Longitudinal Early-onset Alzheimer's Disease Study Protocol

NCT03507257 | Recruiting DMC FDA Drug

• 2 other identifiers: ATRI-003R56AG057195
• Study Type: observational
• Target: 850
• Locations: 6 countries
• Sites: 23

Brief Summary

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a non-randomized, natural history, non-treatment study designed to look at disease progression in individuals with early onset cognitive impairment. Clinical, cognitive, imaging, biomarker, and genetic characteristics will be assessed across three cohorts: (1) early onset Alzheimer's Disease (EOAD) participants, (2) early onset non-Alzheimer's Disease (EOnonAD) participants, and (3) cognitively normal (CN) control participants.

Conditions

Alzheimer Disease; Mild Cognitive Impairment; Early Onset Alzheimer Disease

Keywords

Cognitively Normal; Amyloid; Plaques; Neuroimaging; Biomarkers; Cognition Disorder; Dementia; Tau; Early Onset Alzheimer's Disease; Alzheimer's Disease; Mild Cognitive Impairment

Outcome Measures

Primary Outcomes (1)

• Rate of change in cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog13)

  The ADAS-Cog is an in-person examiner-administered, structured scale that evaluates memory (word recall, word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions are also obtained.

  Month 0, Month 12, Month 24, Month 36 (EOAD/EOnonAD only) and Month 48 (EOAD/EOnonAD only)

Secondary Outcomes (7)

• Rate of change in cognition as measured by the Clinical Dementia Rating - Sum of Boxes (CDR-SB)

  CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48

• Change in tau deposition as measured by flortaucipir (18F-AV-1451) Positron Emission Tomography (PET) imaging

  Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD and EOnonAD amyloid positive participants only)

• Change in amyloid deposition as measured by florbetaben using Positron Emission Tomography (PET) imaging

  Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD/EOnonAD only

• Neurodegeneration as measured by fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) imaging compared to magnetic resonance imaging (MRI)

  Month 12 (EOnonAD only) and Month 24 (CN only)

• Change in brain structure using magnetic resonance imaging (MRI)

  CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24 and Month 36

Study Arms (3)

Early Onset Alzheimer's Disease (EOAD)

* Diagnosis of NIA-AA criteria of MCI due to AD or probable AD dementia * Amyloid positive status (florbetaben PET scan with evidence of elevated amyloid as determined by a central read) * CDR score ≤ 1.0 * flortaucipir (18F-AV-1451) PET scanning

Drug: Flortaucipir; Drug: Florbetaben

Cognitively Normal (CN) Controls

* Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions and activities of daily living * Mini-Mental State Exam score between 26-30 * CDR score = 0 * flortaucipir (18F-AV-1451) PET scanning

Drug: Flortaucipir; Drug: Florbetaben; Drug: Fluorodeoxyglucose

Early Onset non-Alzheimer's Disease (EOnonAD)

* Diagnosis of NIA-AA criteria of MCI due to AD or probable AD dementia * Amyloid negative status (florbetaben PET scan with no evidence of elevated amyloid as determined by a central read) * CDR score ≤ 1.0 * flortaucipir (18F-AV-1451) PET scanning

Drug: Flortaucipir; Drug: Florbetaben; Drug: Fluorodeoxyglucose

Interventions

Flortaucipir DRUG

All participants will receive a single bolus intravenous injection of approximately 10 mCi (+/- 10%, 20μg mass dose) of flortaucipir (18F-AV-1451). At approximately 75-minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.

Also known as: 18F-AV-1451 (also known as [F-18]T807 or LY3191748)

Cognitively Normal (CN) Controls; Early Onset Alzheimer's Disease (EOAD); Early Onset non-Alzheimer's Disease (EOnonAD)

Florbetaben DRUG

All participants will receive a single bolus intravenous injection of approximately 8 mCi +/- .8mCi of florbetaben (AV-45). At approximately 90-minutes (+/- 10 minutes) post dose, scanning will begin. An approximately 20-minute image acquisition scan will be performed.

Also known as: AV-45, Neuraceq

Cognitively Normal (CN) Controls; Early Onset Alzheimer's Disease (EOAD); Early Onset non-Alzheimer's Disease (EOnonAD)

Fluorodeoxyglucose DRUG

All participants will receive a single bolus intravenous injection of approximately 5 mCi (+/- 10%, 0.5 mCi) of fluorodeoxyglucose. At approximately 30 minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.

Also known as: FDG

Cognitively Normal (CN) Controls; Early Onset non-Alzheimer's Disease (EOnonAD)

Eligibility Criteria

• Age: 40 Years - 64 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Cognitively Impaired Participants (ie: Early Onset Alzheimer's Disease (EOAD) and Early Onset non-Alzheimer's Disease (EOnonAD)) and Cognitively Normal (CN) Control Participants

You may qualify if:

• Meets NIA-AA criteria for MCI due to AD or probable AD dementia
• Have a global CDR score ≤ 1.0
• Have capacity to provide informed consent (IC) or has a legal authorized representative or guardian who provides IC
• Age between 40-64 years (inclusive) at the time of consent
• Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends at least 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI
• Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
• Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan
• Fluent in English or Spanish if enrolled in the U.S.
• Fluent in English, Spanish, Dutch or Swedish for sites outside the U.S., according to site's spoken language(s).
• Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living
• Have a global CDR score = 0
• Have capacity to provide informed consent
• Have a Mini-Mental State Exam score between 26-30 (inclusive). Exceptions may be made for participant with less than 8 years of education at the discretion of the Site PI
• Age between 40-64 years (inclusive) at the time of consent
• Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI

You may not qualify if:

• Meets core clinical criteria for non-AD dementia
• Two or more first degree relatives with a history of early-onset dementia suggestive of autosomal dominant transmission, unless known pathogenic mutations in APP, PSEN1, PSEN2, MAPT, GRN and C9ORF72 have been excluded
• Known CLIA certified mutation in an ADAD gene (APP, PSEN1, PSEN2), or other autosomal dominant genes associated with other neurodegenerative disorders (MAPT, GRN, C9ORF72)
• Contraindications to 3T MRI (e.g., claustrophobia, pacemaker, select aneurismal clip, artificial heart valve, select ear implants, select stents incompatible with 3T MRI, metal fragments or foreign objects in the eyes, skin or body, etc.)
• Lifetime medical history of a brain disorder other than the disorder causing dementia except for headache (exceptions are allowed at the discretion of the Site PI - e.g., seizure disorder thought to be due to EOAD).
• MRI scan with evidence of infection or focal lesions, cortical strokes, multiple lacunes (single lacune is allowable unless it meets criteria for strategic lacune affecting cognition)
• Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the Site PI)
• Investigational agents are prohibited 30 days prior to entry
• Previous enrollment in a therapeutic trial targeting amyloid or tau.
• Participation in other clinical studies with neuropsychological measures, with the exception of participants who are co-enrolled in the NACC Uniform Data Set (UDS) protocol (Note: This criterion is intended to reduce repeat measures effects during neuropsychological testing. Exceptions are allowed at the discretion of the Site PI)
• Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria)
• Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder with or without psychotic features
• Current history (in previous 6 months) of moderate or severe substance abuse (nicotine or caffeine is allowed)
• Suicidal behaviors in the past 12 months or active suicidal ideations
• Residing in a 24-hour care skilled nursing facility (at the time of screening)

Sponsors & Collaborators

• Indiana University: lead
• National Institute on Aging (NIA): collaborator
• Alzheimer's Association: collaborator
• Alzheimer's Therapeutic Research Institute: collaborator

Study Sites (23)

Banner Sun Health Research Institute

Sun City, Arizona, 85351, United States

COMPLETED

University of California, Los Angeles

Los Angeles, California, 90095, United States

RECRUITING

Stanford University

Palo Alto, California, 94304, United States

RECRUITING

University of California, San Francisco

San Francisco, California, 94121, United States

RECRUITING

Georgetown University

Washington D.C., District of Columbia, 20057, United States

COMPLETED

Mayo Clinic, Jacksonville

Jacksonville, Florida, 32224, United States

RECRUITING

Wien Center

Miami Beach, Florida, 33140, United States

COMPLETED

Emory University

Atlanta, Georgia, 30322, United States

RECRUITING

Northwestern University

Chicago, Illinois, 60611, United States

COMPLETED

Indiana University

Indianapolis, Indiana, 47405, United States

RECRUITING

Johns Hopkins University

Baltimore, Maryland, 21218, United States

RECRUITING

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

Mayo Clinic, Rochester

Rochester, Minnesota, 55905, United States

RECRUITING

Washington University, St. Louis

St Louis, Missouri, 63130, United States

RECRUITING

Columbia University

New York, New York, 10032, United States

RECRUITING

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Butler Hospital

Providence, Rhode Island, 02906, United States

RECRUITING

Houston Methodist Hospital

Houston, Texas, 77030, United States

RECRUITING

Fleni

Buenos Aires, C1428 CABA, Argentina

RECRUITING

Amsterdam UMC

Amsterdam, 1081 HZ, Netherlands

NOT YET RECRUITING

Hospital de la Santa Creu i Sant Pau

Barcelona, 8041, Spain

RECRUITING

Lund University

Malmo, 214 28, Sweden

NOT YET RECRUITING

University College London

London, WC1N 3BG, United Kingdom

NOT YET RECRUITING

Related Publications (57)

• Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C; Medical Research Council Cognitive Function and Ageing Study. Age, neuropathology, and dementia. N Engl J Med. 2009 May 28;360(22):2302-9. doi: 10.1056/NEJMoa0806142.

  PMID: 19474427 BACKGROUND

• Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007 Dec 11;69(24):2197-204. doi: 10.1212/01.wnl.0000271090.28148.24. Epub 2007 Jun 13.

  PMID: 17568013 BACKGROUND

• Szigeti K, Doody RS. Should EOAD patients be included in clinical trials? Alzheimers Res Ther. 2011 Feb 8;3(1):4. doi: 10.1186/alzrt63.

  PMID: 21345175 BACKGROUND

• Wingo TS, Lah JJ, Levey AI, Cutler DJ. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol. 2012 Jan;69(1):59-64. doi: 10.1001/archneurol.2011.221. Epub 2011 Sep 12.

  PMID: 21911656 BACKGROUND

• Koedam EL, Lauffer V, van der Vlies AE, van der Flier WM, Scheltens P, Pijnenburg YA. Early-versus late-onset Alzheimer's disease: more than age alone. J Alzheimers Dis. 2010;19(4):1401-8. doi: 10.3233/JAD-2010-1337.

  PMID: 20061618 BACKGROUND

• Mendez MF, Lee AS, Karve SJ, Shapira JS. Nonamnestic presentations of early-onset Alzheimer's disease. Am J Alzheimers Dis Other Demen. 2012 Sep;27(6):413-20. doi: 10.1177/1533317512454711. Epub 2012 Aug 7.

  PMID: 22871906 BACKGROUND

• Snowden JS, Stopford CL, Julien CL, Thompson JC, Davidson Y, Gibbons L, Pritchard A, Lendon CL, Richardson AM, Varma A, Neary D, Mann D. Cognitive phenotypes in Alzheimer's disease and genetic risk. Cortex. 2007 Oct;43(7):835-45. doi: 10.1016/s0010-9452(08)70683-x.

  PMID: 17941342 BACKGROUND

• Jacobs D, Sano M, Marder K, Bell K, Bylsma F, Lafleche G, Albert M, Brandt J, Stern Y. Age at onset of Alzheimer's disease: relation to pattern of cognitive dysfunction and rate of decline. Neurology. 1994 Jul;44(7):1215-20. doi: 10.1212/wnl.44.7.1215.

  PMID: 8035918 BACKGROUND

• Koss E, Edland S, Fillenbaum G, Mohs R, Clark C, Galasko D, Morris JC. Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer's disease: A CERAD analysis, Part XII. Neurology. 1996 Jan;46(1):136-41. doi: 10.1212/wnl.46.1.136.

  PMID: 8559362 BACKGROUND

• Xia CF, Arteaga J, Chen G, Gangadharmath U, Gomez LF, Kasi D, Lam C, Liang Q, Liu C, Mocharla VP, Mu F, Sinha A, Su H, Szardenings AK, Walsh JC, Wang E, Yu C, Zhang W, Zhao T, Kolb HC. [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease. Alzheimers Dement. 2013 Nov;9(6):666-76. doi: 10.1016/j.jalz.2012.11.008. Epub 2013 Feb 12.

  PMID: 23411393 BACKGROUND

• Frisoni GB, Testa C, Sabattoli F, Beltramello A, Soininen H, Laakso MP. Structural correlates of early and late onset Alzheimer's disease: voxel based morphometric study. J Neurol Neurosurg Psychiatry. 2005 Jan;76(1):112-4. doi: 10.1136/jnnp.2003.029876.

  PMID: 15608008 BACKGROUND

• Kim EJ, Cho SS, Jeong Y, Park KC, Kang SJ, Kang E, Kim SE, Lee KH, Na DL. Glucose metabolism in early onset versus late onset Alzheimer's disease: an SPM analysis of 120 patients. Brain. 2005 Aug;128(Pt 8):1790-801. doi: 10.1093/brain/awh539. Epub 2005 May 11.

  PMID: 15888536 BACKGROUND

• Rabinovici GD, Furst AJ, Alkalay A, Racine CA, O'Neil JP, Janabi M, Baker SL, Agarwal N, Bonasera SJ, Mormino EC, Weiner MW, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ. Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden. Brain. 2010 Feb;133(Pt 2):512-28. doi: 10.1093/brain/awp326. Epub 2010 Jan 15.

  PMID: 20080878 BACKGROUND

• Lehmann M, Ghosh PM, Madison C, Laforce R Jr, Corbetta-Rastelli C, Weiner MW, Greicius MD, Seeley WW, Gorno-Tempini ML, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer's disease. Brain. 2013 Mar;136(Pt 3):844-58. doi: 10.1093/brain/aws327. Epub 2013 Jan 28.

  PMID: 23358601 BACKGROUND

• Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. doi: 10.1016/S1474-4422(11)70156-9. Epub 2011 Jul 27.

  PMID: 21802369 BACKGROUND

• Ossenkoppele R, Cohn-Sheehy BI, La Joie R, Vogel JW, Moller C, Lehmann M, van Berckel BN, Seeley WW, Pijnenburg YA, Gorno-Tempini ML, Kramer JH, Barkhof F, Rosen HJ, van der Flier WM, Jagust WJ, Miller BL, Scheltens P, Rabinovici GD. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease. Hum Brain Mapp. 2015 Nov;36(11):4421-37. doi: 10.1002/hbm.22927. Epub 2015 Aug 11.

  PMID: 26260856 BACKGROUND

• Ossenkoppele R, Pijnenburg YA, Perry DC, Cohn-Sheehy BI, Scheltens NM, Vogel JW, Kramer JH, van der Vlies AE, La Joie R, Rosen HJ, van der Flier WM, Grinberg LT, Rozemuller AJ, Huang EJ, van Berckel BN, Miller BL, Barkhof F, Jagust WJ, Scheltens P, Seeley WW, Rabinovici GD. The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features. Brain. 2015 Sep;138(Pt 9):2732-49. doi: 10.1093/brain/awv191. Epub 2015 Jul 2.

  PMID: 26141491 BACKGROUND

• Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56.

  PMID: 9343467 BACKGROUND

• Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer's disease. Lancet Neurol. 2013 Jan;12(1):92-104. doi: 10.1016/S1474-4422(12)70259-4.

  PMID: 23237904 BACKGROUND

• Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE, Perry RT, Bassett SS, Chase G, Meyers D, Albert MS, Tanzi R. ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology. 1997 Jan;48(1):139-47. doi: 10.1212/wnl.48.1.139.

  PMID: 9008509 BACKGROUND

• van der Flier WM, Pijnenburg YA, Fox NC, Scheltens P. Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE varepsilon4 allele. Lancet Neurol. 2011 Mar;10(3):280-8. doi: 10.1016/S1474-4422(10)70306-9. Epub 2010 Dec 22.

  PMID: 21185234 BACKGROUND

• Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX, Chen L, Huang Y. Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010 Oct 13;30(41):13707-17. doi: 10.1523/JNEUROSCI.4040-10.2010.

  PMID: 20943911 BACKGROUND

• Filippini N, Rao A, Wetten S, Gibson RA, Borrie M, Guzman D, Kertesz A, Loy-English I, Williams J, Nichols T, Whitcher B, Matthews PM. Anatomically-distinct genetic associations of APOE epsilon4 allele load with regional cortical atrophy in Alzheimer's disease. Neuroimage. 2009 Feb 1;44(3):724-8. doi: 10.1016/j.neuroimage.2008.10.003. Epub 2008 Nov 1.

  PMID: 19013250 BACKGROUND

• Knickmeyer RC, Wang J, Zhu H, Geng X, Woolson S, Hamer RM, Konneker T, Lin W, Styner M, Gilmore JH. Common variants in psychiatric risk genes predict brain structure at birth. Cereb Cortex. 2014 May;24(5):1230-46. doi: 10.1093/cercor/bhs401. Epub 2013 Jan 2.

  PMID: 23283688 BACKGROUND

• Leung L, Andrews-Zwilling Y, Yoon SY, Jain S, Ring K, Dai J, Wang MM, Tong L, Walker D, Huang Y. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice. PLoS One. 2012;7(12):e53569. doi: 10.1371/journal.pone.0053569. Epub 2012 Dec 31.

  PMID: 23300939 BACKGROUND

• Wolk DA, Dickerson BC; Alzheimer's Disease Neuroimaging Initiative. Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10256-61. doi: 10.1073/pnas.1001412107. Epub 2010 May 17.

  PMID: 20479234 BACKGROUND

• Geroldi C, Pihlajamaki M, Laakso MP, DeCarli C, Beltramello A, Bianchetti A, Soininen H, Trabucchi M, Frisoni GB. APOE-epsilon4 is associated with less frontal and more medial temporal lobe atrophy in AD. Neurology. 1999 Nov 10;53(8):1825-32. doi: 10.1212/wnl.53.8.1825.

  PMID: 10563634 BACKGROUND

• Hashimoto M, Yasuda M, Tanimukai S, Matsui M, Hirono N, Kazui H, Mori E. Apolipoprotein E epsilon 4 and the pattern of regional brain atrophy in Alzheimer's disease. Neurology. 2001 Oct 23;57(8):1461-6. doi: 10.1212/wnl.57.8.1461.

  PMID: 11673590 BACKGROUND

• Hirono N, Hashimoto M, Yasuda M, Ishii K, Sakamoto S, Kazui H, Mori E. The effect of APOE epsilon4 allele on cerebral glucose metabolism in AD is a function of age at onset. Neurology. 2002 Mar 12;58(5):743-50. doi: 10.1212/wnl.58.5.743.

  PMID: 11889238 BACKGROUND

• Lehtovirta M, Soininen H, Helisalmi S, Mannermaa A, Helkala EL, Hartikainen P, Hanninen T, Ryynanen M, Riekkinen PJ. Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: relation to apolipoprotein E polymorphism. Neurology. 1996 Feb;46(2):413-9. doi: 10.1212/wnl.46.2.413.

  PMID: 8614504 BACKGROUND

• Schott JM, Ridha BH, Crutch SJ, Healy DG, Uphill JB, Warrington EK, Rossor MN, Fox NC. Apolipoprotein e genotype modifies the phenotype of Alzheimer disease. Arch Neurol. 2006 Jan;63(1):155-6. doi: 10.1001/archneur.63.1.155. No abstract available.

  PMID: 16401755 BACKGROUND

• van der Flier WM, Schoonenboom SN, Pijnenburg YA, Fox NC, Scheltens P. The effect of APOE genotype on clinical phenotype in Alzheimer disease. Neurology. 2006 Aug 8;67(3):526-7. doi: 10.1212/01.wnl.0000228222.17111.2a.

  PMID: 16894123 BACKGROUND

• van der Vlies AE, Pijnenburg YA, Koene T, Klein M, Kok A, Scheltens P, van der Flier WM. Cognitive impairment in Alzheimer's disease is modified by APOE genotype. Dement Geriatr Cogn Disord. 2007;24(2):98-103. doi: 10.1159/000104467. Epub 2007 Jun 26.

  PMID: 17596691 BACKGROUND

• Crutch SJ, Lehmann M, Schott JM, Rabinovici GD, Rossor MN, Fox NC. Posterior cortical atrophy. Lancet Neurol. 2012 Feb;11(2):170-8. doi: 10.1016/S1474-4422(11)70289-7.

  PMID: 22265212 BACKGROUND

• Migliaccio R, Agosta F, Rascovsky K, Karydas A, Bonasera S, Rabinovici GD, Miller BL, Gorno-Tempini ML. Clinical syndromes associated with posterior atrophy: early age at onset AD spectrum. Neurology. 2009 Nov 10;73(19):1571-8. doi: 10.1212/WNL.0b013e3181c0d427.

  PMID: 19901249 BACKGROUND

• Cacace R, Sleegers K, Van Broeckhoven C. Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimers Dement. 2016 Jun;12(6):733-48. doi: 10.1016/j.jalz.2016.01.012. Epub 2016 Mar 24.

  PMID: 27016693 BACKGROUND

• Nicolas G, Wallon D, Charbonnier C, Quenez O, Rousseau S, Richard AC, Rovelet-Lecrux A, Coutant S, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Munter HM, Bourque G, Auld D, Montpetit A, Lathrop M, Guyant-Marechal L, Martinaud O, Pariente J, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonniere C, Thomas-Anterion C, Paquet C, Sauvee M, Moreaud O, Gabelle A, Sellal F, Ceccaldi M, Chamard L, Blanc F, Frebourg T, Campion D, Hannequin D. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2016 May;24(5):710-6. doi: 10.1038/ejhg.2015.173. Epub 2015 Aug 5.

  PMID: 26242991 BACKGROUND

• Miller ZA, Mandelli ML, Rankin KP, Henry ML, Babiak MC, Frazier DT, Lobach IV, Bettcher BM, Wu TQ, Rabinovici GD, Graff-Radford NR, Miller BL, Gorno-Tempini ML. Handedness and language learning disability differentially distribute in progressive aphasia variants. Brain. 2013 Nov;136(Pt 11):3461-73. doi: 10.1093/brain/awt242. Epub 2013 Sep 20.

  PMID: 24056533 BACKGROUND

• Rogalski E, Johnson N, Weintraub S, Mesulam M. Increased frequency of learning disability in patients with primary progressive aphasia and their first-degree relatives. Arch Neurol. 2008 Feb;65(2):244-8. doi: 10.1001/archneurol.2007.34.

  PMID: 18268195 BACKGROUND

• Miller ZA, Rankin KP, Graff-Radford NR, Takada LT, Sturm VE, Cleveland CM, Criswell LA, Jaeger PA, Stan T, Heggeli KA, Hsu SC, Karydas A, Khan BK, Grinberg LT, Gorno-Tempini ML, Boxer AL, Rosen HJ, Kramer JH, Coppola G, Geschwind DH, Rademakers R, Seeley WW, Wyss-Coray T, Miller BL. TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry. 2013 Sep;84(9):956-62. doi: 10.1136/jnnp-2012-304644. Epub 2013 Mar 30.

  PMID: 23543794 BACKGROUND

• Miller ZA, Sturm VE, Camsari GB, Karydas A, Yokoyama JS, Grinberg LT, Boxer AL, Rosen HJ, Rankin KP, Gorno-Tempini ML, Coppola G, Geschwind DH, Rademakers R, Seeley WW, Graff-Radford NR, Miller BL. Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: Completing the picture. Neurol Neuroimmunol Neuroinflamm. 2016 Oct 28;3(6):e301. doi: 10.1212/NXI.0000000000000301. eCollection 2016 Dec.

  PMID: 27844039 BACKGROUND

• Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412-4. doi: 10.1212/wnl.43.11.2412-a. No abstract available.

  PMID: 8232972 BACKGROUND

• Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. J Gerontol. 1982 May;37(3):323-9. doi: 10.1093/geronj/37.3.323.

  PMID: 7069156 BACKGROUND

• Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994 Dec;44(12):2308-14. doi: 10.1212/wnl.44.12.2308.

  PMID: 7991117 BACKGROUND

• Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res. 1982-1983;17(1):37-49. doi: 10.1016/0022-3956(82)90033-4.

  PMID: 7183759 BACKGROUND

• Panchal H, Paholpak P, Lee G, Carr A, Barsuglia JP, Mather M, Jimenez E, Mendez MF. Neuropsychological and Neuroanatomical Correlates of the Social Norms Questionnaire in Frontotemporal Dementia Versus Alzheimer's Disease. Am J Alzheimers Dis Other Demen. 2016 Jun;31(4):326-32. doi: 10.1177/1533317515617722. Epub 2015 Dec 8.

  PMID: 26646114 BACKGROUND

• Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.

  PMID: 15817019 BACKGROUND

• Monsell SE, Dodge HH, Zhou XH, Bu Y, Besser LM, Mock C, Hawes SE, Kukull WA, Weintraub S; Neuropsychology Work Group Advisory to the Clinical Task Force. Results From the NACC Uniform Data Set Neuropsychological Battery Crosswalk Study. Alzheimer Dis Assoc Disord. 2016 Apr-Jun;30(2):134-9. doi: 10.1097/WAD.0000000000000111.

  PMID: 26485498 BACKGROUND

• McKoon G, Ratcliff R. Semantic associations and elaborative inference. J Exp Psychol Learn Mem Cogn. 1989 Mar;15(2):326-38. doi: 10.1037//0278-7393.15.2.326.

  PMID: 2522518 BACKGROUND

• Weintraub S, Mesulam MM, Wieneke C, Rademaker A, Rogalski EJ, Thompson CK. The northwestern anagram test: measuring sentence production in primary progressive aphasia. Am J Alzheimers Dis Other Demen. 2009 Oct-Nov;24(5):408-16. doi: 10.1177/1533317509343104. Epub 2009 Aug 21.

  PMID: 19700669 BACKGROUND

• Lee J, Thompson CK. Phonological facilitation effects on naming latencies and viewing times during noun and verb naming in agrammatic and anomic aphasia. Aphasiology. 2015;29(10):1164-1188. doi: 10.1080/02687038.2015.1035225.

  PMID: 26412922 BACKGROUND

• Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984 Nov;141(11):1356-64. doi: 10.1176/ajp.141.11.1356.

  PMID: 6496779 BACKGROUND

• Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. doi: 10.1016/0022-3956(75)90026-6. No abstract available.

  PMID: 1202204 BACKGROUND

• Possin KL, Moskowitz T, Erlhoff SJ, Rogers KM, Johnson ET, Steele NZR, Higgins JJ, Stiver J, Alioto AG, Farias ST, Miller BL, Rankin KP. The Brain Health Assessment for Detecting and Diagnosing Neurocognitive Disorders. J Am Geriatr Soc. 2018 Jan;66(1):150-156. doi: 10.1111/jgs.15208.

  PMID: 29355911 BACKGROUND

• Duits FH, Martinez-Lage P, Paquet C, Engelborghs S, Lleo A, Hausner L, Molinuevo JL, Stomrud E, Farotti L, Ramakers IHGB, Tsolaki M, Skarsgard C, Astrand R, Wallin A, Vyhnalek M, Holmber-Clausen M, Forlenza OV, Ghezzi L, Ingelsson M, Hoff EI, Roks G, de Mendonca A, Papma JM, Izagirre A, Taga M, Struyfs H, Alcolea DA, Frolich L, Balasa M, Minthon L, Twisk JWR, Persson S, Zetterberg H, van der Flier WM, Teunissen CE, Scheltens P, Blennow K. Performance and complications of lumbar puncture in memory clinics: Results of the multicenter lumbar puncture feasibility study. Alzheimers Dement. 2016 Feb;12(2):154-163. doi: 10.1016/j.jalz.2015.08.003. Epub 2015 Sep 11.

  PMID: 26368321 BACKGROUND

• Engelborghs S, Niemantsverdriet E, Struyfs H, Blennow K, Brouns R, Comabella M, Dujmovic I, van der Flier W, Frolich L, Galimberti D, Gnanapavan S, Hemmer B, Hoff E, Hort J, Iacobaeus E, Ingelsson M, Jan de Jong F, Jonsson M, Khalil M, Kuhle J, Lleo A, de Mendonca A, Molinuevo JL, Nagels G, Paquet C, Parnetti L, Roks G, Rosa-Neto P, Scheltens P, Skarsgard C, Stomrud E, Tumani H, Visser PJ, Wallin A, Winblad B, Zetterberg H, Duits F, Teunissen CE. Consensus guidelines for lumbar puncture in patients with neurological diseases. Alzheimers Dement (Amst). 2017 May 18;8:111-126. doi: 10.1016/j.dadm.2017.04.007. eCollection 2017.

  PMID: 28603768 BACKGROUND

• Pontecorvo MJ, Siderowf A, Dubois B, Doraiswamy PM, Frisoni GB, Grundman M, Nobili F, Sadowsky CH, Salloway S, Arora AK, Chevrette A, Deberdt W, Dell'Agnello G, Flitter M, Galante N, Lowrey MJ, Lu M, McGeehan A, Devous MD Sr, Mintun MA. Effectiveness of Florbetapir PET Imaging in Changing Patient Management. Dement Geriatr Cogn Disord. 2017;44(3-4):129-143. doi: 10.1159/000478007. Epub 2017 Aug 5.

  PMID: 28787712 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

blood, cerebrospinal fluid

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction; Plaque, Amyloid; Cognition Disorders; Dementia; Pick Disease of the Brain

Interventions

7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole; 4-(N-methylamino)-4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)stilbene; Fluorodeoxyglucose F18

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Frontotemporal Dementia; Frontotemporal Lobar Degeneration

Intervention Hierarchy (Ancestors)

Deoxyglucose; Deoxy Sugars; Carbohydrates

Study Officials

• Liana Apostolova, MD

  Indiana University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

IU LEADS Team

CONTACT

317-963-7436; iuLEADS@iupui.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor in Neurology, Radiology, Medical and Molecular Genetics

Study Record Dates

• First Submitted: April 4, 2018
• First Posted: April 25, 2018
• Study Start: April 30, 2018
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): May 31, 2026
• Last Updated: February 18, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF

Locations

SE (1); US (18); ES (1); GB (1); NL (1); AR (1)