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Category: neuroscience – Page 78

High-Level Alzheimer Disease Neuropathological Change Following Iatrogenic Exposure

Patients treated with cadaveric pituitary-derived human growth hormone contaminated with amyloid-β developed early-onset AlzheimerDisease with prominent language deficits and histopathological features consistent with AD.

Question What are the clinical and postmortem findings in iatrogenic Alzheimer disease (iAD) consequent to treatment with cadaveric pituitary–derived human growth hormone (c-hGH)?

Findings This case series describes a c-hGH recipient with early-onset dementia and prominent language involvement, in whom postmortem examination showed unequivocal neuropathological features of AD, including severe tauopathy. Three additional c-hGH recipients have similar cognitive syndromes characterized by prominent language involvement.

Meaning These results demonstrate that patients with iAD can have histopathological findings classically found in sporadic AD and that prominent language involvement might be an important phenotypic feature in this AD subtype.

A long-term and scalable system to record from neural organoids

Driving liver inflammation in MASH via multiple pathways.

Metabolic dysfunction-associated steatohepatitis (MASH) if not treated early, may lead to liver cirrhosis and hepatocellular carcinoma (liver cancer).

Hepatic lipotoxicity, intestinal dysbiosis, and pro-inflammatory diets have been attributed to the development of MASH. Moreover, obesity-induced adipose tissue inflammation also contributes to MASH.

The researchers in this review unravel complex, multiple parallel inflammatory mechanisms in MASH and describe how MASH drugs exert their effects. # sciencenewshighlights ScienceMission https://sciencemission.com/liver-inflammation-in-MASH

Intra-and extrahepatic inflammation in MASH is driven by various hits such as lipotoxicity, the gut microbiome, and proinflammatory diets. Inflammation contributes to hepatic and systemic complications, including cardiovascular diseases. Beneficial drugs in MASH might target metabolic and inflammatory pathways.

Signal, Speculation, and Standards of Proof in Iatrogenic AD

💬 Editorial: Current evidence supports iatrogenic transmission of cerebral amyloid angiopathy but not AlzheimerDisease; a definitive causal link between contaminated growth hormone exposure and AD remains speculative.

Neurodegenerative diseases caused by protein misfolding (eg, Alzheimer disease [AD], frontotemporal lobar degeneration, Parkinson disease) share many similarities with prion diseases. All demonstrate template-directed protein misfolding and propagation in vivo. However, with 1 exception, they have not exhibited interindividual or zoonotic transmission as observed in iatrogenic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease, respectively. An important unresolved question is whether other proteinopathies are transmissible between individuals, and if so, their potential impact on public health. To address these concerns, several prion centers have re-assessed cases of iatrogenic Creutzfeldt-Jakob disease due to cadaver-derived human growth hormone (c-hGH) and dura mater grafts. Although amyloid β (Aβ) plaques and cerebral amyloid angiopathy were commonly seen, tau pathology necessary for a diagnosis of AD was not.1,2 Thus, while there is adequate evidence that cerebral amyloid angiopathy may be acquired through iatrogenic mechanisms, iatrogenic transmission of AD pathology remained speculative.3

In 2024, Banerjee et al published an article entitled, “Iatrogenic Alzheimer’s Disease in Recipients of Cadaveric Pituitary-Derived Growth Hormone.”4 This assertion of iatrogenic AD (iAD) was largely predicated on the detection of Aβ seeds contaminating the c-hGH used in 8 recipients who later presented with concerns of cognitive impairment. The recipients had a variety of premorbid neurologic conditions that led to the need for hGH, many of which are themselves associated with later-life neuropathology, perhaps most notably radiotherapy and epilepsy. This report was met with some skepticism, given how the cases were diagnosed and the lack of biological evidence to confirm AD pathology in most participants.5,6

In this issue of JAMA Neurol ogy, the same group presents a report of an autopsy-confirmed case of AD in a c-hGH recipient and describes the clinical phenotype of 3 other c-hGH recipients.7 In their autopsy case, they describe cerebral amyloid angiopathy and high-level AD neuropathologic change (A3B3C3), providing the strongest confirmation of an AD diagnosis in their cohort. Additionally, this individual had limited premorbid medical conditions (complex partial seizures) and required hGH due to idiopathic growth hormone deficiency. They describe the clinical presentation as a mixed primary progressive aphasia phenotype and remark that 3 other c-hGH recipients presented similar primary progressive aphasia phenotypes. One of these was diagnosed with atypical AD due to unspecified single-photon emission computed tomography imaging findings and the other through a reduced Aβ42/40-cerebrospinal fluid ratio.

Brain Disease Decades Later? Study Links Childhood Surgery to Amyloid Build-Up

A new report describes two unusually young patients who developed cerebral amyloid angiopathy decades after childhood cardiac surgery. Researchers suspect amyloid-beta may have been inadvertently transmitted through cadaver-derived surgical material used at the time. The finding does not mean Alzheimer’s is contagious in everyday life, but it does add to evidence that rare past medical exposures may seed abnormal brain protein buildup years later.

Reference #18.45a42617.1774897640.756bc240

https://errors.edgesuite.net/18.45a42617.1774897640.756bc240

Newly discovered recessive neurodevelopmental disorder may be most prevalent ever

Researchers at the Icahn School of Medicine at Mount Sinai in New York have identified and described a previously unknown recessive neurodevelopmental disorder (NDD) that appears to be the most prevalent ever discovered. The condition is caused by changes in a small noncoding gene called RNU2-2. It is estimated to affect thousands of individuals in the United States and account for about 10% of all recessive NDD cases with a known genetic cause.

The work was done in collaboration with U.S. collaborators in the Undiagnosed Diseases Network led by colleagues at Stanford University and international collaborators in the United Kingdom, the Netherlands, Belgium, and Italy. The findings, published in the March 30 issue of Nature Genetics, provide long-awaited answers for many families and may inform future drug development.

The team found that the disorder is caused by a near-complete absence of a molecule called U2-2 RNA, which is produced by the RNU2-2 gene. Children with the condition typically inherit one altered copy of the gene from each parent, although sometimes changes arise spontaneously by genetic mutation. While the parents are unaffected, the combined effect on both copies of the gene in their children leads to disrupted brain development in their child.

This tiny implant, smaller than a grain of salt, can read your brain

A new neural implant is so small it can rest on a grain of salt, yet it can track and wirelessly transmit brain activity for over a year. It’s powered by laser light that safely passes through tissue and communicates using tiny infrared signals. This ultra-miniature device could transform how scientists study the brain without invasive wiring.

Epigenetic regulation of serine biosynthesis by PHF8 during neurogenesis

Linking epigenetics and metabolism in neurogenesis!

Epigenetic regulation and metabolism are tightly coordinated during progenitor cell growth but the processes linking this crosstalk is not well understood.

The researchers examined in neural stem cells the role of PHF8, a histone demethylase whose mutations are linked to Siderius-Hamel syndrome, a rare neurodevelopmental disorder.

The authors show that PHF8 regulates neural progenitor proliferation by coordinating epigenetic and metabolic programs and drives serine biosynthesis by maintaining chromatin accessibility of serine synthesis genes.

They also demonstrate that loss of PHF8 disrupts metabolism, autophagy, and vesicle formation and its deficiency leads to DNA damage and halts neurogenesis in vivo. sciencenewshighlights ScienceMission https://sciencemission.com/Epigenetic-regulation-of-serine-biosynthesis

Progenitor proliferation during neurodevelopment requires tight coordination of epigenetic regulation and metabolism. However, the crosstalk between these processes remains poorly understood. To investigate this, we examine in neural stem cells the role of PHF8, a histone demethylase whose mutations are linked to Siderius-Hamel syndrome, a rare neurodevelopmental disorder. Through an integrated multi-omics approach — combining transcriptomics, epigenomics, and metabolomics — we identify PHF8 as a key driver of the serine biosynthesis pathway, safeguarding the intracellular serine pool essential for neural progenitor proliferation. PHF8 fine-tunes chromatin accessibility at promoters of metabolic genes, ensuring their activation during development. Loss of PHF8 disrupts amino acid metabolism, blocks autophagy, and hinders vesicle formation.

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