PET Imaging Tau Accumulation in FTLD and Atypical Alzheimer's Using PI-2620

The investigators will compare PI-2620 tau PET scans from patients with frontotemporal lobar degeneration (FTLD), patients with non-amnestic presentations of Alzheimer's disease (naAD), and demographically matched cognitively normal seniors.

The current study is a companion imaging study to IRB# 842873, "University of Pennsylvania Centralized Observational Research Repository on Neurodegenerative Disease" (UNICORN). UNICORN is an observational study that aims to collect and store cross-sectional and longitudinal data from brain imaging, clinical and neuropsychological assessment, biomarker assays, and genetic testing of participants to improve clinical assessment and basic scientific understanding of multiple neurodegenerative conditions. The UNICORN cohort includes neurodegenerative disease patients who have been evaluated by trained neurologists in the Penn Cognitive Neurology Clinic according to published clinical research diagnostic criteria and reviewed at a weekly multidisciplinary consensus conference; as well as individuals with normal cognition recruited from the general community or from among caregivers/relatives of patients participating in research. As part of the UNICORN study, participants are asked to undergo periodic (typically annual) magnetic resonance imaging (MRI) and clinical/neuropsychological assessment. Participants may also be asked to undergo genetic testing to detect known variants associated with increased neurodegenerative disease risk. UNICORN participants are also asked to undergo a one-time lumbar puncture to assess cerebrospinal fluid protein levels, including amyloid-ß1-42, an established biomarker for Alzheimer's disease (AD) neuropathologic change. As an alternative method of assessing amyloid status, some UNICORN participants may elect to undergo an [18F] florbetaben amyloid PET scan under protocol #824869. All participants in the current study must be concurrently enrolled in UNICORN. The current study comprises a recruitment/screening visit and a single PET imaging scan using the PI-2620 tracer. The central hypotheses are 1) that PI-2620 PET will distinguish Alzheimer's disease (AD) or frontotemporal lobar degeneration (FTLD) tauopathy from the brains of both healthy seniors and patients with FTLD due to accumulation of transactive response DNA binding protein 43 kDA (TDP-43); and 2) that in FTLD and AD tauopathies, PI-2620 will be associated with patients' current and future cognitive, motor, and functional impairment. Participants will be assigned to one of 7 groups, including cognitively and neurologically normal seniors (CN; planned enrollment of n=12); non-amnestic AD (naAD, n=15); frontotemporal lobar degeneration (FTLD) due to tauopathy (FTLD-tau, n=12); FTLD due to TDP-43 (n=12); FTLD-tau due to a known genetic mutation in the MAPT gene (genetic FTLD-tau, n=3); FTLD-TDP due to a known mutation in the GRN gene or open reading frame 72 of chromosome 9 (C9orf72) (genetic FTLD-TDP, n=3); and amnestic MCI/AD (aAD, n=15), Total planned enrollment is thus 72 participants; recruitment and data acquisition for the study are projected to take approximately 3 years.

Whole-brain and regionally specific standardized uptake value ratio (SUVR) calculated over a 30 minute imaging period beginning 45 minutes (groups 1, 2, 4, 6, & 7) after tracer injection

Regionally specific standardized uptake value ratio (SUVR) calculated over a 30 minute period beginning at either 30 minutes (groups 3 & 5 plus half of group 1) or 45 minutes (groups 2, 4, & 6 & 7 plus half of group 1) after PET imaging tracer injection.

Inclusion Criteria: participants must fulfill all of the criteria for one of the following groups. Group 1: cognitively and neurologically normal seniors (CN, n=12) Male or female ≥ 45 years of age currently enrolled in UNICORN (IRB #842873) If female, post-menopausal or surgically sterile (i.e., unable to have children due to hysterectomy, removal of the Fallopian tubes, tubal ligation, or similar surgery). 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 ≥ 45 years of age currently enrolled in UNICORN (IRB #842873) If female, post-menopausal or surgically sterile (i.e., unable to have children due to hysterectomy, removal of the Fallopian tubes, tubal ligation, or similar surgery). Clinically diagnosed by a trained clinician as having logopenic-variant primary progressive aphasia (lvPPA) or posterior cortical atrophy (PCA). 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 or legally authorized representative who can accompany the participant for all screening and study activities. 3. Group 3: FTLD due to tau (FTLD-tau, n=12) Male or female ≥ 45 years of age currently enrolled in UNICORN (IRB #842873) If female, post-menopausal or surgically sterile. (i.e., unable to have children due to hysterectomy, removal of the Fallopian tubes, tubal ligation, or similar surgery). Clinically diagnosed by a trained clinician as having progressive supranuclear palsy (PSP), non-fluent agrammatic primary progressive aphasia (naPPA), or behavioral-variant frontotemporal dementia (bvFTD) consistent with Pick's disease. 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 or legally authorized representative who can accompany the participant for all screening and study activities. 4. Group 4: FTLD due to TDP-43 (FTLD-TDP, n=12) Male or female ≥ 45 years of age currently enrolled in UNICORN (IRB #842873) If female, post-menopausal or surgically sterile (i.e., unable to have children due to hysterectomy, removal of the Fallopian tubes, tubal ligation, or similar surgery). Clinically diagnosed by a trained clinician as having amyotropic 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 or legally authorized representative who can accompany the participant for all screening and study activities. 5. Group 5: FTLD-tau due to a known genetic mutation (genetic FTLD-tau, n=3) Male or female ≥ 45 years of age Currently enrolled in UNICORN (IRB #842873) with a genetic test result indicating a mutation in the MAPT gene. If female, post-menopausal or surgically sterile (i.e., unable to have children due to hysterectomy, removal of the Fallopian tubes, tubal ligation, or similar surgery). Clinically diagnosed by a trained clinician as having progressive supranuclear palsy (PSP), non-fluent agrammatic primary progressive aphasia (naPPA), or behavioral-variant frontotemporal dementia (bvFTD) consistent with Pick's disease. 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 or legally authorized representative who can accompany the participant for all screening and study activities. 6. Group 6: FTLD-TDP due to a known genetic mutation (genetic FTLD-TDP, n=3) Male or female ≥ 45 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). If female, post-menopausal or surgically sterile (i.e., unable to have children due to hysterectomy, removal of the Fallopian tubes, tubal ligation, or similar surgery). Clinically diagnosed by a trained clinician as having amyotropic 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 or legally authorized representative who can accompany the participant for all screening and study activities. Group 7: amnestic Alzheimer's disease (naAD, n=15) 1. Male or female ≥ 45 years of age currently enrolled in UNICORN (IRB #842873) 2. If female, post-menopausal or surgically sterile (i.e., unable to have children due to hysterectomy, removal of the Fallopian tubes, tubal ligation, or similar surgery). 3. Clinically diagnosed by a trained clinician as having amnestic mild cognitive impairment (MCI) or amnestic Alzheimer's disease (aAD). 4. 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 or legally authorized representative who can accompany the participant for all screening and study activities. 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 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. The participant has a history of significant or ongoing alcohol abuse or substance abuse, or dependence based on medical record review or self-reported. The participant is enrolled in a clinical trial for a disease-modifying treatment that targets the molecular pathology underlying their neurodegenerative disease.