Lumbar punctures are safe in patients with ALS and have a risk profile similar to that in the non-ALS population.

INTRODUCTION/AIMS: Analysis of biofluids, especially cerebrospinal fluid (CSF), is critically important for amyotrophic lateral sclerosis (ALS) research. Collection of CSF is typically performed by lumbar puncture (LP). Previous studies have demonstrated the safety of LPs in patients with other neurodegenerative diseases, such as Alzheimer's disease, although there are no published studies of the safety of LPs in patients with ALS. We performed a retrospective analysis of complications resulting from LPs. METHODS: This is a retrospective study of LPs performed between 2015 and 2021 on a total of 233 participants (healthy controls [n = 63], ALS [n = 154], and disease controls [n = 16]) as part of clinical research studies at the Washington University ALS Center. We used bivariate logistical analyses looking for associations between participant characteristics and adverse events (AEs), and likelihood ratio tests were used for significance testing. RESULTS: We found an overall AE rate of 21.03%. AEs included headache, back pain, vasovagal syncope, and severe headache requiring epidural blood patch. Participants with ALS were not more likely to experience post-LP AEs compared to controls (odds ratio [OR] 0.61 [0.32-1.18]). Post-LP headaches were significantly less likely in participants with ALS (OR 0.36 [0.15-0.83]). DISCUSSION: Our findings demonstrate that LP is a safe procedure for participants with ALS, with a similar or lower rate of AEs than in participants without ALS.

Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model.

OBJECTIVE: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. METHODS: We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. RESULTS: We observed previously established medical associations for MND and an inverse dose-response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. INTERPRETATION: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881-892.

Antisense Oligonucleotides for the Study and Treatment of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.

Adult-Onset Subacute Sclerosing Panencephalitis With a 30-Year Latent Period.

Subacute sclerosing panencephalitis (SSPE) is a rare progressive neuroinfectious disease due to a late complication of the measles virus. The hallmark clinical features of this disease include behavioral changes, myoclonus, dementia, visual disturbances, and pyramidal and extrapyramidal signs. The presence of characteristic high-amplitude periodic complexes on electroencephalography and raised antibody titers against measles in the cerebrospinal fluid help solidify the diagnosis. We present a case of a 40-year-old patient with SSPE who initially developed ophthalmologic manifestations 30 years after the primary measles infection. This case highlights both typical and atypical features of SSPE and provides a diagnostic framework for evaluating cases that fall outside of the standard scope of this disease.

Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation.

Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a common and devastating problem. Because impaired breathing is thought to play a critical role in these deaths, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We took advantage of an extraordinary clinical opportunity to study a research participant with medically intractable epilepsy who had extensive bilateral frontotemporal electrode coverage while breathing was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We found that central apnea and O2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. The participants were completely unaware of the apnea evoked by stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding of similar duration caused severe dyspnea. These findings suggest a functional connection between the amygdala and medullary respiratory network in humans. Moreover, they suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP. SIGNIFICANCE STATEMENT: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Impaired breathing during and after seizures is common and suspected to play a role in SUDEP. Understanding the cause of this peri-ictal hypoventilation may lead to preventative strategies. In epilepsy patients, we found that seizure invasion of the amygdala co-occurred with apnea and oxygen desaturation, and electrical stimulation of the amygdala reproduced these respiratory findings. Strikingly, the subjects were unaware of the apnea. These findings indicate a functional connection between the amygdala and brainstem respiratory network in humans and suggest that amygdala seizures may cause loss of spontaneous breathing of which patients are unaware-a combination that could be deadly.

The bed nucleus of the stria terminalis is critical for anxiety-related behavior evoked by CO2 and acidosis.

Carbon dioxide (CO2) inhalation lowers brain pH and induces anxiety, fear, and panic responses in humans. In mice, CO2 produces freezing and avoidance behavior that has been suggested to depend on the amygdala. However, a recent study in humans with bilateral amygdala lesions revealed that CO2 can trigger fear and panic even in the absence of amygdalae, suggesting the importance of extra-amygdalar brain structures. Because the bed nucleus of the stria terminalis (BNST) contributes to fear- and anxiety-related behaviors and expresses acid-sensing ion channel-1A (ASIC1A), we hypothesized that the BNST plays an important role in CO2-evoked fear-related behaviors in mice. We found that BNST lesions decreased both CO2-evoked freezing and CO2-conditioned place avoidance. In addition, we found that CO2 inhalation caused BNST acidosis and that acidosis was sufficient to depolarize BNST neurons and induce freezing behavior; both responses depended on ASIC1A. Finally, disrupting Asic1a specifically in the BNST reduced CO2-evoked freezing, whereas virus-vector-mediated expression of ASIC1A in the BNST of Asic1a(-/-) and Asic1a(+/+) mice increased CO2-evoked freezing. Together, these findings identify the BNST as an extra-amygdalar fear circuit structure important in CO2-evoked fear-related behavior.

Drug abuse and the simplest neurotransmitter.

Neurotransmitter vesicles are known to concentrate hydrogen ions (or protons), the simplest ion, and to release them during neurotransmission. Furthermore, receptors highly sensitive to protons, acid-sensing ion channels (ASICs), were previously localized on the opposite side of the synaptic cleft on dendritic spines. Now, recent experiments provide some of the strongest support to date that protons function as a neurotransmitter in mice, crossing synapses onto medium spiny neurons of the nucleus accumbens (NAc), activating ASICs, and ultimately suppressing drug abuse-related behaviors.

Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity.

Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission.

Acid-sensing ion channels in pain and disease.

Why do neurons sense extracellular acid? In large part, this question has driven increasing investigation on acid-sensing ion channels (ASICs) in the CNS and the peripheral nervous system for the past two decades. Significant progress has been made in understanding the structure and function of ASICs at the molecular level. Studies aimed at clarifying their physiological importance have suggested roles for ASICs in pain, neurological and psychiatric disease. This Review highlights recent findings linking these channels to physiology and disease. In addition, it discusses some of the implications for therapy and points out questions that remain unanswered.