Human iPSC-derived pericyte-like cells carrying APP Swedish mutation overproduce beta-amyloid and induce cerebral amyloid angiopathy-like changes.

Background: Patients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aβ) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis, and vessel stability. Despite the known impact of vascular dysfunction on the progression of neurodegenerative diseases, the specific role of pericytes in AD pathology remains to be elucidated.

T1 relaxation and axon fibre configuration in human white matter.

Understanding the effects of white matter (WM) axon fibre microstructure on T1 relaxation is important for neuroimaging. Here, we have studied the interrelationship between T1 and axon fibre configurations at 3T and 7T. T1 and S0 (=signal intensity at zero TI) were computed from MP2RAGE images acquired with six inversion recovery times.

Long-term complications in acute porphyria.

New treatment options and low attack-related mortality have changed the life expectancy of patients with acute porphyria (AP) to that of the general population. Clinicians should therefore be aware of the long-term complications of AP, which typically include chronic neuropathy and encephalopathy, high blood pressure and porphyria-associated kidney disease. Patients have an increased risk of primary liver cancer (PLC), but no increased risk of non-hepatic cancers.

Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation.

Defects in hydroxymethylbilane synthase (HMBS) can cause acute intermittent porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ∼⅓ of clinical HMBS variants are missense variants, and most clinically reported HMBS missense variants are designated as "variants of uncertain significance" (VUSs). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino acid substitutions.

Axon fiber orientation as the source of T relaxation anisotropy in white matter: A study on corpus callosum in vivo and ex vivo.

Purpose: Recent studies indicate that T in white matter (WM) is influenced by fiber orientation in B . The purpose of the study was to investigate the interrelationships between axon fiber orientation in corpus callosum (CC) and T relaxation time in humans in vivo as well as in rat brain ex vivo.

Methods: Volunteers were scanned for relaxometric and diffusion MRI at 3 T and 7 T.

Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation.

Defects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~⅓ of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as "variants of uncertain significance" (VUS). Using saturation mutagenesis, selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino-acid substitutions.

Pathogenesis of acute encephalopathy in acute hepatic porphyria.

Acute encephalopathy (AE) can be a manifestation of an acute porphyric attack. Clinical data were studied in 32 patients during AE with or without polyneuropathy (PNP) together with 12 subjects with PNP but no AE, and 17 with dysautonomia solely. Brain neuroimaging was done in 20 attacks during AE, and PEPT2 polymorphisms were studied in 56 subjects, 24 with AE.

Effects of rifampicin on porphyrin metabolism in healthy volunteers.

Pregnane X receptor (PXR) is known to stimulate haem synthesis, but detailed knowledge on the effects of PXR activation on porphyrin metabolism in humans is lacking. We utilized a randomized, crossover, open (blinded laboratory) and placebo-controlled trial with 600-mg rifampicin or placebo dosed for a week to investigate the effects of PXR activation on erythrocyte, plasma, faecal and urine porphyrins. Sixteen healthy volunteers participated on the trial, but the number of volunteers for blood and urine porphyrin analyses was 15 while the number of samples for faecal analyses was 14.

EXPLORE B: A prospective, long-term natural history study of patients with acute hepatic porphyria with chronic symptoms.

One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. EXPLORE B is a long-term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with ≥1 attack in the 12 months before enrollment or receiving hemin or gonadotropin-releasing hormone prophylaxis.

White matter microstructure and longitudinal relaxation time anisotropy in human brain at 3 and 7 T.

A high degree of structural order by white matter (WM) fibre tracts creates a physicochemical environment where water relaxations are rendered anisotropic. Recently, angularly dependent longitudinal relaxation has been reported in human WM. We have characterised interrelationships between T1 relaxation and diffusion MRI microstructural indices at 3 and 7 T.

Long-term follow-up of acute porphyria in female patients: Update of clinical outcome and life expectancy.

Background: Acute hepatic porphyria includes four inherited disorders caused by partial deficiencies of enzymes related to the heme biosynthesis. Clinical manifestations include acute attacks, occurring mainly among female patients. This study describes the diversity of acute symptoms, changes in triggering factors and life expectancy among female patients during the past five decades.

T2 heterogeneity as an in vivo marker of microstructural integrity in medial temporal lobe subfields in ageing and mild cognitive impairment.

A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer's disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative MRI measure of early pathology than absolute T2.

Accelerated long-term forgetting in healthy older adults predicts cognitive decline over 1 year.

Background: Here, we address a pivotal factor in Alzheimer's prevention-identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer's disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer's disease.

T2 heterogeneity: a novel marker of microstructural integrity associated with cognitive decline in people with mild cognitive impairment.

Background: Early Alzheimer's disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, several microstructural changes take place as a result of Alzheimer's pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death.

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

Background: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.

Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.

Prospective memory in prodromal Alzheimer's disease: Real world relevance and correlations with cortical thickness and hippocampal subfield volumes.

Introduction: Prospective memory (PM) is a marker of independent living in Alzheimer's disease. PM requires cue identification (prospective component) and remembering what should happen in response to the cue (retrospective component). We assessed neuroanatomical basis and functional relevance of PM.

Penetrance and predictive value of genetic screening in acute porphyria.

Objective: Penetrance, predictive value and female patients' perspectives on genetic testing were evaluated among Finnish patients with acute porphyria. We conducted a retrospective study to evaluate prognosis among at-risk female family members depending on the primary method of diagnosis.

Methods: The penetrance was calculated among 23 genetically heterogeneous families selected from the Finnish porphyria registry (n = 515, AIP 333; VP 182).

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

Background And Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.

Determining T2 relaxation time and stroke onset relationship in ischaemic stroke within apparent diffusion coefficient-defined lesions. A user-independent method for quantifying the impact of stroke in the human brain.

Background And Objective: In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions.

The first year of treatment predicts the prognosis of asthma over 25 y-A prospective study.

Background: An investigator-driven, real-life follow-up study of adult-onset steroid-naïve, newly diagnosed asthma (162 patients) to investigate the treatment results over the 25-year course of the disease and whether the first treatment year's forced expiratory volume in one second (FEV ) predicts the long-term prognosis.

Methods: Eighty-three per cent of the 133 living patients participated in the 25-year examinations. At this visit, basic asthma examinations including lung function, as well as questionnaires for health-related quality of life (HRQoL), GINA and the Asthma Control Test, were used for evaluation.

International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias.

With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs with biochemically and clinically verified information.