- Email: [email protected]
IN VIVO TAU IMAGING BY POSITRON EMISSION TOMOGRAPHY IN PATIENTS WITH C9ORF72 HEXANUCLEOTIDE REPEAT EXPANSIONS
P904
Podium Presentations: Tuesday, July 18, 2017
to established brain-behavior relationships (Figure 1). This pattern of regional associations remained essentially unchanged – although less spatially extended – when gray matter volume or 11C-PiB uptake maps were added as covariates (Figure 2). Mediation analyses revealed both direct and gray matter-mediated effects of 18F-AV1451 uptake on cognitive performance (Figure 3). Conclusions: Tau pathology is related in a region-specific manner to cognitive impairment in AD. These regional relationships are weakly related to amyloid burden, but are in part mediated by gray matter volumes. These results suggest that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted, to neuronal loss.
O3-03-04
AV1451-PET UPTAKE AND CSF BIOMARKERS IN A HETEROGENEOUS CLINICAL SAMPLE: TWO SIDES OF THE SAME COIN?
Renaud La Joie1, Alexandre Bejanin2, Anne M. Fagan3, Nagehan Ayakta2, Suzanne L. Baker4, Viktoriya Bourakova1, Anna Karydas5, Gina Jerome6, James P. O’Neil4, Julie Pham1, Adrienne Visani1, Howard J. Rosen7, Adam L. Boxer8, Bruce L. Miller8, William J. Jagust9, Gil D. Rabinovici7, 1 University of California, San Francisco, San Francisco, CA, USA; 2 Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA; 3Washington University School of Medicine, St. Louis, MO, USA; 4Lawrence Berkeley National Laboratory, Berkeley, CA, USA; 5 University of California - San Francisco, San Francisco, CA, USA; 6 Washington University in Saint Louis, Saint Louis, MO, USA; 7University of California San Francisco, San Francisco, CA, USA; 8University of California, San Francisco, San Francisco, CA, USA; 9University of California Berkeley, Berkeley, CA, USA. Contact e-mail: renaud.lajoie@ ucsf.edu Background: Thanks to recent radiotracer developments, both PET imaging and fluid biomarkers can now be used to assess AD pathophysiological mechanisms in vivo, and notably tau pathology. The present study aims to determine the relationships between tau-PET using 18F-AV1451 and cerebrospinal fluid (CSF) biomarkers in a heterogeneous sample of patients encompassing AD and non-AD etiologies. Methods: We studied patients seen at UCSF Memory and Aging Center with available AV1451-PET, PIB-PET and CSF biomarkers (median between PET and lumbar puncture: 114 days). This included 19 PIB-positive patients with AD and 13 patients with suspected non-AD etiologies (PSP, bvFTD, nfPPA). CSF samples were analyzed for total tau (T-tau), phosphorylated tau (P-tau), and Ab42 at Washington University using AlzBio3 xMAP immunoassay (Fujirebio). AV1451 data were processed using Freesurfer 5.3 and SPM12. We examined associations between CSF markers and metrics derived from AV1451-PET: the “global burden” (i.e. total gray matter uptake) and the “spatial extent” (i.e. the percentage of gray matter voxels with Z 2 compared to 41 Ab-PET-negative healthy older adults). Lastly, we ran voxelwise correlation analyses to assess regional relationships. Results: In the full patient sample (n¼32), both P-tau and T-tau, but not Ab42, were strongly correlated with AV1451-PET measures (Figure 1); the same pattern of correlations was observed when restricting the analyses to PIB-PET-positive AD patients (Figure 2). When entering all three CSF measures in a multiple regression model, P-tau was the sole significant predictor of global AV1451-uptake. Voxel-wise analyses showed that P-tau was associated with AV1451 retention in cingulate, precuneus and lateral parietal areas, whereas T-tau was related to increased medial prefrontal uptake (Figure 3). Conclusions: Among all three CSF biomarkers, P-tau
was the best correlate of AV1451-PET findings, consistent with the biomarker classification proposed in the A/T/N system (Jack et al, Neurology 2016). Correlations between P-tau and AV1451 remained significant in patients with AD, suggesting that both measures not only reflect the presence of an AD-type tau pathology, but also its severity. P-tau and T-tau showed distinct regional correlations with AV1451 uptake, indicating they may be capturing different elements or stages of disease pathophysiology.
O3-03-05
IN VIVO TAU IMAGING BY POSITRON EMISSION TOMOGRAPHY IN PATIENTS WITH C9ORF72 HEXANUCLEOTIDE REPEAT EXPANSIONS
Cindy V. Ly1, Lauren Koenig2, Helen Beaumont3, Brian A. Gordon3,4, Jon Christensen3, Yi Su4,5, Brittany Nelson1, Jennifer Jockel-Balsarotti6, Caroline Drain2, Gina Jerome2, Anne M. Fagan3,4,7, Matthew Harms8, Tammie L. S. Benzinger5,9, Timothy M. Miller6, Beau M. Ances3,4, 1 Washington University at Saint Louis, Saint Louis, MO, USA; 2Washington University in Saint Louis, Saint Louis, MO, USA; 3Washington University School of Medicine, St. Louis, MO, USA; 4Knight Alzheimer’s Disease
Podium Presentations: Tuesday, July 18, 2017
P905
Research Center, St. Louis, MO, USA; 5Washington University in St. Louis School of Medicine, St. Louis, MO, USA; 6Washington University School of Medicine, St. Louis, MO, USA; 7Hope Center for Neurological Disorders, St. Louis, MO, USA; 8Columbia University, New York, NY, USA; 9Knight Alzheimer Disease Research Center, St. Louis, MO, USA. Contact e-mail: [email protected] Background: C9orf72 repeat-related disease is the most common
cause of hereditary amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Similar to Alzheimer’s disease (AD), some C9orf72 expansion carriers who are cognitively impaired have been shown to have increases in tau neurofibrillary tangles at autopsy. Recently developed tau positron emission tomography (PET) imaging could potentially be an in vivo method to assess tau accumulation in C9orf72-related disease. We evaluated AV1451 PET as a diagnostic and prognostic biomarker for disease caused by C9orf72 repeat expansions. Methods: Eight C9orf72 expansion carriers (mean age: 63.4 6 4.1 years) and sixteen age and gender matched cognitively normal individuals (mean age: 63.6 6 5.0 years) underwent tau PET imaging. Regional AV1451 SUVR normalized to brainstem intensity from various brain regions was used to assess tau deposition between groups and corrected for multiple comparisons using a false discovery rate of 1%. Pearson correlation was used to evaluate tau deposition SUVR values and clinical characteristics including ALS-FRS (ALS functional ratting scale), disease duration, neuropsychiatric measures, as well as AD markers in CSF. Results: Symptomatic C9orf72 expansion carriers had an ALS-FRS of 26 6 10 (range 13-39), a disease duration of 2.59 6 1.16 years (range 1.21-4.19 years), and MMSE score of 27.0 6 3.1. Three quarters of the patients were symptomatic. C9orf72 expansion carriers had increased AV1451 uptake in the entorhinal cortex compared to a reference population of cognitively normal controls (C9: 1.0960.29, control: 0.7360.11, p¼0.0002). The entorhinal AV-1451 SUVR exceeds an a priori cutoff for tau deposition of 1.00 for brainstem-normalized values in 75% of C9orf72 subjects and in none of the controls. AV-1451 uptake within entorhinal, limbic, and cortical areas, corresponding to regional progression of tau pathology by Braak staging, did not correlate with clinical measures of severity (ALS-FRS and disease duration), neurocognitive performance defined by MMSE, executive, and visuospatial measures, or CSF markers of disease (Ab, total tau, and phospho-tau). Conclusions: C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to controls suggesting that tau
Table 1 Clinical Characteristics of C9orf72 Patients
Subject Age
Disease Site of Duration Gender Onset (years)
ALS-FRS MMSE (/48) (/30)
1 2 3 4 5 6 7 8 Avg
Female Male Male Female Male Male Female Female N/A
13 N/A 37 22 21 25 N/A 39 26 6 10
64 60 60 65 64 69 57 68 63.4 6 4.1
Spinal N/A Bulbar Bulbar Spinal Spinal N/A Bulbar N/A
1.57 N/A 1.21 3.67 4.19 2.67 N/A 2 25 2.59 6 1.16
N/A 30 30 27 23 24 25 30 27.0 6 3.1
deposition may contribute to development of mild cognitive impairment in this condition.
O3-03-06
18 F-AV-1451 BINDING IN FAMILIAL FRONTOTEMPORAL LOBAR DEGENERATION WITH TAU PATHOLOGY
William Charles Kreisl1, Stephanie Cosentino1, Gayathri Cheran2, Masood Manoochehri2, Sarah Cines2, Jill Goldman2, Edward D. Huey2, 1Taub Institute at Columbia University, New York, NY, USA; 2Gertrude H. Sergievsky Center at Columbia University, New York, NY, USA. Contact e-mail: [email protected] Background: In familial frontotemporal lobar degeneration with tau
pathology (FTLD-tau), different mutations in the microtubule associated protein tau (MAPT) gene result in aggregation of different tau isoform conformations. 18F-AV-1451 is a PET radioligand developed to bind to the tau aggregates found in Alzheimer’s disease, which are composed of both 3-repeat and 4-repeat (3R+4R) tau isoforms. We sought to evaluate the ability of 18F-AV-1451 to detect tau aggregates in different MAPTmutations. Methods: A total of seven members of three different families with MAPT mutations underwent PET imaging with 18F-AV-1451. MAPT mutations were associated with either 4R (P301L) or 3R+4R (V337M or R406W) tau aggregates. Symptomatic (n ¼ 4) and asymptomatic carriers (n ¼ 1) and non-carriers (n ¼ 2) were included. PET images were acquired 80-100 min after injection of 10 mCi 18F-AV-1451. PNEURO tool in PMOD was used to create gray matter regions of interest. Regional standardized uptake value ratios (SUVR) were obtained by dividing uptake in target regions to that in cerebral gray matter. Results:The three symptomatic V337M carriers (age 50-59 years, CDR ¼ 0.5) had the greatest amount of 18F-AV-1451 binding, with highest SUVRs in orbitofrontal cortex, anterior and ventral temporal cortex, and amygdala. The asymptomatic V337M carrier (age 33 years) and the symptomatic P301L carrier (age 56 years, CDR ¼ 1) had 18F-AV-1451 binding similar to that in the two non-carriers (ages 28 and 60 years). When the P301L subject was excluded, semantic verbal fluency performance correlated with 18F-AV-1451 binding in orbitofrontal, anterior temporal, and ventral temporal cortex (p < 0.05). Conclusions: 18F-AV-1451 detects tau aggregates in V337M carriers and therefore may be helpful in monitoring progression in patients with 3R+4R mutations. Additional scans are required to confirm the conformational specificity of 18F-AV-1451 in FTLD-tau
Podium Presentations: Tuesday, July 18, 2017
to established brain-behavior relationships (Figure 1). This pattern of regional associations remained essentially unchanged – although less spatially extended – when gray matter volume or 11C-PiB uptake maps were added as covariates (Figure 2). Mediation analyses revealed both direct and gray matter-mediated effects of 18F-AV1451 uptake on cognitive performance (Figure 3). Conclusions: Tau pathology is related in a region-specific manner to cognitive impairment in AD. These regional relationships are weakly related to amyloid burden, but are in part mediated by gray matter volumes. These results suggest that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted, to neuronal loss.
O3-03-04
AV1451-PET UPTAKE AND CSF BIOMARKERS IN A HETEROGENEOUS CLINICAL SAMPLE: TWO SIDES OF THE SAME COIN?
Renaud La Joie1, Alexandre Bejanin2, Anne M. Fagan3, Nagehan Ayakta2, Suzanne L. Baker4, Viktoriya Bourakova1, Anna Karydas5, Gina Jerome6, James P. O’Neil4, Julie Pham1, Adrienne Visani1, Howard J. Rosen7, Adam L. Boxer8, Bruce L. Miller8, William J. Jagust9, Gil D. Rabinovici7, 1 University of California, San Francisco, San Francisco, CA, USA; 2 Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA; 3Washington University School of Medicine, St. Louis, MO, USA; 4Lawrence Berkeley National Laboratory, Berkeley, CA, USA; 5 University of California - San Francisco, San Francisco, CA, USA; 6 Washington University in Saint Louis, Saint Louis, MO, USA; 7University of California San Francisco, San Francisco, CA, USA; 8University of California, San Francisco, San Francisco, CA, USA; 9University of California Berkeley, Berkeley, CA, USA. Contact e-mail: renaud.lajoie@ ucsf.edu Background: Thanks to recent radiotracer developments, both PET imaging and fluid biomarkers can now be used to assess AD pathophysiological mechanisms in vivo, and notably tau pathology. The present study aims to determine the relationships between tau-PET using 18F-AV1451 and cerebrospinal fluid (CSF) biomarkers in a heterogeneous sample of patients encompassing AD and non-AD etiologies. Methods: We studied patients seen at UCSF Memory and Aging Center with available AV1451-PET, PIB-PET and CSF biomarkers (median between PET and lumbar puncture: 114 days). This included 19 PIB-positive patients with AD and 13 patients with suspected non-AD etiologies (PSP, bvFTD, nfPPA). CSF samples were analyzed for total tau (T-tau), phosphorylated tau (P-tau), and Ab42 at Washington University using AlzBio3 xMAP immunoassay (Fujirebio). AV1451 data were processed using Freesurfer 5.3 and SPM12. We examined associations between CSF markers and metrics derived from AV1451-PET: the “global burden” (i.e. total gray matter uptake) and the “spatial extent” (i.e. the percentage of gray matter voxels with Z 2 compared to 41 Ab-PET-negative healthy older adults). Lastly, we ran voxelwise correlation analyses to assess regional relationships. Results: In the full patient sample (n¼32), both P-tau and T-tau, but not Ab42, were strongly correlated with AV1451-PET measures (Figure 1); the same pattern of correlations was observed when restricting the analyses to PIB-PET-positive AD patients (Figure 2). When entering all three CSF measures in a multiple regression model, P-tau was the sole significant predictor of global AV1451-uptake. Voxel-wise analyses showed that P-tau was associated with AV1451 retention in cingulate, precuneus and lateral parietal areas, whereas T-tau was related to increased medial prefrontal uptake (Figure 3). Conclusions: Among all three CSF biomarkers, P-tau
was the best correlate of AV1451-PET findings, consistent with the biomarker classification proposed in the A/T/N system (Jack et al, Neurology 2016). Correlations between P-tau and AV1451 remained significant in patients with AD, suggesting that both measures not only reflect the presence of an AD-type tau pathology, but also its severity. P-tau and T-tau showed distinct regional correlations with AV1451 uptake, indicating they may be capturing different elements or stages of disease pathophysiology.
O3-03-05
IN VIVO TAU IMAGING BY POSITRON EMISSION TOMOGRAPHY IN PATIENTS WITH C9ORF72 HEXANUCLEOTIDE REPEAT EXPANSIONS
Cindy V. Ly1, Lauren Koenig2, Helen Beaumont3, Brian A. Gordon3,4, Jon Christensen3, Yi Su4,5, Brittany Nelson1, Jennifer Jockel-Balsarotti6, Caroline Drain2, Gina Jerome2, Anne M. Fagan3,4,7, Matthew Harms8, Tammie L. S. Benzinger5,9, Timothy M. Miller6, Beau M. Ances3,4, 1 Washington University at Saint Louis, Saint Louis, MO, USA; 2Washington University in Saint Louis, Saint Louis, MO, USA; 3Washington University School of Medicine, St. Louis, MO, USA; 4Knight Alzheimer’s Disease
Podium Presentations: Tuesday, July 18, 2017
P905
Research Center, St. Louis, MO, USA; 5Washington University in St. Louis School of Medicine, St. Louis, MO, USA; 6Washington University School of Medicine, St. Louis, MO, USA; 7Hope Center for Neurological Disorders, St. Louis, MO, USA; 8Columbia University, New York, NY, USA; 9Knight Alzheimer Disease Research Center, St. Louis, MO, USA. Contact e-mail: [email protected] Background: C9orf72 repeat-related disease is the most common
cause of hereditary amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Similar to Alzheimer’s disease (AD), some C9orf72 expansion carriers who are cognitively impaired have been shown to have increases in tau neurofibrillary tangles at autopsy. Recently developed tau positron emission tomography (PET) imaging could potentially be an in vivo method to assess tau accumulation in C9orf72-related disease. We evaluated AV1451 PET as a diagnostic and prognostic biomarker for disease caused by C9orf72 repeat expansions. Methods: Eight C9orf72 expansion carriers (mean age: 63.4 6 4.1 years) and sixteen age and gender matched cognitively normal individuals (mean age: 63.6 6 5.0 years) underwent tau PET imaging. Regional AV1451 SUVR normalized to brainstem intensity from various brain regions was used to assess tau deposition between groups and corrected for multiple comparisons using a false discovery rate of 1%. Pearson correlation was used to evaluate tau deposition SUVR values and clinical characteristics including ALS-FRS (ALS functional ratting scale), disease duration, neuropsychiatric measures, as well as AD markers in CSF. Results: Symptomatic C9orf72 expansion carriers had an ALS-FRS of 26 6 10 (range 13-39), a disease duration of 2.59 6 1.16 years (range 1.21-4.19 years), and MMSE score of 27.0 6 3.1. Three quarters of the patients were symptomatic. C9orf72 expansion carriers had increased AV1451 uptake in the entorhinal cortex compared to a reference population of cognitively normal controls (C9: 1.0960.29, control: 0.7360.11, p¼0.0002). The entorhinal AV-1451 SUVR exceeds an a priori cutoff for tau deposition of 1.00 for brainstem-normalized values in 75% of C9orf72 subjects and in none of the controls. AV-1451 uptake within entorhinal, limbic, and cortical areas, corresponding to regional progression of tau pathology by Braak staging, did not correlate with clinical measures of severity (ALS-FRS and disease duration), neurocognitive performance defined by MMSE, executive, and visuospatial measures, or CSF markers of disease (Ab, total tau, and phospho-tau). Conclusions: C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to controls suggesting that tau
Table 1 Clinical Characteristics of C9orf72 Patients
Subject Age
Disease Site of Duration Gender Onset (years)
ALS-FRS MMSE (/48) (/30)
1 2 3 4 5 6 7 8 Avg
Female Male Male Female Male Male Female Female N/A
13 N/A 37 22 21 25 N/A 39 26 6 10
64 60 60 65 64 69 57 68 63.4 6 4.1
Spinal N/A Bulbar Bulbar Spinal Spinal N/A Bulbar N/A
1.57 N/A 1.21 3.67 4.19 2.67 N/A 2 25 2.59 6 1.16
N/A 30 30 27 23 24 25 30 27.0 6 3.1
deposition may contribute to development of mild cognitive impairment in this condition.
O3-03-06
18 F-AV-1451 BINDING IN FAMILIAL FRONTOTEMPORAL LOBAR DEGENERATION WITH TAU PATHOLOGY
William Charles Kreisl1, Stephanie Cosentino1, Gayathri Cheran2, Masood Manoochehri2, Sarah Cines2, Jill Goldman2, Edward D. Huey2, 1Taub Institute at Columbia University, New York, NY, USA; 2Gertrude H. Sergievsky Center at Columbia University, New York, NY, USA. Contact e-mail: [email protected] Background: In familial frontotemporal lobar degeneration with tau
pathology (FTLD-tau), different mutations in the microtubule associated protein tau (MAPT) gene result in aggregation of different tau isoform conformations. 18F-AV-1451 is a PET radioligand developed to bind to the tau aggregates found in Alzheimer’s disease, which are composed of both 3-repeat and 4-repeat (3R+4R) tau isoforms. We sought to evaluate the ability of 18F-AV-1451 to detect tau aggregates in different MAPTmutations. Methods: A total of seven members of three different families with MAPT mutations underwent PET imaging with 18F-AV-1451. MAPT mutations were associated with either 4R (P301L) or 3R+4R (V337M or R406W) tau aggregates. Symptomatic (n ¼ 4) and asymptomatic carriers (n ¼ 1) and non-carriers (n ¼ 2) were included. PET images were acquired 80-100 min after injection of 10 mCi 18F-AV-1451. PNEURO tool in PMOD was used to create gray matter regions of interest. Regional standardized uptake value ratios (SUVR) were obtained by dividing uptake in target regions to that in cerebral gray matter. Results:The three symptomatic V337M carriers (age 50-59 years, CDR ¼ 0.5) had the greatest amount of 18F-AV-1451 binding, with highest SUVRs in orbitofrontal cortex, anterior and ventral temporal cortex, and amygdala. The asymptomatic V337M carrier (age 33 years) and the symptomatic P301L carrier (age 56 years, CDR ¼ 1) had 18F-AV-1451 binding similar to that in the two non-carriers (ages 28 and 60 years). When the P301L subject was excluded, semantic verbal fluency performance correlated with 18F-AV-1451 binding in orbitofrontal, anterior temporal, and ventral temporal cortex (p < 0.05). Conclusions: 18F-AV-1451 detects tau aggregates in V337M carriers and therefore may be helpful in monitoring progression in patients with 3R+4R mutations. Additional scans are required to confirm the conformational specificity of 18F-AV-1451 in FTLD-tau