DOCSLIB.ORG

Cerebral Amyloid Angiopathy: a Systematic Review

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cerebral Amyloid Angiopathy: a Systematic Review REVIEW Print ISSN 1738-6586 / On-line ISSN 2005-5013 J Clin Neurol 2011;7:1-9 10.3988/jcn.2011.7.1.1 Cerebral Amyloid Angiopathy: A Systematic Review Alessandro Biffi,a,b,c Steven M. Greenbergb,c aCenter for Human Genetic Research, Massachusetts General Hospital, Boston MA, USA bDepartment of Neurology, Massachusetts General Hospital, Boston MA, USA cProgram in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA Received September 2, 2010 Cerebral amyloid angiopathy (CAA) is a disorder characterized by amyloid deposition in the walls Revised September 17, 2010 of leptomeningeal and cortical arteries, arterioles, and less often capillaries and veins of the cen- Accepted September 17, 2010 tral nervous system. CAA occurs mostly as a sporadic condition in the elderly, its incidence asso- Correspondence ciating with advancing age. All sporadic CAA cases are due to deposition of amyloid-β, originat- Alessandro Biffi, MD ing from proteolytic cleavage of the Amyloid Precursor Protein. Hereditary forms of CAA are Hemorrhagic Stroke Research generally familial (and therefore rare in the general population), more severe and earlier in onset. Group and Center for Human CAA-related lobar intracerebral hemorrhage is the most well-studied clinical condition associated Genetics Research, with brain amyloid deposition. Despite ever increasing understanding of CAA pathogenesis and Department of Neurology, availability of reliable clinical and diagnostic tools, preventive and therapeutic options remain very Massachusetts General Hospital, limited. Further research efforts are required in order to identify biological targets for novel CAA 185 Cambridge Street, treatment strategies. We present a systematic review of existing evidence regarding the epidemi- CPZN 6818, Boston, ology, genetics, pathogenesis, diagnosis and clinical management of CAA. MA 02114, USA J Clin Neurol 2011;7:1-9 Tel +1-617-643-3304 Fax +1-617-643-3293 Key Wordszzcerebral amyloid angiopathy, cerebral hemorrhage, dementia. E-mail [email protected] Introduction of CAA, provide an overview of diagnostic tools available to clinical neurologists, as well as summarize current guidelines The term cerebral amyloid angiopathy (CAA) describes an het- and recommendation for prevention and treatment of CAA-in- erogeneous group of biochemically and genetically diverse tracerebral hemorrhage (ICH)(See Appendix for literature central nervous system (CNS) disorders. All these medical con- Search criteria). ditions share a characteristic morphological finding on patho- logical examination, i.e. amyloid fibrils deposited in the walls Historical Perspective of small to medium-sized, blood vessels mostly arterial. In some instances amyloid deposits have been also observed in the cap- Vascular β-amyloid deposition in the central nervous system illaries of CNS parenchyma and of the leptomeninges. CAA was first described by Gustav Oppenheim in 1909. Oppenheim mostly occurs in the sporadic form in the elderly, while rare fa- found foci of necrosis in the brain parenchyma adjacent to hy- milial forms occur in younger patients and are generally lead to alinized capillary walls in 6 of 14 brains of autopsied individ- more severe clinical manifestations. While more than 25 hu- uals with senile dementia and the pathological changes of AD.4 man proteins or have been found to form amyloid fibrils in In 1938, Scholz published the first article focusing solely on vivo, only 7 have been described in CNS disorders,1,2 and all cerebral vascular abnormalities now recognized as CAA.5 The sporadic forms and most hereditary forms of CAA affecting the observation that CAA is limited to the vascular media without human brain are of the Aβ type (Aβ-CAA)(Table 1). In Aβ-CAA adjacent parenchymal involvement was made in 1954 by Ste- the action of β- and γ-secretases on the amyloid precursor pro- fanos Pantelakis.6 He also described many of the hallmark tein (APP) lead to deposition of amyloid-β (Aβ) peptide, mirror- pathological features of CAA: 1) preferential involvement of the ing some aspect of Alzheimer’s disease (AD) patophysiology.3 small arteries and capillaries of the meninges, cerebral cortex, In this review we will present a summary of existing evi- and cerebellar cortex; 2) topographical distribution favoring the dence regarding the epidemiology, genetics and pathogenesis posterior brain regions; 3) lack of staining of vessels in the white Copyright © 2011 Korean Neurological Association 1 Cerebral Amyloid Angiopathy: A Systematic Review Table 1. Sporadic and familial (hereditary) CAA forms Amyloid Precursor Chromo- Hemorrhagic Disease Notes peptide protein some stroke Aβ APP - Sporadic CAA + Aβ APP - CAA related to sporadic AD No increase in lobar ICH risk - Aβ APP 21 CAA related to familial AD Associated to presenilin-1 and presenilin-2 mutations - Aβ APP 21 CAA in Down syndrome Lobar ICH is rarely observed - Aβ APP 21 Hereditary Cerebral Described in 2 large families from the Netherlands + Hemorrhage with Amyloidosis: Age at onset: 50 years Dutch type Lobar hemorrhages, focal neurological deficits, dementia, and leukoencephalopathy Aβ APP 21 Hereditary Cerebral Hemorrhage Described in 3 Italian families + with Amyloidosis: Italian type Age at onset: 50 years Lobar hemorrhages and dementia Aβ APP 21 Hereditary Cerebral Described in a dutch family (discovered in Belgium, +/- Hemorrhage with Amyloidosis: therefore called “Flemish”) and a British family Flemish type Age at onset: 45 years Progressive AD-like dementia, in some patients associated with a lobar hemorrhage Aβ APP 21 Hereditary Cerebral Described in a Iowa family and a Spanish family +/- Hemorrhage with Amyloidosis: Age at onset: 50-66 years Iowa type Memory impairment, expressive language dysfunction, personality changes, myoclonic jerks, short-stepped gait, no clinically manifest ICH (family from Iowa) or lobar hemorrhages (family from Spain) Aβ APP 21 Hereditary Cerebral Hemorrhage Described in one family from Piedmont (Italy) + with Amyloidosis: Piedmont type Age at onset: 50-70 years Recurrent lobar hemorrhages, cognitive decline Aβ APP 21 Hereditary Cerebral Hemorrhage Described in one family from northern Sweden - with Amyloidosis: Age at onset: -60 years Arctic (Icelandic) type Progressive cognitive decline (no strokes) ACys Cystatin C 20 Hereditary Cerebral Hemorrhage Described in 9 sub-families in Iceland + with Amyloidosis: Icelandic type (one sporadic case in the US) Causes systemic amyloidosis Age at onset: 20-30 years Recurrent lobar hemorrhages ATTR Transthyretin 18 Meningovascular amyloidosis Polyneuropathy is the main clinical symptom In some Rarer findings: ataxia, spasticity and dementia families (rare) Systemic amyloidosis AGel Gelsolin 9 Familial Amyloidosis- Progressive corneal lattice dystrophy, cranial and - Finnish Type peripheral neuropathy, cutaneous amyloidosis Systemic amyloidosis PrPSc Prion 20 Gerstmann-Sträussler- Described in one family - Protein Scheinker syndrome Progressive cognitive decline ABri ABri 13 Familial British Dementia Described in 4 families - precursor Age at onset: 45-50 years protein Progressive dementia, cerebellar ataxia, spastic tetraparesis ADan ADan 13 Familial Danish Dementia Described in 1 family from Denmark - precursor Age at onset: 30 years protein Cataracts, deafness, progressive ataxia, dementia (previously known as “heredopatia ophtalmo-oto-encephalica”) AD: Alzheimer’s disease, CAA: cerebral amyloid angiopathy, ICH: intracerebral hemorrhage. 2 J Clin Neurol 2011;7:1-9 Biffi A and Greenberg SM matter; 4) association with increased age and dementia; 5) in the elderly attributable to CAA range from 10% to 20% in lack of association with hypertension and arteriosclerosis; 6) autopsy series to 34% in clinical series.12,15 lack of association with amyloidosis of the other organs. Over the following 20 years multiple case reports and small series Pathogenesis suggested an association between CAA and lobar ICH. Okaza- The 40-amino-acid-long Aβ (Aβ 1-40) is more soluble than ki and colleagues published a seminal article in 1979, clarify- the longer Aβ 1-42 and the two molecules differ in the distribu- ing the relationship between CAA and lobar ICH.7 They iden- tion in brain and vessel walls. Aβ 1-40 tends to be the major tified 23 consecutive cases of moderate to severe CAA from au- form in the amyloid in artery walls in CAA, whereas Aβ1-42 is topsies at Mayo Clinic (Rochester, MN). A history of lobar, mul- more prominent in the plaques in brain tissue.16,17 It is generally tiple hemorrhages was very common in these patients. Fibrinoid accepted that conformational transitions occurring in native sol- degeneration of the vessel walls with microaneurysm forma- uble amyloid molecules increase their content in β-sheet struc- tion was sometimes seen, as well as a double-barreled vessel tures, thus favoring the formation and deposition of more insol- wall appearance caused by cracking of the arterial media. Based uble oligomeric structures. In turn, these deposits trigger a se- on these findings, the authors concluded that CAA was an un- condary cascade of events including, among others, release of der-recognized cause of lobar ICH in the elderly, thus provid- inflammatory components, activation of the complement sys- ing the foundation for further exploration of CAA and CAA- tem, oxidative stress, alteration of the blood-brain barrier (BBB) related lobar ICH (CAA-ICH). permeability, and cell toxicity.18,19 While both deposited and soluble Aβ molecules are identi- Sporadic
Load more

Recommended publications
  • The Study of the Formation of Oligomers and Amyloid Plaques from Amylin by Capillary Electrophoresis and Fluorescent Microchip E
    University of Arkansas, Fayetteville ScholarWorks@UARK Biological and Agricultural Engineering Biological and Agricultural Engineering Undergraduate Honors Theses 5-2015 The tuds y of the formation of oligomers and amyloid plaques from Amylin by capillary electrophoresis and fluorescent microchip electrophoresis Shane Weindel University of Arkansas, Fayetteville Follow this and additional works at: http://scholarworks.uark.edu/baeguht Part of the Engineering Commons Recommended Citation Weindel, Shane, "The tudys of the formation of oligomers and amyloid plaques from Amylin by capillary electrophoresis and fluorescent microchip electrophoresis" (2015). Biological and Agricultural Engineering Undergraduate Honors Theses. 25. http://scholarworks.uark.edu/baeguht/25 This Thesis is brought to you for free and open access by the Biological and Agricultural Engineering at ScholarWorks@UARK. It has been accepted for inclusion in Biological and Agricultural Engineering Undergraduate Honors Theses by an authorized administrator of ScholarWorks@UARK. For more information, please contact [email protected], [email protected]. The Study of the Formation of Oligomers and Amyloid Plaques from Amylin by Capillary Electrophoresis and Fluorescent Microchip Electrophoresis Shane Weindel, Biological Engineering Undergraduate Christa Hestekin, Chemical Engineering Assistant Professor Department of Biological & Agricultural Engineering 203 Engineering Hall 1 University of Arkansas Abstract Amylin, a pancreatic β-cell hormone, was the focus of this research project. This hormone is co-localized and co-secreted with insulin in response to nutrient stimuli. The hormone inhibits food intake, gastric emptying and glucagon secretion. Insulin and amylin appear to complement each other in the control of plasma glucose levels. Human amylin has a propensity to self-aggregate and to form insoluble bodies.
    [Show full text]
  • Familial Mediterranean Fever: Effects of Genotype and Ethnicity on Inflammatory Attacks and Amyloidosis
    Familial Mediterranean Fever: Effects of Genotype and Ethnicity on Inflammatory Attacks and Amyloidosis Aviva Mimouni, MD*; Nurit Magal, PhD*; Nava Stoffman, MD*; Tamy Shohat, MD*; Ara Minasian, MD‡; Michael Krasnov, MD*; Gabrielle J. Halpern, MRCPsych*; Jerome I. Rotter, MD§; Nathan Fischel-Ghodsian, MD§; Yehuda L. Danon, MDʈ; and Mordechai Shohat, MD* ABSTRACT. Objective. The gene causing familial factors other than genotype, such as environment or genes Mediterranean fever (FMF)—an autosomal recessive dis- other than MEFV, play a role in the determination of the ease characterized by recurrent short episodes of fever severity of the inflammatory attacks in FMF. Pediatrics associated most commonly with peritonitis, pleuritis, 2000;105(5). URL: http://www.pediatrics.org/cgi/content/ and arthritis—has recently been found and several mu- full/105/5/e70; amyloidosis, specific mutation, phenotype-ge- tations identified. The most severe complication of the notype correlation, ethnicity. disease is amyloidosis, which can lead to renal failure. The aim of this study was to investigate the role of genetic versus nongenetic factors on the phenotype as ABBREVIATIONS. FMF, familial Mediterranean fever; MEFV, well as on the development of amyloidosis in FMF in a Mediterranean fever (the FMF gene); PCR, polymerase chain re- large and heterogeneous group of patients. action; CI, confidence interval. Methodology. We studied 382 patients from 4 ethnic origins living in different environments: North African amilial Mediterranean fever (FMF) is an auto- Jews, other Jews, Turks, Armenians living in the United somal recessive disease affecting primarily non- States, and Armenians from Yerevan, Armenia. Informa- tion regarding amyloidosis was available for 371 pa- Ashkenazi Jews, Armenians, Turks, and Ar- F1 tients.
    [Show full text]
  • Beta Amyloid Imaging with Positron Emission Tomography For
    Corporate Medical Policy Beta Amyloid Imaging With Positron Emission Tomography for Alzheimer’s Disease File Name: beta_amyloid_imaging_with_positron_emission_tomography_for_alzheimers_disease Origination: 10/2014 Last CAP Review: 5/2021 Next CAP Review: 5/2022 Last Review: 5/2021 Description of Procedure or Service Three radioactive tracers (florbetapir F18, flutemetamol F18, florbetaben F18) that bind to beta amyloid and can be detected in vivo with positron emission tomography (PET) have been developed. This technology is being evaluated to detect beta amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer disease (AD) and/or other causes of cognitive decline. Background The diagnosis of AD is divided into 3 categories: possible, probable, and definite AD. A diagnosis of definite AD requires postmortem confirmation of AD pathology, including the presence of extracellular beta amyloid plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. There can be a range of beta amyloid plaques and neurofibrillary tanges on histopathology that support a low, intermediate or high probability of AD. Probable AD dementia is diagnosed clinically when the patient meets core clinical criteria for dementia and has a typical clinical course for AD. A typical clinical course is defined as an insidious onset, with the initial and most prominent cognitive deficits being either amnestic or nonamnestic, e.g., language, visuospatial, or executive function deficits, and a history of progressively worsening cognition over time. A diagnosis of possible AD dementia is made when the patient meets the core clinical criteria for AD dementia but has an atypical course or an etiologically mixed presentation. Mild cognitive impairment (MCI) may be diagnosed when there is a change in cognition, but impairment is insufficient for the diagnosis of dementia.
    [Show full text]
  • A Guide to Transthyretin Amyloidosis
    A Guide to Transthyretin Amyloidosis Authored by Teresa Coelho, Bo-Goran Ericzon, Rodney Falk, Donna Grogan, Shu-ichi Ikeda, Mathew Maurer, Violaine Plante-Bordeneuve, Ole Suhr, Pedro Trigo 2016 Edition Edited by Merrill Benson, Mathew Maurer What is amyloidosis? Amyloidosis is a systemic disorder characterized by extra cellular deposition of a protein-derived material, known as amyloid, in multiple organs. Amyloidosis occurs when native or mutant poly- peptides misfold and aggregate as fibrils. The amyloid deposits cause local damage to the cells around which they are deposited leading to a variety of clinical symptoms. There are at least 23 different proteins associated with the amyloidoses. The most well-known type of amyloidosis is associated with a hematological disorder, in which amyloid fibrils are derived from monoclonal immunoglobulin light-chains (AL amyloidosis). This is associated with a clonal plasma cell disorder, closely related to and not uncommonly co-existing with multiple myeloma. Chronic inflammatory conditions such as rheumatoid arthritis or chronic infections such as bronchiectasis are associated with chronically elevated levels of the inflammatory protein, serum amyloid A, which may misfold and cause AA amyloidosis. The hereditary forms of amyloidosis are autosomal dominant diseases characterized by deposition of variant proteins, in dis- tinctive tissues. The most common hereditary form is transthyretin amyloidosis (ATTR) caused by the misfolding of protein monomers derived from the tetrameric protein transthyretin (TTR). Mutations in the gene for TTR frequently re- sult in instability of TTR and subsequent fibril formation. Closely related is wild-type TTR in which the native TTR protein, particu- larly in the elderly, can destabilize and re-aggregate causing non- familial cases of TTR amyloidosis.
    [Show full text]
  • Once AL Amyloidosis: Not Always AL Amyloidosis
    Amyloid The Journal of Protein Folding Disorders ISSN: 1350-6129 (Print) 1744-2818 (Online) Journal homepage: http://www.tandfonline.com/loi/iamy20 Once AL amyloidosis: not always AL amyloidosis Tulip Jhaveri, Shayna Sarosiek, Frederick L. Ruberg, Omar Siddiqi, John L. Berk & Vaishali Sanchorawala To cite this article: Tulip Jhaveri, Shayna Sarosiek, Frederick L. Ruberg, Omar Siddiqi, John L. Berk & Vaishali Sanchorawala (2018): Once AL amyloidosis: not always AL amyloidosis, Amyloid, DOI: 10.1080/13506129.2018.1449104 To link to this article: https://doi.org/10.1080/13506129.2018.1449104 Published online: 08 Mar 2018. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iamy20 AMYLOID, 2018 https://doi.org/10.1080/13506129.2018.1449104 LETTER TO THE EDITOR Once AL amyloidosis: not always AL amyloidosis Amyloid cardiomyopathy could be related to AL amyloidosis, He continued with haematologic complete response at this wild-type transthyretin amyloidosis (ATTRwt) or hereditary time without recurrence of lymphoma. In view of continued amyloidosis (ATTRm). It is crucial to distinguish and accur- hematologic CR and new cardiomyopathy, an endomyocardial ately type the precursor amyloidogenic protein in order to biopsy (age 76 years) revealed amyloid deposition by Congo offer appropriate treatment, prognosis and genetic counsel- red staining. Microdissection and liquid chromatography ing. Treatment for AL amyloidosis is directed towards the with laser capture tandem mass spectrometry identified plasma cell dyscrasia, whereas treatment for transthyretin transthyretin protein as the precursor amyloid protein. Serum amyloidosis is directed towards stabilization of misfolded isoelectric focusing and genetic testing demonstrated normal TTR [1] or reduction in production of mutant TTR [2,3].
    [Show full text]
  • Expert Consensus Recommendations to Improve Diagnosis of ATTR Amyloidosis with Polyneuropathy
    Journal of Neurology https://doi.org/10.1007/s00415-019-09688-0 REVIEW Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy David Adams1 · Yukio Ando2 · João Melo Beirão3 · Teresa Coelho4 · Morie A. Gertz5 · Julian D. Gillmore6 · Philip N. Hawkins6 · Isabelle Lousada7 · Ole B. Suhr8 · Giampaolo Merlini9,10 Received: 10 December 2019 / Revised: 20 December 2019 / Accepted: 23 December 2019 © The Author(s) 2020 Abstract Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic infammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormali- ties. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertro- phy.
    [Show full text]
  • Cerebral Amyloidosis, Amyloid Angiopathy, and Their Relationship to Stroke and Dementia
    65 Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia ∗ Jorge Ghiso and Blas Frangione β-pleated sheet structure, the conformation responsi- Department of Pathology, New York University School ble for their physicochemical properties and tinctoreal of Medicine, New York, NY, USA characteristics. So far, 20 different proteins have been identified as subunits of amyloid fibrils [56,57,60 (for review and nomenclature)]. Although collectively they Cerebral amyloid angiopathy (CAA) is the common term are products of normal genes, several amyloid precur- used to define the deposition of amyloid in the walls of sors contain abnormal amino acid substitutions that can medium- and small-size leptomeningeal and cortical arteries, arterioles and, less frequently, capillaries and veins. CAA impose an unusual potential for self-aggregation. In- is an important cause of cerebral hemorrhages although it creased levels of amyloid precursors, either in the cir- may also lead to ischemic infarction and dementia. It is a culation or locally at sites of deposition, are usually the feature commonly associated with normal aging, Alzheimer result of overexpression, defective clearance, or both. disease (AD), Down syndrome (DS), and Sporadic Cerebral Of all the amyloid proteins identified, less than half are Amyloid Angiopathy. Familial conditions in which amyloid known to cause amyloid deposition in the central ner- is chiefly deposited as CAA include hereditary cerebral hem- vous system (CNS), which in turn results in cognitive orrhage with amyloidosis of Icelandic type (HCHWA-I), fa- decline, dementia, stroke, cerebellar and extrapyrami- milial CAA related to Aβ variants, including hereditary cere- dal signs, or a combination of them.
    [Show full text]
  • Expression of Atrial and Brain Natriuretic Peptides and Their Genes in Hearts of Patients with Cardiac Amyloidosis
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 754 JACC Vol. 31, No. 4 March 15, 1998:254–65 Expression of Atrial and Brain Natriuretic Peptides and Their Genes in Hearts of Patients With Cardiac Amyloidosis GENZOU TAKEMURA, MD,*† YOSHIKI TAKATSU, MD,* KIYOSHI DOYAMA, MD,‡ HIROSHI ITOH, MD,‡ YOSHIHIKO SAITO, MD,‡ MASATOSHI KOSHIJI, MD,† FUMITAKA ANDO, MD,* TAKAKO FUJIWARA, MD,§ KAZUWA NAKAO, MD,‡ HISAYOSHI FUJIWARA, MD† Hyogo, Gifu and Kyoto, Japan Objectives. We investigated the expression of atrial natriuretic secretory granules in ventricular myoctyes of the patients with peptide (ANP) and brain natriuretic peptide (BNP) and their cardiac amyloidosis, but not in ventricular myocytes from the genes in the hearts of patients with cardiac amyloidosis and those normal control subjects. Double immunocytochemical analysis with isolated atrial amyloidosis. revealed the co-localization of ANP and BNP in the same granules Background. The expression of ANP and BNP is augmented in and that isolated atrial amyloid fibrils were immunoreactive for the ventricles of failing or hypertrophied hearts, or both. The ANP and BNP, whereas ventricular amyloid fibrils were negative expression of ANP and BNP in the ventricles of hearts with for both peptides. Both ANP mRNA and BNP mRNA were cardiac amyloidosis, which is hemodynamically similar to restric- expressed in the ventricles of the patients with cardiac amyloid- tive cardiomyopathy, is not yet known. ANP is the precursor osis but not in the normal ventricles. The autopsy study of four protein of isolated atrial amyloid. patients with cardiac amyloidosis revealed an almost transmural Methods.
    [Show full text]
  • Recognizing TTR-FAP Transthyretin Familial Amyloid Polyneuropathy
    This version is Global RC approved and local adaptation and approval is mandatory before distribution. Countries are responsible for language accuracy. Content to be updated with local information and labeling as required. Recognizing TTR-FAP Transthyretin Familial Amyloid Polyneuropathy About TTR-FAP TTR-FAP is a rare, genetic, TTR-FAP is caused by a mutation in the transthyretin gene, which can result in abnormal and unstable progressive and fatal transthyretin proteins. 2,3 neurodegenerative disease affecting an estimated 10,000 people worldwide.1 TTR-FAP – A Disease of Protein Misfolding Free Tetramer Folded Misfolded Toxic Intermediates Monamer Monamer & Amyloid Fibrils TTR-FAP affects men and women equally. Monamer Aggregation Misfolding Functional TTR Structures TTR Structures Symptoms usually begin to affect Associated with Pathology people in their 30s. These abnormal proteins build up and form toxic This varies with genetics and structures called amyloid fibrils, which may deposit in the peripheral nervous system, leading to a decline in ethnic background.2,3 The life neurologic function, or in other parts of the body, such expectancy for someone who as the heart, digestive system, and kidneys.2,3,4,5,6,7 is diagnosed with TTR-FAP is said to be about 10 years.13 Where is TTR-FAP Most Prevalent? There are clusters of TTR-FAP patients in Portugal, Japan, and Sweden.8 TTR-FAP is also found in countries such as the United States, various countries in Europe (e.g., France, Italy, Spain, Germany, and UK), Brazil, and Taiwan.9 Prevalence of TTR-FAP may vary by country of origin and by the type of TTR gene mutation.10 Symptoms of TTR-FAP Symptoms vary, but often, the feet Later, weakness gets worse in the and legs are affected first—with legs.11 The arms may be affected pain, tingling, numbness, or loss of too, starting at the figertips.11 the ability to feel hot and cold.11 Why Early Diagnosis is Key Although the disease affects people differently, it typically gets worse over time and can progress rapidly.
    [Show full text]
  • Cardiac Amyloidosis
    Cardiac Amyloidosis Ronald Witteles, MD Stanford University & Brendan M. Weiss, MD University of Pennsylvania Amyloidosis: What is it? • Amylum – Starch (Latin) • Generic term for many diseases: • Protein misfolds into β-sheets • Forms into 8-10 nm fibrils • Extracellular deposition into amyloid deposits Types of Amyloid – Incomplete List • Systemic: • Light chains (AL) – “Primary ” • Transthyretin (ATTR) – “Senile ” or “Familial ” or “FAC” or “FAP” • Serum amyloid A (AA) – “Secondary ” • Localized – Not to be memorized! • Beta-2 microglobulin (A-β2) – Dialysis (osteoarticular structures) • Apolipoprotein A-1 (AApoA-I) – Age-related (aortic intima, cardiac, neuropathic) • Apolipoprotein A-2 (AApoA-2) – Hereditary (kidney) • Calcitonin (ACal) – Complication of thyroid medullary CA • Islet amyloid polypeptide (AIAPP) – Age-related (seen in DM) • Atrial natriuretic peptide (AANF) – Age-related (atrial amyloidosis) • Prolactin (APro) – Age-related, pituitary tumors • Insulin (AIns) – Insulin-pump use (local effects) • Amyloid precursor protein (ABeta) – Age-related/hereditary (Alzheimers) • Prion protein (APrPsc) – Hereditary/sporadic (spongiform encephalopathies) • Cystatin-C (ACys) – Hereditary (cerebral hemorrhage) • Fibrinogen alpha chain (AFib) – Hereditary (kidney) • Lysozome (ALys) – Hereditary (Diffuse, especially kidney, spares heart) • Medin/Lactadherin – Age-related (medial aortic amyloidosis) • Gelsolin (AGel) – Hereditary (neuropathic, corneal) • Keratin – Cutaneous AL: A Brief Dive into Hematology… Plasma cells: Make antibodies
    [Show full text]
  • Breakthroughs in Antemortem Diagnosis of Neurodegenerative Diseases COMMENTARY Glenn C
    COMMENTARY Breakthroughs in antemortem diagnosis of neurodegenerative diseases COMMENTARY Glenn C. Tellinga,1 The World Health Organization forecasts that within 2 Abnormal cytoplasmic accumulation of a normally sol- decades neurodegenerative disorders will eclipse can- uble and unfolded protein called α-synuclein is the cer to become the foremost cause of death in the de- hallmark of diseases referred to as synucleinopathies. veloped world after cardiovascular disease. Accurate Neuronal deposition of α-synuclein aggregates in Lewy detection of pathological processes goes hand in hand bodies occurs in Parkinson’s disease (PD) and dementia with the goals of treatment and prevention and, in light with Lewy bodies (DLB). Yet another protein—the prion of their protracted but worsening clinical progression, protein (PrP)—is central to a group of interrelated dis- the earlier a diagnosis can be made the better. How- orders commonly referred to as prion diseases. ever, the challenge underlying accurate detection of Since the concept underlying the diagnostic ap- neurodegenerative diseases during their clinical phase proach taken by Metrick et al. (1) derives from studies is that specific biomarkers are not present at high of prions, it is worth reviewing what we have learned enough concentrations for routine detection in acces- about PrP and the applicability of these findings to sible specimens. Consequently, it has only been pos- other proteopathic diseases. The prion disorders are sible to definitively diagnose these conditions by transmissible neurodegenerative diseases affecting examination of brain pathology after death. The paper animals and humans. The most common human form by Metrick et al. (1) in PNAS addresses the issue of is Creutzfeldt–Jakob disease (CJD) which occurs most improved antemortem biomarker detection for a frequently as a sporadic, rapidly progressive condition spectrum of neurological disorders, using assays of older individuals.
    [Show full text]
  • The Increasing Impact of Cerebral Amyloid Angiopathy: Essential New
    JNNP Online First, published on August 26, 2017 as 10.1136/jnnp-2016-314697 Cerebrovascular disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2016-314697 on 26 August 2017. Downloaded from REVIEW The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice Gargi Banerjee,1 Roxana Carare,2 Charlotte Cordonnier,3 Steven M Greenberg,4 Julie A Schneider,5 Eric E Smith,6 Mark van Buchem,7 Jeroen van der Grond,7 Marcel M Verbeek,8,9 David J Werring1 For numbered affiliations see ABSTRact Furthermore, CAA gained new relevance with the end of article. Cerebral amyloid angiopathy (CAA) has never been advent of anti-Aβ immunotherapies for the treat- more relevant. The last 5 years have seen a rapid ment of Alzheimer’s disease (AD), as a sizeable Correspondence to increase in publications and research in the field, with proportion of those treated went on to develop Dr David J Werring, The National Hospital for Neurology and the development of new biomarkers for the disease, imaging features of CAA-related inflammation as 5 Neurosurgery, UCL Institute thanks to advances in MRI, amyloid positron emission an unintended consequence. This, together with of Neurology, Queen Square, tomography and cerebrospinal fluid biomarker analysis. advances in our understanding of the impact of London WC1N 3BG, UK; d. The inadvertent development of CAA-like pathology CAA on cognition, in the context of ICH, ageing werring@ ucl. ac. uk in patients treated with amyloid-beta immunotherapy and AD, has broadened the clinical spectrum Received 1 March 2017 for Alzheimer’s disease has highlighted the importance of disease to which the contribution of CAA is Revised 26 April 2017 of establishing how and why CAA develops; without recognised.
    [Show full text]