- Email: [email protected]
TDP-43 and mixed pathologies in normal cognition, mild cognitive impairment and dementia
P334
Oral Sessions: O2-10: Diagnosis and Prognosis: Neuropathology
and AD patients and controls. In case of diagnostic doubt between FTD and non-neurodegenerative disorders, an increased CSF tau level is strongly in favor of FTD. ORAL SESSIONS: O2-10 DIAGNOSIS AND PROGNOSIS: NEUROPATHOLOGY O2-10-01
TDP-43 AND MIXED PATHOLOGIES IN NORMAL COGNITION, MILD COGNITIVE IMPAIRMENT AND DEMENTIA
Bryan James1, David Bennett2, Patricia Boyle2, Robert Wilson2, John Trojanowski3, Julie Schneider1, 1Rush Alzheimer’s Disease Center, Chicago, Illinois, United States; 2Rush University Medical Center, Chicago, Illinois, United States; 3University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States. Contact e-mail: Bryan_James@ rush.edu Background: TAR DNA-binding protein (TDP-43) is a pathologic protein associated with Frontotemporal lobar degeneration, commonly present in older brains, especially those with Alzheimer’s disease (AD) pathology. Recent studies suggest that TDP-43 pathology in older persons is associated with dementia. We extend our previous work on mixed pathologies to include TDP-43. Methods: We assessed clinical and neuropathologic data from persons aged 69-104 (mean age¼88.4, SD¼7.3) at death from the Religious Orders Study, a longitudinal clinic-pathologic studies of aging. Persons were evaluated on average 6 months before death using standard criteria for dementia and mild cognitive impairment (MCI). At autopsy, TDP-43 pathology was investigated in the amygdala, hippocampal, entorhinal, frontal and temporal cortices. Brains were also evaluated for a pathologic diagnosis of AD (NIA-Reagan criteria), neocortical Lewy bodies (LB), and old gross and microscopic cerebral infarcts. Persons with complete pathologic data (n¼147) were included in this study. Results: TDP43 was present in 50.0% of all brains. It was often but not always associated with AD pathology (TDP-43 with AD: 68.1%; TDP-43 without AD: 31.9%). TDP was also seen coexisting with infarcts (41.7%) and LB (11.1%). TDP was more common in those with dementia (46/69, 46.9%) but was also present in those with no cognitive impairment (NCI) (11/39, 26.5%) and MCI (15/39, 39%). In persons with dementia, AD was the most common pathology (71.0%), followed by TDP-43 (66.7%), infarcts (53.6%), and LB (15.9%). Considering TDP-43 as an additional pathology greatly increased the proportion of persons labeled as having mixed pathologies (more than one pathology) in all three cognitive groups: 10.3% vs. 25.6% in NCI, 12.8% vs. 41.0% in MCI, and 44.9% vs. 76.8% in dementia (all p-values < 0.01). In persons with dementia, AD was more likely to coexist with TDP-43 pathology (71.4%) than with infarcts (51.0%) or LB (14.3%); only 4 (4.7%) had AD with no other pathologies. Conclusions: TDP-43 is highly prevalent in the brains of older adults, particularly in those with dementia. TDP-43 pathology is the most common pathology to coexist with AD pathology. Considering TDP-43 as a separate pathology greatly increases the proportion of older persons labeled as having mixed brain pathologies. O2-10-02
IMPORTANCE OF COINCIDENT NEURODEGENERATIVE DISEASES
Jon Toledo1, Steven Arnold2, Johannes Brettschneider2, Edward Lee2, David Irwin2, Sharon Xie2, Murray Grossman3, Sarah Monsell4, Walter Kukull4, John Trojanowski2, 1Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 2University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 3University of Pennsylvania, Philadelphia, Pennsylvania, United States; 4National Alzheimer’s Coordinating Center, Seattle, Washington, United States. Contact e-mail: [email protected] Background: Dementia clinical studies and trials are designed to study and treat patients with a single neurodegenerative disease (ND). However, there is increasing evidence of the presence of coincident NDs based on neuropathological studies. Therefore, we sought to study and characterize the
presence of coincident NDs in a multi-center study comprised of patients followed up to autopsy in the National Institute of Aging-funded AD Centers (ADCs) across the United States. Methods: Demographic, clinical and autopsy data from 9,953 demented patients with a ND followed in 35 past and present ADC was analyzed. Results: 7,482, 2,385, 79 and 7 patients had one, two, three and four NDs, respectively. The most common single ND in the demented patients was Alzheimer’s disease (AD) (n¼6,026), and the second most common category was coincident AD and Lewy Body disease pathology (n¼1,832). Subjects with three (p¼0.007) and four (p¼0.0008) coincident NDs were older than subjects with a single ND. Gender was not associated with the number of NDs. Conclusions: Coincident NDs are a frequent finding in neuropathological studies of patients followed in specialized dementia centers (24.8% of cases), and are the second most common neurodegenerative cause of dementia. Combinations of different biomarker panels are necessary to diagnose and characterize the causes of underlying dementia. Coincident NDs are highly prevalent and should be studied in appropriate cohort studies and identified in clinical trials as a potential cause of treatment failure in disease specific targeted therapies. O2-10-03
UTILITY OF AMYLOID PET IN THE DIFFERENTIAL DIAGNOSIS OF DEMENTIA: AN AUTOPSY-CONFIRMED SERIES
Manja Lehmann1, William Seeley1, Pia Ghosh1, Cindee Madison2, Bruce Miller1, Lea Grinberg1, John Trojanowski3, Mario Mendez4, Harry Vinters4, William Jagust5, Gil Rabinovici1, 1University of California, San Francisco, Memory and Aging Center, San Francisco, California, United States; 2Helen Wills Neuroscience Institute, Berkeley, California, United States; 3University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 4University of California, Los Angeles, Los Angeles, California, United States; 5University of California, Berkeley, Berkeley, California, United States. Contact e-mail: mlehmann@ memory.ucsf.edu Background: Most data correlating amyloid PET with autopsy are derived from end-of-life patients, and prospective studies in more representative clinical populations are lacking. We compared PiB-PET during life with postmortem diagnosis and amyloid burden in a consecutive series of patients from an academic memory clinic. Methods: 25 patients (age 67.868.6, 72% male) underwent PiB-PET and autopsy (2.861.8 years after PET). Clinical diagnoses included Alzheimer’s disease (AD, N¼6), frontotemporal dementia (FTD, N¼13), corticobasal syndrome (CBS, N¼4), mild cognitive impairment (N¼2). Autopsies were performed at UCSF, Penn and UCLA. Amyloid assessment at autopsy included beta-amyloid immunohistochemistry (N¼21), Bielschowsky (N¼3) and Thioflavin-S (N¼1). Neuritic plaques were graded with modified CERAD (unadjusted for age). PiB scans were visually assessed as PiB+/PiB- blinded to clinical diagnosis. PiB distribution volume ratios (DVR) were used to assess PiB binding in 20 patients using a global measure (PiB Index). Threshold for PiB DVR Index positivity was 1.16. PiB visual ratings and PiB Index were compared to CERAD-frequent and NIA-Reagan high-likelihood to assess diagnostic accuracy. Results: Pathology diagnoses included: 10 NIA-Reagan high-likelihood AD (2 mixed with frontotemporal lobar degeneration (FTLD)), 8 FTLD-TDP, 6 FTLDTau, and 1 argyrophilic grain disease (AGD). PiB visual ratings correctly identified all high-likelihood AD patients as PiB+, with only one low-likelihood case (primary AGD) rated PiB+ due to focal PiB binding (accuracy 94%, sensitivity 100%, specificity 91%). All other absent to intermediatelikelihood AD patients were PiB-. All CERAD-frequent patients were visually rated as PiB+ (Figure), except one with primary FTLD-TDP and incidental AD pathology (CERAD-frequent but NIA-Reagan low-likelihood) (accuracy 92%, sensitivity 93%, specificity 91%). Using a quantitative measure of PiB threshold (PiB Index), two patients fell below the cut-off, resulting in 78% sensitivity and 100% specificity for both CERAD-frequent and NIAReagan high-likelihood. PiB imaging correctly identified two CBS cases as having primary AD pathology. However, one patient with CBS and another with FTD were PiB+ but had FTLD-Tau and AD co-pathology at autopsy. Conclusions: PiB+ scans reflect high burden of amyloid pathology,
Oral Sessions: O2-10: Diagnosis and Prognosis: Neuropathology
and AD patients and controls. In case of diagnostic doubt between FTD and non-neurodegenerative disorders, an increased CSF tau level is strongly in favor of FTD. ORAL SESSIONS: O2-10 DIAGNOSIS AND PROGNOSIS: NEUROPATHOLOGY O2-10-01
TDP-43 AND MIXED PATHOLOGIES IN NORMAL COGNITION, MILD COGNITIVE IMPAIRMENT AND DEMENTIA
Bryan James1, David Bennett2, Patricia Boyle2, Robert Wilson2, John Trojanowski3, Julie Schneider1, 1Rush Alzheimer’s Disease Center, Chicago, Illinois, United States; 2Rush University Medical Center, Chicago, Illinois, United States; 3University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States. Contact e-mail: Bryan_James@ rush.edu Background: TAR DNA-binding protein (TDP-43) is a pathologic protein associated with Frontotemporal lobar degeneration, commonly present in older brains, especially those with Alzheimer’s disease (AD) pathology. Recent studies suggest that TDP-43 pathology in older persons is associated with dementia. We extend our previous work on mixed pathologies to include TDP-43. Methods: We assessed clinical and neuropathologic data from persons aged 69-104 (mean age¼88.4, SD¼7.3) at death from the Religious Orders Study, a longitudinal clinic-pathologic studies of aging. Persons were evaluated on average 6 months before death using standard criteria for dementia and mild cognitive impairment (MCI). At autopsy, TDP-43 pathology was investigated in the amygdala, hippocampal, entorhinal, frontal and temporal cortices. Brains were also evaluated for a pathologic diagnosis of AD (NIA-Reagan criteria), neocortical Lewy bodies (LB), and old gross and microscopic cerebral infarcts. Persons with complete pathologic data (n¼147) were included in this study. Results: TDP43 was present in 50.0% of all brains. It was often but not always associated with AD pathology (TDP-43 with AD: 68.1%; TDP-43 without AD: 31.9%). TDP was also seen coexisting with infarcts (41.7%) and LB (11.1%). TDP was more common in those with dementia (46/69, 46.9%) but was also present in those with no cognitive impairment (NCI) (11/39, 26.5%) and MCI (15/39, 39%). In persons with dementia, AD was the most common pathology (71.0%), followed by TDP-43 (66.7%), infarcts (53.6%), and LB (15.9%). Considering TDP-43 as an additional pathology greatly increased the proportion of persons labeled as having mixed pathologies (more than one pathology) in all three cognitive groups: 10.3% vs. 25.6% in NCI, 12.8% vs. 41.0% in MCI, and 44.9% vs. 76.8% in dementia (all p-values < 0.01). In persons with dementia, AD was more likely to coexist with TDP-43 pathology (71.4%) than with infarcts (51.0%) or LB (14.3%); only 4 (4.7%) had AD with no other pathologies. Conclusions: TDP-43 is highly prevalent in the brains of older adults, particularly in those with dementia. TDP-43 pathology is the most common pathology to coexist with AD pathology. Considering TDP-43 as a separate pathology greatly increases the proportion of older persons labeled as having mixed brain pathologies. O2-10-02
IMPORTANCE OF COINCIDENT NEURODEGENERATIVE DISEASES
Jon Toledo1, Steven Arnold2, Johannes Brettschneider2, Edward Lee2, David Irwin2, Sharon Xie2, Murray Grossman3, Sarah Monsell4, Walter Kukull4, John Trojanowski2, 1Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 2University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 3University of Pennsylvania, Philadelphia, Pennsylvania, United States; 4National Alzheimer’s Coordinating Center, Seattle, Washington, United States. Contact e-mail: [email protected] Background: Dementia clinical studies and trials are designed to study and treat patients with a single neurodegenerative disease (ND). However, there is increasing evidence of the presence of coincident NDs based on neuropathological studies. Therefore, we sought to study and characterize the
presence of coincident NDs in a multi-center study comprised of patients followed up to autopsy in the National Institute of Aging-funded AD Centers (ADCs) across the United States. Methods: Demographic, clinical and autopsy data from 9,953 demented patients with a ND followed in 35 past and present ADC was analyzed. Results: 7,482, 2,385, 79 and 7 patients had one, two, three and four NDs, respectively. The most common single ND in the demented patients was Alzheimer’s disease (AD) (n¼6,026), and the second most common category was coincident AD and Lewy Body disease pathology (n¼1,832). Subjects with three (p¼0.007) and four (p¼0.0008) coincident NDs were older than subjects with a single ND. Gender was not associated with the number of NDs. Conclusions: Coincident NDs are a frequent finding in neuropathological studies of patients followed in specialized dementia centers (24.8% of cases), and are the second most common neurodegenerative cause of dementia. Combinations of different biomarker panels are necessary to diagnose and characterize the causes of underlying dementia. Coincident NDs are highly prevalent and should be studied in appropriate cohort studies and identified in clinical trials as a potential cause of treatment failure in disease specific targeted therapies. O2-10-03
UTILITY OF AMYLOID PET IN THE DIFFERENTIAL DIAGNOSIS OF DEMENTIA: AN AUTOPSY-CONFIRMED SERIES
Manja Lehmann1, William Seeley1, Pia Ghosh1, Cindee Madison2, Bruce Miller1, Lea Grinberg1, John Trojanowski3, Mario Mendez4, Harry Vinters4, William Jagust5, Gil Rabinovici1, 1University of California, San Francisco, Memory and Aging Center, San Francisco, California, United States; 2Helen Wills Neuroscience Institute, Berkeley, California, United States; 3University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 4University of California, Los Angeles, Los Angeles, California, United States; 5University of California, Berkeley, Berkeley, California, United States. Contact e-mail: mlehmann@ memory.ucsf.edu Background: Most data correlating amyloid PET with autopsy are derived from end-of-life patients, and prospective studies in more representative clinical populations are lacking. We compared PiB-PET during life with postmortem diagnosis and amyloid burden in a consecutive series of patients from an academic memory clinic. Methods: 25 patients (age 67.868.6, 72% male) underwent PiB-PET and autopsy (2.861.8 years after PET). Clinical diagnoses included Alzheimer’s disease (AD, N¼6), frontotemporal dementia (FTD, N¼13), corticobasal syndrome (CBS, N¼4), mild cognitive impairment (N¼2). Autopsies were performed at UCSF, Penn and UCLA. Amyloid assessment at autopsy included beta-amyloid immunohistochemistry (N¼21), Bielschowsky (N¼3) and Thioflavin-S (N¼1). Neuritic plaques were graded with modified CERAD (unadjusted for age). PiB scans were visually assessed as PiB+/PiB- blinded to clinical diagnosis. PiB distribution volume ratios (DVR) were used to assess PiB binding in 20 patients using a global measure (PiB Index). Threshold for PiB DVR Index positivity was 1.16. PiB visual ratings and PiB Index were compared to CERAD-frequent and NIA-Reagan high-likelihood to assess diagnostic accuracy. Results: Pathology diagnoses included: 10 NIA-Reagan high-likelihood AD (2 mixed with frontotemporal lobar degeneration (FTLD)), 8 FTLD-TDP, 6 FTLDTau, and 1 argyrophilic grain disease (AGD). PiB visual ratings correctly identified all high-likelihood AD patients as PiB+, with only one low-likelihood case (primary AGD) rated PiB+ due to focal PiB binding (accuracy 94%, sensitivity 100%, specificity 91%). All other absent to intermediatelikelihood AD patients were PiB-. All CERAD-frequent patients were visually rated as PiB+ (Figure), except one with primary FTLD-TDP and incidental AD pathology (CERAD-frequent but NIA-Reagan low-likelihood) (accuracy 92%, sensitivity 93%, specificity 91%). Using a quantitative measure of PiB threshold (PiB Index), two patients fell below the cut-off, resulting in 78% sensitivity and 100% specificity for both CERAD-frequent and NIAReagan high-likelihood. PiB imaging correctly identified two CBS cases as having primary AD pathology. However, one patient with CBS and another with FTD were PiB+ but had FTLD-Tau and AD co-pathology at autopsy. Conclusions: PiB+ scans reflect high burden of amyloid pathology,