- Email: [email protected]
Tau phosphorylation is exaggerated in Alzheimer disease with psychosis
2013 AAGP Annual Meeting 1
University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA University of Pittsburgh School of Medicine, Department of Neurology, Pittsburgh, PA 3 VAPHS, Mental Illness Research, Education and Clinical Centers, Pittsburgh, PA 4 University of Pittsburgh School of Medicine, Divison of Neuropathology, Department of Pathology, Pittsburgh, PA 2
Introduction: TAR-DNA-binding protein 43 (TDP-43) has been identified as a major disease protein in the pathologic lesions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 proteinopathy has also been observed in neurodegenerative disorders characterized by tau pathology including Alzheimer’s disease. Recent studies identified AD cases with characteristic distribution of TDP-43 in entorhinal cortex, dentate gyrus ("limbic" distribution pattern); temporal and frontal cortices. Alzheimer’s disease subjects with psychotic symptoms (AD+P) represents a subgroup characterized by greater impairment of frontal cortex dependent cognitive functions, and more frequent behavioral disinhibition as compared to AD without psychosis (AD-P). The aim of this study is to determine if there is an association between TDP-43 pathology and AD+P. We hypothesized that TDP-43 pathology would be more frequent in AD+P than AD-P. Methods: We studied the presence and distribution of TDP-43 pathology by immunohistochemistry in the dentate gyrus and frontal cortex of postmortem brain specimens from 59 consecutive subjects with a primary neuropathologic diagnosis of Alzheimer Disease as determined by the Neuropathology Core of the University of Pittsburgh Alzheimer Disease Research Center. All subjects had been characterized while alive by the ADRC clinical core on a variety of measures, including structured assessment of psychotic symptoms. Results: Forty-three (72.9%) of subjects were classified as AD+P. AD+P and AD-P subjects did not differ in sex, race, age at death, at onset of AD, nor in duration of illness. Twelve subjects (20.3%) demonstrated pathologic TDP-43 deposition in Dentate Gyrus, 6 (10.2%) subjects had pathologic TDP-43 deposition in frontal cortex, 4 (6.8%) subjects were positive in both regions. Contrary to our expectation we observed a significant association between TDP-43 presence in frontal cortex and AD without psychosis (c2¼ 5.28, df¼1, p ¼0.022). There was no significant association between TDP-43 presence in dentate gyrus and AD with psychosis (c2¼ 0.83, df¼1, p ¼0.362). Conclusions: Our findings indicate that TDP-43 neuropathology in frontal cortex and dentate gyrus is not associated with an increased risk of psychosis during Alzheimer’s disease; moreover, the results suggest that TDP-43 pathology at least in the frontal cortex might somehow contribute to prevention of psychotic symptoms in patients with AD. Further studies may increase our current understanding on the relationship between TDP-43 pathology and AD+P.
Poster Number: EI 25
Tau phosphorylation is exaggerated in Alzheimer disease with psychosis
Patrick S. Murray, PhD1,3; Caitlin M. Kirkwood, BS1,3; Milos D. Ikonomovic, MD2,4; Kenneth N. Fish, PhD1,3; Robert A. Sweet, MD1,3 1
University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA University of Pittsburgh School of Medicine, Department of Neurology, Pittsburgh, PA 3 VAPHS, Mental Illness Research, Education and Clinical Centers, Pittsburgh, PA 4 VAPHS, Geriatric Research, Education and Clinical Centers, Pittsburgh, PA 2
Introduction: The occurrence of psychotic symptoms in Alzheimer’s disease subjects (AD+P) represents a subgroup characterized by more severe impairment and more rapid decline in cognition compared to AD without psychosis (AD-P). AD+P aggregates within families with an estimated heritability of 61%, indicating a substantial genetic component. Since the strongest correlate of cognitive impairment in AD is synapse loss across cortical regions, we hypothesize that the genetic architecture of AD+P leads to exaggerated synaptic vulnerability. In dorsolateral prefrontal cortex (DLPFC) we previously found increased disruption of synapse integrity, lower kalirin expression, and greater Ab42/Ab40 ratio in AD+P cases. Methods: Since hyperphosphorylated tau may be a necessary mediator of Ab-induced synaptic toxicity, we evaluated DLPFC grey matter phospho-tau (pTau) in a well-matched cohort of 26 AD+P and 19 AD-P cases. We used AT8, an antibody for a triple phosphorylation site epitope (ser199/ser202/thr205) on pTau-associated dystrophic neurites, neuropil threads, and neurofibrillary tangles, and assessed both mean fluorescence intensity, indicative of relative pTau concentration (pTC), and pTau volume fraction (pTVV; fraction of total grey matter volume occupied by pTau) in the DLPFC.
S80
Am J Geriatr Psychiatry 21:3, Supplement 1
2013 AAGP Annual Meeting Results: Both of our measures were significantly correlated with Braak stage (pTC rs ¼ 0.491, p < 0.001; pTVV rs ¼ 0.758, p < 0.001). In AD+P, we found that pTC was greater (p ¼ 0.006) and that pTVV trended toward an increase (p ¼ 0.082). We then evaluated whether pTC and/or pTVV affected cognitive impairment by examining the most recent scores on the mini-mental status exam (MMSE), as an indication of global cognitive function, and on the digit span backwards test (DSB), as an indicator of cognitive function associated specifically with the DLPFC. Consistent with previous findings, AD+P cases scored lower on the mini-mental status exam (MMSE; p ¼ 0.026), despite similar durations of illness in the two groups. Lower scores on the MMSE were influenced by higher pTC (p ¼ 0.006), and pTVV (p ¼ 0.030); lower scores on the DSB were also influenced by pTC (p ¼ 0.013) and pTVV (p ¼ 0.008). Conclusions: These novel findings indicate that while higher pTC and pTVV are associated with worse cognitive impairment, pTC is specifically higher in AD+P. This suggests that phosphorylation of tau may be exaggerated in AD+P, which along with our previous findings, points to more severe pathological dynamics in AD+P.
Poster Number: EI 26
A study on reliability and validity of Montreal Cognitive Assessment in Eastern China: Preliminary findings Hu Jianbo, Master of Medicine; Jinwen Huang, Master of Medicine; Shaohua Hu, Doctor of Medicine; Manli Huang, Doctor of Medicine; Wei Ning, Doctor of Medicine; Weihua Zhou, Doctor of Medicine; Hongli Qi, Master of Medicine; Yi Xu, MD, Doctor of Medicine The first affiliated Hospital, medicine of college, Zhejiang university # Corresponding author: Yi XU, Hangzhou, China Introduction: Validation of Chinese version of Montreal Cognitive Assessment (MOCA) for the elderly population in Eastern China Methods: 72 patients with AD, 84 patients with mild cognitive impairment (MCI) and146 cases of the normal population sample of elderly from community in Hangzhou. Each sample were evaluated for the Montreal Cognitive Assessment Scale (MoCA-C), Mini-mental state examination (MMSE), Hasegawa Dementia Scale (HDS), Clinical Dementia Scale (CDR) and other neuropsychological tests .Through by The use of internal consistency, test-retest reliability, content validity, criterion validity, the principal component / factor analysis to evaluate the test results. Results: The mean age and education level for the total sample was 64.4 years and 9.4 years, respectively. No differences were found between groups in terms of education level, or gender, but on average patients with MCI (60.7 years) were significantly younger (p<0.001) than those with AD (68.4 years) or normal cognitive function (67.2 years). Gender was not related to MMSE or MoCA-C scores. The time required of MoCA and MMSE in the three groups were compared differences (tAD¼5.77, tMCI¼7.16, tNC¼14.71, P<0.01). MoCA’s internal consistency coefficient (Cronbach’s alpha) was 0.867. Testretest reliability ICC value was 0.912 (P<0.01). MoCA score and MMSE were highly correlated (r ¼ 0.912, P <0.01). Each item with total score correlation were 0.686-0.884. Factor analysis to extract two common factors that can explain the total variance of 71.882%, Factor 1 called executive function/attention factor, Factor 2 called memory factor. Conclusions: The Montreal Cognitive Assessment Scale of Chinese Version (MoCA) has good reliability and validity and feasibility in Hangzhou, it is a good cognitive screen scale especially for population of mainland China in community. Table 1. MoCA each sub-test with the correlation of total score (n¼302) sub- group score Visuospatial/Executive Functions(5) Naming(3) Attention(6) Language(3) Abstraction(2) Recall(5) Orientation(6) Moca Score(30)
Am J Geriatr Psychiatry 21:3, Supplement 1
4.381.23 2.760.55 5.510.95 2.630.68 1.370.68 2.831.46 4.851.02 24.335.17
correlation coefficient
P
0.884 0.806 0.840 0.686 0.703 0.811 0.688
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01
S81
University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA University of Pittsburgh School of Medicine, Department of Neurology, Pittsburgh, PA 3 VAPHS, Mental Illness Research, Education and Clinical Centers, Pittsburgh, PA 4 University of Pittsburgh School of Medicine, Divison of Neuropathology, Department of Pathology, Pittsburgh, PA 2
Introduction: TAR-DNA-binding protein 43 (TDP-43) has been identified as a major disease protein in the pathologic lesions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 proteinopathy has also been observed in neurodegenerative disorders characterized by tau pathology including Alzheimer’s disease. Recent studies identified AD cases with characteristic distribution of TDP-43 in entorhinal cortex, dentate gyrus ("limbic" distribution pattern); temporal and frontal cortices. Alzheimer’s disease subjects with psychotic symptoms (AD+P) represents a subgroup characterized by greater impairment of frontal cortex dependent cognitive functions, and more frequent behavioral disinhibition as compared to AD without psychosis (AD-P). The aim of this study is to determine if there is an association between TDP-43 pathology and AD+P. We hypothesized that TDP-43 pathology would be more frequent in AD+P than AD-P. Methods: We studied the presence and distribution of TDP-43 pathology by immunohistochemistry in the dentate gyrus and frontal cortex of postmortem brain specimens from 59 consecutive subjects with a primary neuropathologic diagnosis of Alzheimer Disease as determined by the Neuropathology Core of the University of Pittsburgh Alzheimer Disease Research Center. All subjects had been characterized while alive by the ADRC clinical core on a variety of measures, including structured assessment of psychotic symptoms. Results: Forty-three (72.9%) of subjects were classified as AD+P. AD+P and AD-P subjects did not differ in sex, race, age at death, at onset of AD, nor in duration of illness. Twelve subjects (20.3%) demonstrated pathologic TDP-43 deposition in Dentate Gyrus, 6 (10.2%) subjects had pathologic TDP-43 deposition in frontal cortex, 4 (6.8%) subjects were positive in both regions. Contrary to our expectation we observed a significant association between TDP-43 presence in frontal cortex and AD without psychosis (c2¼ 5.28, df¼1, p ¼0.022). There was no significant association between TDP-43 presence in dentate gyrus and AD with psychosis (c2¼ 0.83, df¼1, p ¼0.362). Conclusions: Our findings indicate that TDP-43 neuropathology in frontal cortex and dentate gyrus is not associated with an increased risk of psychosis during Alzheimer’s disease; moreover, the results suggest that TDP-43 pathology at least in the frontal cortex might somehow contribute to prevention of psychotic symptoms in patients with AD. Further studies may increase our current understanding on the relationship between TDP-43 pathology and AD+P.
Poster Number: EI 25
Tau phosphorylation is exaggerated in Alzheimer disease with psychosis
Patrick S. Murray, PhD1,3; Caitlin M. Kirkwood, BS1,3; Milos D. Ikonomovic, MD2,4; Kenneth N. Fish, PhD1,3; Robert A. Sweet, MD1,3 1
University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA University of Pittsburgh School of Medicine, Department of Neurology, Pittsburgh, PA 3 VAPHS, Mental Illness Research, Education and Clinical Centers, Pittsburgh, PA 4 VAPHS, Geriatric Research, Education and Clinical Centers, Pittsburgh, PA 2
Introduction: The occurrence of psychotic symptoms in Alzheimer’s disease subjects (AD+P) represents a subgroup characterized by more severe impairment and more rapid decline in cognition compared to AD without psychosis (AD-P). AD+P aggregates within families with an estimated heritability of 61%, indicating a substantial genetic component. Since the strongest correlate of cognitive impairment in AD is synapse loss across cortical regions, we hypothesize that the genetic architecture of AD+P leads to exaggerated synaptic vulnerability. In dorsolateral prefrontal cortex (DLPFC) we previously found increased disruption of synapse integrity, lower kalirin expression, and greater Ab42/Ab40 ratio in AD+P cases. Methods: Since hyperphosphorylated tau may be a necessary mediator of Ab-induced synaptic toxicity, we evaluated DLPFC grey matter phospho-tau (pTau) in a well-matched cohort of 26 AD+P and 19 AD-P cases. We used AT8, an antibody for a triple phosphorylation site epitope (ser199/ser202/thr205) on pTau-associated dystrophic neurites, neuropil threads, and neurofibrillary tangles, and assessed both mean fluorescence intensity, indicative of relative pTau concentration (pTC), and pTau volume fraction (pTVV; fraction of total grey matter volume occupied by pTau) in the DLPFC.
S80
Am J Geriatr Psychiatry 21:3, Supplement 1
2013 AAGP Annual Meeting Results: Both of our measures were significantly correlated with Braak stage (pTC rs ¼ 0.491, p < 0.001; pTVV rs ¼ 0.758, p < 0.001). In AD+P, we found that pTC was greater (p ¼ 0.006) and that pTVV trended toward an increase (p ¼ 0.082). We then evaluated whether pTC and/or pTVV affected cognitive impairment by examining the most recent scores on the mini-mental status exam (MMSE), as an indication of global cognitive function, and on the digit span backwards test (DSB), as an indicator of cognitive function associated specifically with the DLPFC. Consistent with previous findings, AD+P cases scored lower on the mini-mental status exam (MMSE; p ¼ 0.026), despite similar durations of illness in the two groups. Lower scores on the MMSE were influenced by higher pTC (p ¼ 0.006), and pTVV (p ¼ 0.030); lower scores on the DSB were also influenced by pTC (p ¼ 0.013) and pTVV (p ¼ 0.008). Conclusions: These novel findings indicate that while higher pTC and pTVV are associated with worse cognitive impairment, pTC is specifically higher in AD+P. This suggests that phosphorylation of tau may be exaggerated in AD+P, which along with our previous findings, points to more severe pathological dynamics in AD+P.
Poster Number: EI 26
A study on reliability and validity of Montreal Cognitive Assessment in Eastern China: Preliminary findings Hu Jianbo, Master of Medicine; Jinwen Huang, Master of Medicine; Shaohua Hu, Doctor of Medicine; Manli Huang, Doctor of Medicine; Wei Ning, Doctor of Medicine; Weihua Zhou, Doctor of Medicine; Hongli Qi, Master of Medicine; Yi Xu, MD, Doctor of Medicine The first affiliated Hospital, medicine of college, Zhejiang university # Corresponding author: Yi XU, Hangzhou, China Introduction: Validation of Chinese version of Montreal Cognitive Assessment (MOCA) for the elderly population in Eastern China Methods: 72 patients with AD, 84 patients with mild cognitive impairment (MCI) and146 cases of the normal population sample of elderly from community in Hangzhou. Each sample were evaluated for the Montreal Cognitive Assessment Scale (MoCA-C), Mini-mental state examination (MMSE), Hasegawa Dementia Scale (HDS), Clinical Dementia Scale (CDR) and other neuropsychological tests .Through by The use of internal consistency, test-retest reliability, content validity, criterion validity, the principal component / factor analysis to evaluate the test results. Results: The mean age and education level for the total sample was 64.4 years and 9.4 years, respectively. No differences were found between groups in terms of education level, or gender, but on average patients with MCI (60.7 years) were significantly younger (p<0.001) than those with AD (68.4 years) or normal cognitive function (67.2 years). Gender was not related to MMSE or MoCA-C scores. The time required of MoCA and MMSE in the three groups were compared differences (tAD¼5.77, tMCI¼7.16, tNC¼14.71, P<0.01). MoCA’s internal consistency coefficient (Cronbach’s alpha) was 0.867. Testretest reliability ICC value was 0.912 (P<0.01). MoCA score and MMSE were highly correlated (r ¼ 0.912, P <0.01). Each item with total score correlation were 0.686-0.884. Factor analysis to extract two common factors that can explain the total variance of 71.882%, Factor 1 called executive function/attention factor, Factor 2 called memory factor. Conclusions: The Montreal Cognitive Assessment Scale of Chinese Version (MoCA) has good reliability and validity and feasibility in Hangzhou, it is a good cognitive screen scale especially for population of mainland China in community. Table 1. MoCA each sub-test with the correlation of total score (n¼302) sub- group score Visuospatial/Executive Functions(5) Naming(3) Attention(6) Language(3) Abstraction(2) Recall(5) Orientation(6) Moca Score(30)
Am J Geriatr Psychiatry 21:3, Supplement 1
4.381.23 2.760.55 5.510.95 2.630.68 1.370.68 2.831.46 4.851.02 24.335.17
correlation coefficient
P
0.884 0.806 0.840 0.686 0.703 0.811 0.688
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01
S81