Molecular pathology of hereditary cerebral hemorrhage with amyloidosis-Dutch type

Hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D) is an early onset hereditary form of Cerebral amyloid angiopathy (CAA) caused by a point mutation of the Amyloid Precursor protein (APP). CAA refers to the accumulation of Amyloid β (Aβ) peptide, resulting from APP protein cleavage, in intracerebral vessels. CAA pathology is present in the majority of Alzheimer’s Disease (AD) brains and is associated with intracerebral hemorrhages in the elderly. The general aim of this thesis is to decipher the molecular pathogenesis of HCHWA-D. Since no proven therapeutic treatment exists to prevent or even delay the disease onset, the understanding of underlying pathomechanisms in HCHWA-D is important. It may help discovering new therapeutic targets and biomarkers that can be used to assess the efficacy of candidate drugs in treatment trials. The main finding of this thesis is that Transforming growth factor β (TGFβ) deregulation plays a central role in HCHWA-D pathogenesis. In the final chapter, the beneficial and detrimental aspects of TGFβ on the vascular and parenchymal brain components are reviewed and the possible causes of TGFβ activation in HCHWA-D as well as its implication for future studies and therapeutic intervention are discussed.Bontius Stichting (Leiden, Netherlands), the Dutch CAA Foundation (Rotterdam, Netherlands) and the Netherlands Organization for Scientific Research (NWO, The Hague, Netherlands), under research program VIDI, project “Amyloid and Vessels,” number 864.13.014LUMC / Geneeskund

Human-brain ferritin studied by muon spin rotation : a pilot study

Muon spin rotation is employed to investigate the spin dynamics of ferritin proteins isolated from the brain of an Alzheimer's disease (AD) patient and of a healthy control, using a sample of horse-spleen ferritin as a reference. A model based on the N\ue9el theory of superparamagnetism is developed in order to interpret the spin relaxation rate of the muons stopped by the core of the protein. Using this model, our preliminary observations show that ferritins from the healthy control are filled with a mineral compatible with ferrihydrite, while ferritins from the AD patient contain a crystalline phase with a larger magnetocrystalline anisotropy, possibly compatible with magnetite or maghemite

Human-brain ferritin studied by muon spin rotation: a pilot study

Muon Spin Rotation is employed to investigate the spin dynamics of ferritin proteins isolated from the brain of an Alzheimer's disease (AD) patient and of a healthy control, using a sample of horse-spleen ferritin as a reference. A model based on the N\'eel theory of superparamagnetism is developed in order to interpret the spin relaxation rate of the muons stopped by the core of the protein. Using this model, our preliminary observations show that ferritins from the healthy control are filled with a mineral compatible with ferrihydrite, while ferritins from the AD patient contain a crystalline phase with a larger magnetocrystalline anisotropy, possibly compatible with magnetite or maghemite.Comment: 16 pages, 9 figure

Amyloid imaging of dutch-type hereditary cerebral amyloid angiopathy carriers

Objective: To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular β-amyloid (Aβ) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) mutation. Methods: PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB-PET in 19 D-CAA mutation carriers (M+; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M−). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+, 8 M−). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aβ concentrations in 17 M+ and 11 M− participants who underwent lumbar puncture and compared the findings to PiB-PET and CSF Aβ in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. Results: D-CAA M+ showed greater age-dependent FLR PiB retention (p < 0.001) than M−, and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+, greater FLR PiB retention associated with reduced CSF concentrations of Aβ40 (r = −0.55, p = 0.021) but not Aβ42 (r = 0.01, p = 0.991). Despite comparably low CSF Aβ40 and Aβ42, PiB retention was substantially less in D-CAA than ADAD (p < 0.001). Interpretation: Increased PiB retention in D-CAA and correlation with reduced CSF Aβ40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019