Volume 3, Issue 1, 2021

This study investigates the disease-modifying effect of acetyl-DL-leucine in two neurodegenerative lysosomal storage diseases with different aetiologies: Niemann-Pick type C and GM2 gangliosidosis in both murine models and clinical studies. Acetyl-DL-leucine and its L enantiomer provide neuroprotection likely by altering metabolism – a new therapeutic approach for these diseases.

GABA_A receptors containing the α5 subunit (α5) mediate tonic inhibition and impair memory. McGinnity et al. imaged α5 and compared individuals with TLE, but normal structural imaging, and healthy controls. Patients had reduced memory performance and bilaterally higher temporal lobe α5, but lower α1/2/3 in the ipsilateral hippocampus.

Mahadevan et al. identified a pentanucleotide (TTTCA)_n insertional expansion in intron 4 of the SAMD12 gene as a causal mutation for autosomal dominant cortical tremor, myoclonus and epilepsy in 102 patients, in the largest study of the racial clustering of autosomal dominant cortical tremor, myoclonus and epilepsy in a unique ethnic group in south India.

Van den Bossche et al. report a blood monocyte subset carrying brain-specific proteins and that relatively increases in case of brain tissue damage such as in glioma, brain metastases and stroke, which can be used to detect and monitor disease. Moreover, these monocytes predict survival in glioblastoma patients at presentation.

D’Souza et al. applied graph network measures to connectivity patterns in patients with unilateral glioma to assess global efficiency, modularity, and connectivity dependent on glioma localization, size, and distance from graph nodes. Results highlight cross-patient structural network changes that help identify susceptible hubs dependent on location of the lesion.

In right-hemispheric patients with neglect, the ability to benefit from non-spatial warning tones to shorten reaction times to visual stimuli depends on the integrity of the anterior insula and inferior frontal gyrus. Cazzoli et al. propose these regions as a hub through which the ventral attentional network ‘alerts’ its dorsal counterpart.

Varhaug et al. compared the utility of three serum biomarkers in mitochondrial disease—neurofilament light chain (NF-L), fibroblast growth factor-21 (FGF-21) and growth differentiation factor 15 (GDF-15). As expected, FGF-21 and GDF-15 were highest in patients with predominantly muscular symptoms. NF-L correlated with structural involvement of the brain especially where epilepsy occurred.

Thalamocortical hyperperfusion on arterial spin labelling MRI could be a new biomarker of non-convulsive status epilepticus according to the Salzburg criteria in critically ill patients. This thalamic hyperperfusion might contribute to the periodic discharges and rhythmic delta activity associated with non-convulsive status epilepticus.

As more patients with congenital heart disease are surviving into adulthood, interest mounts in the link between congenital heart disease and neurodevelopment across the lifespan. This is the first study in adults with congenital heart disease, demonstrating widespread alterations in white matter microstructure and an association with executive function deficits.

Mak et al. showed that elevated amyloid burden among people with Down syndrome is associated with reduced cerebral perfusion. Perfusion deficits were independent of grey-matter atrophy and also correlated with worse cognitive performance. These findings demonstrate the potential utility of perfusion imaging as a surrogate marker of disease progression.

The TRIDENT trial uses a ‘Trial Within a Cohort’ design to assess the safety and feasibility of escalating doses of foetal cells in participants with Huntington’s disease. This study focuses on addressing the many of constraints facing evaluation of advanced, non-pharmacological therapies in this and other neurodegenerative diseases.

Traumatic brain injury (TBI) is a leading cause of cognitive disability and often associated with episodic memory impairment. Adamovich-Zeitlin et al. reveal that neural biomarkers of variable mnemonic function (see figure) appear highly conserved in epileptic patients with and without significant TBI history, which may guide future neuromodulatory therapies.

As therapeutic hypothermia is partially protective in neonatal encephalopathy, adjunct therapies are required. In a piglet model of perinatal asphyxia, Pang et al. report that melatonin and erythropoietin are safe and individually augment cooling through different mechanisms. Staggered rather than concomitant dosing may be optimal for brain protection.

White-matter health deterioration plays a role in cognitive ageing. Using longitudinal imaging data, Poulakis et al. found four heterogeneous clusters of individuals with distinct spatial patterns of white-matter integrity trajectories. This heterogeneity was related to systemic health and not to brain amyloidosis and was associated with distinct cognitive trajectories.

Polymicrogyria is a common cortical malformation, yet genetic causes remain unclear. Stutterd et al. ascertained 123 patients for deep sequencing. Pathogenic variants were identified in 20.3% (25% mosaic). The two most commonly mutated genes were TUBA1A and PIK3R2. A genetic diagnosis found in ∼60% of patients with macrocephaly.

Degenerative cervical myelopathy is a relatively common spinal cord condition with variable presentation and a wide range of outcomes. Using both human and mouse data, Laliberte et al. demonstrate a link between elevated microRNA-21-5p expression and increased severity, inflammation and poor treatment outcomes in degenerative cervical myelopathy.

Landles et al. report that they have developed novel bioassays to provide a tool kit for the detection of soluble and aggregated isoforms of the HTT protein in tissue lysates from mouse models of Huntington’s disease on three bioassay platforms.

Using a computerized circle-tracing task with direct and indirect visual feedback, Lu et al. report the first evidence of visuomotor integration deficits in both familial and sporadic preclinical Alzheimer’s disease groups, suggesting that these deficits might precede the onset of clinical symptoms by several years.

Female sex, age and carriage of the APOE e4 allele are the greatest risk factors for sporadic Alzheimer's disease. Analysis of these three risk factors on hippocampal and subfield volumes in 36 653 healthy ageing individuals show two factors—female sex and APOE e4 status—confer selective vulnerability of specific hippocampal subfields to volume loss.

Schmidt et al. report that connectivity at rest within the brain’s reward system predicted changes in weight, differentiated between lean and participants with obesity, increased after gastric bypass surgery and correlated to circulating levels of the satiety hormone leptin. These findings show neural and hormonal determinants of weight change.

Somatic mutations can cause brain diseases. Currently, the only established route to study the brain-only somatic mutations is by sequencing brain tissues obtained from neurosurgery or autopsy. Ye et al. report a new strategy to use CSF cell-free DNA to detect brain-only somatic mutations as a surrogate for brain tissues.

Morgan et al. report that a novel candidate mutation in the HPDL gene (but not GAD1) segregates with disease status within a kindred in which a locus for autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513, GAD1) was mapped previously (in part of the kindred).

Homeostatic microglial marker P2Y12 receptor was accumulated around amyloid plaques in mouse models; this receptor was reduced in tauopathy mouse models prior to massive tangle formation. The down-regulation of P2Y12 receptor could be a sensitive index for neuroinflammatory responses to tau-induced neurodegeneration.

FMR1-premutation carriers can present clinically with a range of symptoms, including neuropsychiatric symptoms. Pathologically, the nuclear inclusions are positive for FMRpolyG and in the donors discussed here, also present in the vasculature. This has not been described before and this finding possibly contributes to the complex phenotype.

We previously identified a pro-epileptic gene network positively regulated by sestrin3 (SESN3). Here, we found that SESN3 knock-out rats have decreased susceptibility to seizures and reduced propensity to anxiety, suggesting that SESN3 may regulate mechanisms causally involved in the pathogenesis of both epilepsy and its comorbidities.

Banerji et al. identified a gluconeogenesis modulator, PK11195, a known mitochondrial translocator protein ligand that normalized metabolic deficits and suppressed electrographic seizures in a pre-clinical zebrafish model of Dravet syndrome. This suggests a novel metabolism-based therapeutic avenue to treat catastrophic paediatric epilepsies such as Dravet syndrome arising from ion channel mutations.

A small percentage of the US general population meet symptom criteria for traumatic encephalopathy syndrome. People with chronic pain, and those who have experienced suicidality in the past year, were much more likely to meet criteria.

The role of TMEM106B in modifying the progression of lysosomal storage disorders is investigated here. TMEM106B depletion ameliorates neuronal degeneration and some behavioural abnormalities in a pharmacological model of Gaucher disease. On the other hand, TMEM106B loss exacerbates Purkinje cell degeneration and motor deficits in a neuronal ceroid lipofuscinosis genetic mouse model.

Godelaine et al. investigated the prognostic value of serum neurofilament light chain in chronic inflammatory demyelinating polyneuropathy and showed in various logistic regression models that elevated serum neurofilament light chain levels were significantly associated with increased odds of 1-year disease progression, not responding to therapy during follow-up or both.

Tetanus is a severe but preventable infection. Olum et al. studied 190 tetanus admissions to one northern Uganda hospital. The overall mortality was 51.5%, with a marked male preponderance among adults—94 males versus 15 females. Their findings re-emphasise adult tetanus as a major problem in rural low-income settings.

Rod microglia are a variant of activated microglia reported in the brain after neurological injury and disease. Despite their discovery over 100 years ago, little is known about their formation, expression, or function. Advanced molecular tools are required to elucidate the role of rod microglia.

Meier et al. contemplated the similarities of risk factors, neuroinflammatory processes and potential neurological consequences between COVID-19 and Alzheimer’s disease/post-operative cognitive dysfunction. The observations yield the assumption that long-term consequences of COVID-19 may lead to cognitive impairment even in young individuals, affecting today’s workforce and eventually resulting in production loss.