiving a bolt-from-the-blue diagnosis and learning that by that point, more than half the dopamine cells in our brains have already been laid waste. The biomarker kicked down the door to a totally different way forward. From detecting Parkinson's before symptoms develop, to testing next-generation drugs against a wide range of biological targets, to the dream of precision medicine and even disease prevention, we are on the threshold of big things. Fueling PPMI on its path are the efforts of our nonprofit and philanthropic partners, scores of biotech and pharmaceutical companies, and hundreds of thousands of individual donors. For 15 years, alongside study volunteers and leadership, this incredible crew has built toward a cure that is now tantalizingly within reach. Their dedication runs deep — just like my gratitude for them. PPMI was once a bold risk. It's now widely recognized as the premier study in Parkinson's, a transformative resource that researchers can leverage to accelerate measurable scientific progress. But the contributions of strength and courage that got us here are impossible to measure. Thanks to the phenomenal Parkinson's community, PPMI is truly the study that is changing everything — and creating unprecedented opportunity for more breakthroughs. So, let's keep rocking and rolling until Parkinson's is only a memory. Michael J. Fox: Writing – original draft; writing – review and editing.