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Alzheimer disease, type 3(AD)

MedGen UID:
334304
Concept ID:
C1843013
Disease or Syndrome
Synonyms: AD; Alzheimer disease early onset type 3; ALZHEIMER DISEASE, FAMILIAL, 3
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): PSEN1 (14q24.2)
OMIM®: 607822

Definition

Alzheimer disease (AD) is characterized by adult-onset progressive dementia associated with cerebral cortical atrophy, beta-amyloid plaque formation, and intraneuronal neurofibrillary tangles. AD typically begins with subtle memory failure that becomes more severe and is eventually incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, hallucinations, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism. Familial AD (FAD) characterizes families that have more than one member with AD and usually implies multiple affected persons in more than one generation. Early-onset FAD (EOFAD) refers to families in which onset is consistently before age 60 to 65 years and often before age 55 years. [from GTR]

Additional descriptions

From GeneReviews
Alzheimer disease (AD) is characterized by adult-onset progressive dementia associated with cerebral cortical atrophy, beta-amyloid plaque formation, and intraneuronal neurofibrillary tangles. AD typically begins with subtle memory failure that becomes more severe and is eventually incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, hallucinations, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism. Familial AD (FAD) characterizes families that have more than one member with AD and usually implies multiple affected persons in more than one generation. Early-onset FAD (EOFAD) refers to families in which onset is consistently before age 60 to 65 years and often before age 55 years.  https://www.ncbi.nlm.nih.gov/books/NBK1236
From GHR
Alzheimer disease is a degenerative disease of the brain that causes dementia, which is a gradual loss of memory, judgment, and ability to function. This disorder usually appears in people older than age 65, but less common forms of the disease appear earlier in adulthood.Memory loss is the most common sign of Alzheimer disease. Forgetfulness may be subtle at first, but the loss of memory worsens over time until it interferes with most aspects of daily living. Even in familiar settings, a person with Alzheimer disease may get lost or become confused. Routine tasks such as preparing meals, doing laundry, and performing other household chores can be challenging. Additionally, it may become difficult to recognize people and name objects. Affected people increasingly require help with dressing, eating, and personal care.As the disorder progresses, some people with Alzheimer disease experience personality and behavioral changes and have trouble interacting in a socially appropriate manner. Other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. People with this disease usually require total care during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting (inanition).Alzheimer disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear before age 65, while the late-onset form appears after age 65. The early-onset form is much less common than the late-onset form, accounting for less than 5 percent of all cases of Alzheimer disease.  https://ghr.nlm.nih.gov/condition/alzheimer-disease

Clinical features

Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
Agnosia
MedGen UID:
174
Concept ID:
C0001816
Mental or Behavioral Dysfunction
A rare disorder characterized by the lack of ability to recognize individuals, objects, shapes, sounds, or smells. There is no loss of memory. It is caused by neurological damage in the brain, specifically in the occipital or parietal lobes.
Alzheimer disease
MedGen UID:
1853
Concept ID:
C0002395
Disease or Syndrome
Alzheimer disease (AD) is characterized by dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur. Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range from one to 25 years. Approximately 25% of all AD is familial (i.e., =2 persons in a family have AD) of which approximately 95% is late onset (age >60-65 years) and 5% is early onset (age <65 years).
Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
A defect in the understanding of complex motor commands and in the execution of certain learned movements, i.e., deficits in the cognitive components of learned movements.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from CRANIAL NERVE DISEASES; NEUROMUSCULAR DISEASES; CEREBELLAR DISEASES; BASAL GANGLIA DISEASES; BRAIN STEM diseases; or diseases of the corticobulbar tracts (see PYRAMIDAL TRACTS). The cortical language centers are intact in this condition. (From Adams et al., Principles of Neurology, 6th ed, p489)
Dystonia
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
A rapid, involuntary jerk of a muscle or group of muscles.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
A reflex characterized by upward movement of the great toe and an outward movement of the rest of the toes, when the sole of the foot is stroked. It is a normal reflex up to the age of two. Its presence beyond that age indicates neurological damage.
Neurofibrillary tangles
MedGen UID:
39273
Concept ID:
C0085400
Finding
Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) UBIQUITINS. As one of the hallmarks of ALZHEIMER DISEASE, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease.
Memory impairment
MedGen UID:
68579
Concept ID:
C0233794
Mental or Behavioral Dysfunction
An impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Brain atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Personality changes
MedGen UID:
66817
Concept ID:
C0240735
Sign or Symptom
A noticeable change in a person's behavior and thinking. Causes include depression, drug or alcohol abuse, brain injuries, brain tumors, and Alzheimer's disease.
Parkinsonism
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
A group of disorders which feature impaired motor control characterized by bradykinesia, MUSCLE RIGIDITY; TREMOR; and postural instability. Parkinsonian diseases are generally divided into primary parkinsonism (see PARKINSON DISEASE), secondary parkinsonism (see PARKINSON DISEASE, SECONDARY) and inherited forms. These conditions are associated with dysfunction of dopaminergic or closely related motor integration neuronal pathways in the BASAL GANGLIA.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Spastic tetraparesis
MedGen UID:
658719
Concept ID:
C0575059
Disease or Syndrome
Spastic weakness affecting all four limbs.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
A finding referring to walking difficulties.
Lower limb hyperreflexia
MedGen UID:
322973
Concept ID:
C1836696
Finding
Long-tract signs
MedGen UID:
356397
Concept ID:
C1865903
Finding
Spastic tetraparesis
MedGen UID:
658719
Concept ID:
C0575059
Disease or Syndrome
Spastic weakness affecting all four limbs.

Professional guidelines

PubMed

Moore A, Patterson C, Lee L, Vedel I, Bergman H; Canadian Consensus Conference on the Diagnosis and Treatment of Dementia.
Can Fam Physician 2014 May;60(5):433-8. PMID: 24829003Free PMC Article
Williams JW, Plassman BL, Burke J, Benjamin S
Evid Rep Technol Assess (Full Rep) 2010 Apr;(193):1-727. PMID: 21500874Free PMC Article
Hort J, O'Brien JT, Gainotti G, Pirttila T, Popescu BO, Rektorova I, Sorbi S, Scheltens P; EFNS Scientist Panel on Dementia.
Eur J Neurol 2010 Oct;17(10):1236-48. doi: 10.1111/j.1468-1331.2010.03040.x. PMID: 20831773
Burgunder JM, Finsterer J, Szolnoki Z, Fontaine B, Baets J, Van Broeckhoven C, Di Donato S, De Jonghe P, Lynch T, Mariotti C, Schöls L, Spinazzola A, Tabrizi SJ, Tallaksen C, Zeviani M, Harbo HF, Gasser T; EFNS.
Eur J Neurol 2010 May;17(5):641-8. Epub 2010 Mar 9 doi: 10.1111/j.1468-1331.2010.02985.x. PMID: 20298421

Recent clinical studies

Etiology

Xia C, Makaretz SJ, Caso C, McGinnis S, Gomperts SN, Sepulcre J, Gomez-Isla T, Hyman BT, Schultz A, Vasdev N, Johnson KA, Dickerson BC
JAMA Neurol 2017 Apr 1;74(4):427-436. doi: 10.1001/jamaneurol.2016.5755. PMID: 28241163Free PMC Article
Tosto G, Bird TD, Bennett DA, Boeve BF, Brickman AM, Cruchaga C, Faber K, Foroud TM, Farlow M, Goate AM, Graff-Radford NR, Lantigua R, Manly J, Ottman R, Rosenberg R, Schaid DJ, Schupf N, Stern Y, Sweet RA, Mayeux R; National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) Family Study Group.
JAMA Neurol 2016 Oct 1;73(10):1231-1237. doi: 10.1001/jamaneurol.2016.2539. PMID: 27533593Free PMC Article
Hohman TJ, Bush WS, Jiang L, Brown-Gentry KD, Torstenson ES, Dudek SM, Mukherjee S, Naj A, Kunkle BW, Ritchie MD, Martin ER, Schellenberg GD, Mayeux R, Farrer LA, Pericak-Vance MA, Haines JL, Thornton-Wells TA; Alzheimer's Disease Genetics Consortium.
Neurobiol Aging 2016 Feb;38:141-150. Epub 2015 Nov 6 doi: 10.1016/j.neurobiolaging.2015.10.031. PMID: 26827652Free PMC Article
Vardarajan BN, Faber KM, Bird TD, Bennett DA, Rosenberg R, Boeve BF, Graff-Radford NR, Goate AM, Farlow M, Sweet RA, Lantigua R, Medrano MZ, Ottman R, Schaid DJ, Foroud TM, Mayeux R; NIA-LOAD/NCRAD Family Study Group.
JAMA Neurol 2014 Mar;71(3):315-23. doi: 10.1001/jamaneurol.2013.5570. PMID: 24425039Free PMC Article
Aliev G, Shahida K, Gan SH, Firoz C, Khan A, Abuzenadah AM, Kamal W, Kamal MA, Tan Y, Qu X, Reale M
CNS Neurol Disord Drug Targets 2014 Apr;13(3):467-77. PMID: 24059309

Diagnosis

Xia C, Makaretz SJ, Caso C, McGinnis S, Gomperts SN, Sepulcre J, Gomez-Isla T, Hyman BT, Schultz A, Vasdev N, Johnson KA, Dickerson BC
JAMA Neurol 2017 Apr 1;74(4):427-436. doi: 10.1001/jamaneurol.2016.5755. PMID: 28241163Free PMC Article
Aguirre-Acevedo DC, Lopera F, Henao E, Tirado V, Muñoz C, Giraldo M, Bangdiwala SI, Reiman EM, Tariot PN, Langbaum JB, Quiroz YT, Jaimes F
JAMA Neurol 2016 Apr;73(4):431-8. doi: 10.1001/jamaneurol.2015.4851. PMID: 26902171Free PMC Article
Ginter E, Simko V, Weinrebova D, Ladecka Z
Bratisl Lek Listy 2015;116(10):580-1. PMID: 26531866
Vardarajan BN, Faber KM, Bird TD, Bennett DA, Rosenberg R, Boeve BF, Graff-Radford NR, Goate AM, Farlow M, Sweet RA, Lantigua R, Medrano MZ, Ottman R, Schaid DJ, Foroud TM, Mayeux R; NIA-LOAD/NCRAD Family Study Group.
JAMA Neurol 2014 Mar;71(3):315-23. doi: 10.1001/jamaneurol.2013.5570. PMID: 24425039Free PMC Article
Lurain NS, Hanson BA, Martinson J, Leurgans SE, Landay AL, Bennett DA, Schneider JA
J Infect Dis 2013 Aug 15;208(4):564-72. Epub 2013 May 9 doi: 10.1093/infdis/jit210. PMID: 23661800Free PMC Article

Therapy

Xicota L, Rodriguez-Morato J, Dierssen M, de la Torre R
Curr Drug Targets 2017;18(2):174-195. doi: 10.2174/1389450116666150825113655. PMID: 26302801
Østergaard SD, Mukherjee S, Sharp SJ, Proitsi P, Lotta LA, Day F, Perry JR, Boehme KL, Walter S, Kauwe JS, Gibbons LE; Alzheimer’s Disease Genetics Consortium.; GERAD1 Consortium.; EPIC-InterAct Consortium., Larson EB, Powell JF, Langenberg C, Crane PK, Wareham NJ, Scott RA
PLoS Med 2015 Jun;12(6):e1001841; discussion e1001841. Epub 2015 Jun 16 doi: 10.1371/journal.pmed.1001841. PMID: 26079503Free PMC Article
Shao H, Breitner JC, Whitmer RA, Wang J, Hayden K, Wengreen H, Corcoran C, Tschanz J, Norton M, Munger R, Welsh-Bohmer K, Zandi PP; Cache County Investigators.
Neurology 2012 Oct 30;79(18):1846-52. Epub 2012 Oct 24 doi: 10.1212/WNL.0b013e318271f823. PMID: 23100399Free PMC Article
Oulès B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Bréchot P, Trebak M, Checler F, Benfenati F, Chami M
J Neurosci 2012 Aug 22;32(34):11820-34. doi: 10.1523/JNEUROSCI.0875-12.2012. PMID: 22915123Free PMC Article
Gao C, Hölscher C, Liu Y, Li L
Rev Neurosci 2011 Dec 21;23(1):1-11. doi: 10.1515/rns.2011.061. PMID: 22718609

Prognosis

Möller C, Pijnenburg YA, van der Flier WM, Versteeg A, Tijms B, de Munck JC, Hafkemeijer A, Rombouts SA, van der Grond J, van Swieten J, Dopper E, Scheltens P, Barkhof F, Vrenken H, Wink AM
Radiology 2016 Jun;279(3):838-48. Epub 2015 Dec 11 doi: 10.1148/radiol.2015150220. PMID: 26653846
Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gutierrez Gomez M, Langois CM, Langbaum JB, Roontiva A, Thiyyagura P, Lee W, Ayutyanont N, Lopez L, Moreno S, Muñoz C, Tirado V, Acosta-Baena N, Fagan AM, Giraldo M, Garcia G, Huentelman MJ, Tariot PN, Lopera F, Reiman EM
JAMA Neurol 2015 Mar;72(3):316-24. doi: 10.1001/jamaneurol.2014.3314. PMID: 25580592Free PMC Article
Thomas JB, Brier MR, Bateman RJ, Snyder AZ, Benzinger TL, Xiong C, Raichle M, Holtzman DM, Sperling RA, Mayeux R, Ghetti B, Ringman JM, Salloway S, McDade E, Rossor MN, Ourselin S, Schofield PR, Masters CL, Martins RN, Weiner MW, Thompson PM, Fox NC, Koeppe RA, Jack CR Jr, Mathis CA, Oliver A, Blazey TM, Moulder K, Buckles V, Hornbeck R, Chhatwal J, Schultz AP, Goate AM, Fagan AM, Cairns NJ, Marcus DS, Morris JC, Ances BM
JAMA Neurol 2014 Sep;71(9):1111-22. doi: 10.1001/jamaneurol.2014.1654. PMID: 25069482Free PMC Article
Vardarajan BN, Faber KM, Bird TD, Bennett DA, Rosenberg R, Boeve BF, Graff-Radford NR, Goate AM, Farlow M, Sweet RA, Lantigua R, Medrano MZ, Ottman R, Schaid DJ, Foroud TM, Mayeux R; NIA-LOAD/NCRAD Family Study Group.
JAMA Neurol 2014 Mar;71(3):315-23. doi: 10.1001/jamaneurol.2013.5570. PMID: 24425039Free PMC Article
Shah I, Petroczi A, Naughton DP
J Clin Endocrinol Metab 2014 Mar;99(3):808-16. Epub 2014 Jan 13 doi: 10.1210/jc.2013-2872. PMID: 24423328

Clinical prediction guides

Xia C, Makaretz SJ, Caso C, McGinnis S, Gomperts SN, Sepulcre J, Gomez-Isla T, Hyman BT, Schultz A, Vasdev N, Johnson KA, Dickerson BC
JAMA Neurol 2017 Apr 1;74(4):427-436. doi: 10.1001/jamaneurol.2016.5755. PMID: 28241163Free PMC Article
Tosto G, Bird TD, Bennett DA, Boeve BF, Brickman AM, Cruchaga C, Faber K, Foroud TM, Farlow M, Goate AM, Graff-Radford NR, Lantigua R, Manly J, Ottman R, Rosenberg R, Schaid DJ, Schupf N, Stern Y, Sweet RA, Mayeux R; National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) Family Study Group.
JAMA Neurol 2016 Oct 1;73(10):1231-1237. doi: 10.1001/jamaneurol.2016.2539. PMID: 27533593Free PMC Article
Aguirre-Acevedo DC, Lopera F, Henao E, Tirado V, Muñoz C, Giraldo M, Bangdiwala SI, Reiman EM, Tariot PN, Langbaum JB, Quiroz YT, Jaimes F
JAMA Neurol 2016 Apr;73(4):431-8. doi: 10.1001/jamaneurol.2015.4851. PMID: 26902171Free PMC Article
Hohman TJ, Bush WS, Jiang L, Brown-Gentry KD, Torstenson ES, Dudek SM, Mukherjee S, Naj A, Kunkle BW, Ritchie MD, Martin ER, Schellenberg GD, Mayeux R, Farrer LA, Pericak-Vance MA, Haines JL, Thornton-Wells TA; Alzheimer's Disease Genetics Consortium.
Neurobiol Aging 2016 Feb;38:141-150. Epub 2015 Nov 6 doi: 10.1016/j.neurobiolaging.2015.10.031. PMID: 26827652Free PMC Article
Thomas JB, Brier MR, Bateman RJ, Snyder AZ, Benzinger TL, Xiong C, Raichle M, Holtzman DM, Sperling RA, Mayeux R, Ghetti B, Ringman JM, Salloway S, McDade E, Rossor MN, Ourselin S, Schofield PR, Masters CL, Martins RN, Weiner MW, Thompson PM, Fox NC, Koeppe RA, Jack CR Jr, Mathis CA, Oliver A, Blazey TM, Moulder K, Buckles V, Hornbeck R, Chhatwal J, Schultz AP, Goate AM, Fagan AM, Cairns NJ, Marcus DS, Morris JC, Ances BM
JAMA Neurol 2014 Sep;71(9):1111-22. doi: 10.1001/jamaneurol.2014.1654. PMID: 25069482Free PMC Article

Recent systematic reviews

Tang M, Ryman DC, McDade E, Jasielec MS, Buckles VD, Cairns NJ, Fagan AM, Goate A, Marcus DS, Xiong C, Allegri RF, Chhatwal JP, Danek A, Farlow MR, Fox NC, Ghetti B, Graff-Radford NR, Laske C, Martins RN, Masters CL, Mayeux RP, Ringman JM, Rossor MN, Salloway SP, Schofield PR, Morris JC, Bateman RJ; Dominantly Inherited Alzheimer Network (DIAN).
Lancet Neurol 2016 Dec;15(13):1317-1325. Epub 2016 Oct 21 doi: 10.1016/S1474-4422(16)30229-0. PMID: 27777020Free PMC Article
Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JB, Lopera F, Martins R, Masters CL, Mayeux RP, McDade E, Moreno S, Reiman EM, Ringman JM, Salloway S, Schofield PR, Sperling R, Tariot PN, Xiong C, Morris JC, Bateman RJ; Dominantly Inherited Alzheimer Network.
Neurology 2014 Jul 15;83(3):253-60. Epub 2014 Jun 13 doi: 10.1212/WNL.0000000000000596. PMID: 24928124Free PMC Article
Shah R
J Am Med Dir Assoc 2013 Jun;14(6):398-402. Epub 2013 Feb 16 doi: 10.1016/j.jamda.2013.01.014. PMID: 23419980
Vagelatos NT, Eslick GD
Epidemiol Rev 2013;35:152-60. Epub 2013 Jan 11 doi: 10.1093/epirev/mxs012. PMID: 23314404
Costanza A, Xekardaki A, Kövari E, Gold G, Bouras C, Giannakopoulos P
J Alzheimers Dis 2012;32(3):643-52. doi: 10.3233/JAD-2012-120835. PMID: 22842869

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