PET Imaging Tau Accumulation in FTLD and Atypical Alzheimer's Using [18F]-PI-2620

Inclusion Criteria: participants must fulfill all of the criteria for one of the following groups.

• Group 1: cognitively and neurologically normal subjects (CN, n=25)

• Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
• Cognitively and neurologically normal according to one of the following criteria:

i. Mini-Mental Status Exam (MMSE; Folstein et al., 1975) score > 27, OR ii. Montreal Cognitive Assessment (MoCA; Carson et al., 2017; Nasreddine et al., 2005) score > 25, OR iii. Global Clinical Dementia Rating of 0, OR iv. Evaluation by a trained clinician

• Not clinically depressed, according to one of the following criteria:

i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

• No history of early-onset neurodegenerative disease in biological siblings or parents, based on the investigators' assessment of the participant's self-reported history.

• Group 2: non-amnestic Alzheimer's disease (naAD, n=15)

• Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
• Clinically diagnosed by a trained clinician as having a non-amnestic syndrome attributed to likely AD pathology, including but not limited to logopenic-variant primary progressive aphasia (lvPPA), posterior cortical atrophy (PCA), behavioral/dysexecutive AD (bvAD), corticobasal syndrome due to AD (CBS-AD), non-amnestic mild cognitive impairment (naMCI), or non-amnestic AD (naAD).
• Not clinically depressed, according to one of the following criteria:

i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

• Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

• Group 3: FTLD likely due to tau (FTLD-tau, n=25)

• Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
• Clinically diagnosed by a trained clinician as having a neurodegenerative syndrome likely due to tau , including but not limited to progressive supranuclear palsy (PSP), non-fluent agrammatic primary progressive aphasia (naPPA), corticobasal syndrome (CBS), or behavioral-variant frontotemporal dementia (bvFTD).
• Not clinically depressed, according to one of the following criteria:

i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

• Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

• Group 4: FTLD likely due to TDP-43 (FTLD-TDP, n=12)

• Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
• Clinically diagnosed by a trained clinician as having a dementia syndrome associated with likely TDP-43 pathology, including but not limited to amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD) or semantic-variant primary progressive aphasia (svPPA).
• Not clinically depressed, according to one of the following criteria:

i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

• Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.
• Group 5: having a known genetic mutation associated with FTLD-tau (genetic FTLD-tau, n=12)

• Male or female ≥ 18 years of age 2. Currently enrolled in UNICORN (IRB #842873) with a genetic test result indicating a mutation in the MAPT gene.

• Clinically diagnosed by a trained clinician as having an appropriate neurodegenerative condition OR confirmed as an asymptomatic mutation carrier.

• Not clinically depressed, according to one of the following criteria: i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician 5. Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

• Group 6: having a known genetic mutation associated with FTLD-TDP (genetic FTLD-TDP, n=3)

• Male or female ≥ 18 years of age
• Currently enrolled in UNICORN (IRB #842873) with a genetic test result indicating a mutation in the GRN gene or in open reading frame 72 of chromosome 9 (C9orf72).
• Clinically diagnosed by a trained clinician as having an appropriate neurodegenerative condition OR confirmed as an asymptomatic mutation carrier.
• Not clinically depressed, according to one of the following criteria:

i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

• Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

• Group 7: amnestic Alzheimer's disease (naAD, n=15)

• Male or female ≥ 18 years of age currently enrolled in UNICORN (IRB #842873)
• Clinically diagnosed by a trained clinician as having amnestic mild cognitive impairment (MCI) or amnestic Alzheimer's disease (aAD).
• Not clinically depressed, according to one of the following criteria:

i. Geriatric Depression scale ≤ 6 (assessed ≤ 6 months prior to study enrollment), OR ii. Evaluation by a trained clinician

• Have a study partner and LAR (if applicable) who can participate as outlined in the protocol. Please see page 15 for further clarification.

Exclusion Criteria for all groups: Participants will be excluded from enrollment if they meet any of the following criteria.

• The participant has any medical or psychiatric conditions that, in the opinion of the investigator, would compromise the participant's safety or successful participation in the study.
• The investigators of UNICORN (IRB #842873) have determined the participant has evidence of structural abnormalities such as major stroke or mass on MRI scan within \< 6 months prior to enrollment that is likely to interfere with analysis of the PET scan.
• The participant is unable to tolerate or have a contraindication to imaging procedures in the opinion of an investigator.
• Females who are pregnant or breast feeding at the time of the baseline PET/CT scan will not be eligible for this study. A urine pregnancy test will be performed in women of child-bearing potential at screening and within 24 hours of any scheduled PET/CT.
• The participant has a history of significant past or ongoing alcohol abuse or substance abuse, or dependence based on medical record review or self-reported (may be excluded at the discretion of the investigator.)
• The participant is enrolled in a clinical trial for a disease-modifying treatment that targets the molecular pathology underlying their neurodegenerative disease.