The Clinical Promise of Biomarkers of Synapse Damage or Loss in Alzheimer’s Disease

BACKGROUND: Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD.Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance.Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD.Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs.The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. CONCLUSION: A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes

Molecular genetics of Creutzfeldt-Jakob disease and Gerstmann- Sträussler- Scheinker disease

Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker disease (GSS) are distinct clinicopathological phenotypes of human prion diseases or transmissible spongiform encephalopathies (TSEs). TSEs arise either spontaneously (sporadic disease forms such as sporadic CJD/sCJD or sporadic fatal insomnia/sFI), by genetic aberration (genetic CJD/gCJD, GSS, fatal familial insomnia/FFI) or acquired by contact with infectious prions from bovine spongiform encephalopathy (BSE), causing variant CJD (vCJD), or – more or less historically – as iatrogenic CJD (iCJD) from invasive medical procedures such as dural or corneal transplantations, cadaveric pituitary hormone preparations or surgical instruments, or from blood and blood products with vCJD prions. Genetic forms constitute about 10–15% of human prion diseases and result from more than 30 mutations, insertions or rarely deletions in the prion protein (PrP) gene, PRNP. A polymorphism at PRNP codon 129 is an important susceptibility factor and relevant for phenotypic heterogeneity. Other genes have not convincingly been shown to be involved. Key Concepts: Prion diseases are invariably lethal and transmissible neurological disorders that affect humans and animals. In humans, they occur sporadically and can also be acquired or inherited. The infectious agent is considered to be solely an abnormal conformer of the host-encoded prion protein (PrP). Genetic disease forms constitute about 10–15%, result from aberrations in the PrP gene, PRNP, and are inherited as autosomal dominant trait with variable penetrance. There is a broad clinical and neuropathological phenotypic spectrum, which is modulated by molecular factors including PRNP polymorphisms and PrP strains. Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker disease (GSS) are distinct clinicopathological phenotypes. CJD occurs mostly sporadically (sCJD), more rarely by genetic aberration (gCJD), whereas GSS is always of genetic origin. There is no effective treatment yet

sj-csv-3-bna-10.1177_23982128231191046 – Supplemental material for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model

Supplemental material, sj-csv-3-bna-10.1177_23982128231191046 for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model by Caitlin Davies, Jane Tulloch, Ellie Yip, Lydia Currie, Marti Colom-Cadena, Susanne Wegmann, Bradley T Hyman, Lewis Wilkins, Monique Hooley, Makis Tzioras and Tara L Spires-Jones in Brain and Neuroscience Advances</p

sj-Rmd-4-bna-10.1177_23982128231191046 – Supplemental material for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model

Supplemental material, sj-Rmd-4-bna-10.1177_23982128231191046 for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model by Caitlin Davies, Jane Tulloch, Ellie Yip, Lydia Currie, Marti Colom-Cadena, Susanne Wegmann, Bradley T Hyman, Lewis Wilkins, Monique Hooley, Makis Tzioras and Tara L Spires-Jones in Brain and Neuroscience Advances</p

sj-pdf-5-bna-10.1177_23982128231191046 – Supplemental material for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model

Supplemental material, sj-pdf-5-bna-10.1177_23982128231191046 for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model by Caitlin Davies, Jane Tulloch, Ellie Yip, Lydia Currie, Marti Colom-Cadena, Susanne Wegmann, Bradley T Hyman, Lewis Wilkins, Monique Hooley, Makis Tzioras and Tara L Spires-Jones in Brain and Neuroscience Advances</p

sj-csv-1-bna-10.1177_23982128231191046 – Supplemental material for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model

Supplemental material, sj-csv-1-bna-10.1177_23982128231191046 for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model by Caitlin Davies, Jane Tulloch, Ellie Yip, Lydia Currie, Marti Colom-Cadena, Susanne Wegmann, Bradley T Hyman, Lewis Wilkins, Monique Hooley, Makis Tzioras and Tara L Spires-Jones in Brain and Neuroscience Advances</p

sj-Rmd-2-bna-10.1177_23982128231191046 – Supplemental material for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model

Supplemental material, sj-Rmd-2-bna-10.1177_23982128231191046 for Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model by Caitlin Davies, Jane Tulloch, Ellie Yip, Lydia Currie, Marti Colom-Cadena, Susanne Wegmann, Bradley T Hyman, Lewis Wilkins, Monique Hooley, Makis Tzioras and Tara L Spires-Jones in Brain and Neuroscience Advances</p