Faster cognitive decline in dementia due to Alzheimer disease with clinically undiagnosed Lewy body disease

Michael Malek-Ahmadi, Thomas G. Beach, Edward Zamrini, Charles H. Adler, Marwan N. Sabbagh, Holly A. Shill, Sandra A. Jacobson, Christine M. Belden, Richard J. Caselli, Brian K. Woodruff, Steven Z. Rapscak, Geoffrey L. Ahern, Jiong Shi, John N. Caviness, Erika Driver-Dunckley, Shyamal H. Mehta, David R. Shprecher, Bryan M. Spann, Pierre Tariot, Kathryn J. DavisKathy E. Long, Lisa R. Nicholson, Anthony Intorcia, Michael J. Glass, Jessica E. Walker, Michael Callan, Jasmine Curry, Brett Cutler, Javon Oliver, Richard Arce, Douglas G. Walker, Lih Fen Lue, Geidy E. Serrano, Lucia I. Sue, Kewei Chen, Eric M. Reiman

Research output: Contribution to journalArticle

Abstract

Background Neuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimer’s disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimer’s disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course. Methods Subjects with dementia included those with “pure” ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination. Results Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group (β = -0.69, 95% CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not (β = -0.30, 95% CI: -0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66% and 2.1%, respectively, had been diagnosed with LBD at any point during their clinical course. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013). Conclusions The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success.

Original languageEnglish (US)
Article numbere0217566
JournalPloS one
Volume14
Issue number6
DOIs
StatePublished - Jan 1 2019

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Lewy Body Disease
dementia
Alzheimer disease
Lewy Bodies
Dementia
Alzheimer Disease
Cognitive Dysfunction
Lewy bodies
Hallucinations
disease course
Parkinsonian Disorders
Comorbidity
Linear Models
neuropathology
Clinical Trials
Pathology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Malek-Ahmadi, M., Beach, T. G., Zamrini, E., Adler, C. H., Sabbagh, M. N., Shill, H. A., ... Reiman, E. M. (2019). Faster cognitive decline in dementia due to Alzheimer disease with clinically undiagnosed Lewy body disease. PloS one, 14(6), [e0217566]. https://doi.org/10.1371/journal.pone.0217566

Faster cognitive decline in dementia due to Alzheimer disease with clinically undiagnosed Lewy body disease. / Malek-Ahmadi, Michael; Beach, Thomas G.; Zamrini, Edward; Adler, Charles H.; Sabbagh, Marwan N.; Shill, Holly A.; Jacobson, Sandra A.; Belden, Christine M.; Caselli, Richard J.; Woodruff, Brian K.; Rapscak, Steven Z.; Ahern, Geoffrey L.; Shi, Jiong; Caviness, John N.; Driver-Dunckley, Erika; Mehta, Shyamal H.; Shprecher, David R.; Spann, Bryan M.; Tariot, Pierre; Davis, Kathryn J.; Long, Kathy E.; Nicholson, Lisa R.; Intorcia, Anthony; Glass, Michael J.; Walker, Jessica E.; Callan, Michael; Curry, Jasmine; Cutler, Brett; Oliver, Javon; Arce, Richard; Walker, Douglas G.; Lue, Lih Fen; Serrano, Geidy E.; Sue, Lucia I.; Chen, Kewei; Reiman, Eric M.

In: PloS one, Vol. 14, No. 6, e0217566, 01.01.2019.

Research output: Contribution to journalArticle

Malek-Ahmadi, M, Beach, TG, Zamrini, E, Adler, CH, Sabbagh, MN, Shill, HA, Jacobson, SA, Belden, CM, Caselli, RJ, Woodruff, BK, Rapscak, SZ, Ahern, GL, Shi, J, Caviness, JN, Driver-Dunckley, E, Mehta, SH, Shprecher, DR, Spann, BM, Tariot, P, Davis, KJ, Long, KE, Nicholson, LR, Intorcia, A, Glass, MJ, Walker, JE, Callan, M, Curry, J, Cutler, B, Oliver, J, Arce, R, Walker, DG, Lue, LF, Serrano, GE, Sue, LI, Chen, K & Reiman, EM 2019, 'Faster cognitive decline in dementia due to Alzheimer disease with clinically undiagnosed Lewy body disease', PloS one, vol. 14, no. 6, e0217566. https://doi.org/10.1371/journal.pone.0217566
Malek-Ahmadi, Michael ; Beach, Thomas G. ; Zamrini, Edward ; Adler, Charles H. ; Sabbagh, Marwan N. ; Shill, Holly A. ; Jacobson, Sandra A. ; Belden, Christine M. ; Caselli, Richard J. ; Woodruff, Brian K. ; Rapscak, Steven Z. ; Ahern, Geoffrey L. ; Shi, Jiong ; Caviness, John N. ; Driver-Dunckley, Erika ; Mehta, Shyamal H. ; Shprecher, David R. ; Spann, Bryan M. ; Tariot, Pierre ; Davis, Kathryn J. ; Long, Kathy E. ; Nicholson, Lisa R. ; Intorcia, Anthony ; Glass, Michael J. ; Walker, Jessica E. ; Callan, Michael ; Curry, Jasmine ; Cutler, Brett ; Oliver, Javon ; Arce, Richard ; Walker, Douglas G. ; Lue, Lih Fen ; Serrano, Geidy E. ; Sue, Lucia I. ; Chen, Kewei ; Reiman, Eric M. / Faster cognitive decline in dementia due to Alzheimer disease with clinically undiagnosed Lewy body disease. In: PloS one. 2019 ; Vol. 14, No. 6.
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abstract = "Background Neuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimer’s disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimer’s disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course. Methods Subjects with dementia included those with “pure” ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination. Results Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group (β = -0.69, 95{\%} CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not (β = -0.30, 95{\%} CI: -0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66{\%} and 2.1{\%}, respectively, had been diagnosed with LBD at any point during their clinical course. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013). Conclusions The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success.",
author = "Michael Malek-Ahmadi and Beach, {Thomas G.} and Edward Zamrini and Adler, {Charles H.} and Sabbagh, {Marwan N.} and Shill, {Holly A.} and Jacobson, {Sandra A.} and Belden, {Christine M.} and Caselli, {Richard J.} and Woodruff, {Brian K.} and Rapscak, {Steven Z.} and Ahern, {Geoffrey L.} and Jiong Shi and Caviness, {John N.} and Erika Driver-Dunckley and Mehta, {Shyamal H.} and Shprecher, {David R.} and Spann, {Bryan M.} and Pierre Tariot and Davis, {Kathryn J.} and Long, {Kathy E.} and Nicholson, {Lisa R.} and Anthony Intorcia and Glass, {Michael J.} and Walker, {Jessica E.} and Michael Callan and Jasmine Curry and Brett Cutler and Javon Oliver and Richard Arce and Walker, {Douglas G.} and Lue, {Lih Fen} and Serrano, {Geidy E.} and Sue, {Lucia I.} and Kewei Chen and Reiman, {Eric M.}",
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T1 - Faster cognitive decline in dementia due to Alzheimer disease with clinically undiagnosed Lewy body disease

AU - Malek-Ahmadi, Michael

AU - Beach, Thomas G.

AU - Zamrini, Edward

AU - Adler, Charles H.

AU - Sabbagh, Marwan N.

AU - Shill, Holly A.

AU - Jacobson, Sandra A.

AU - Belden, Christine M.

AU - Caselli, Richard J.

AU - Woodruff, Brian K.

AU - Rapscak, Steven Z.

AU - Ahern, Geoffrey L.

AU - Shi, Jiong

AU - Caviness, John N.

AU - Driver-Dunckley, Erika

AU - Mehta, Shyamal H.

AU - Shprecher, David R.

AU - Spann, Bryan M.

AU - Tariot, Pierre

AU - Davis, Kathryn J.

AU - Long, Kathy E.

AU - Nicholson, Lisa R.

AU - Intorcia, Anthony

AU - Glass, Michael J.

AU - Walker, Jessica E.

AU - Callan, Michael

AU - Curry, Jasmine

AU - Cutler, Brett

AU - Oliver, Javon

AU - Arce, Richard

AU - Walker, Douglas G.

AU - Lue, Lih Fen

AU - Serrano, Geidy E.

AU - Sue, Lucia I.

AU - Chen, Kewei

AU - Reiman, Eric M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background Neuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimer’s disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimer’s disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course. Methods Subjects with dementia included those with “pure” ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination. Results Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group (β = -0.69, 95% CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not (β = -0.30, 95% CI: -0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66% and 2.1%, respectively, had been diagnosed with LBD at any point during their clinical course. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013). Conclusions The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success.

AB - Background Neuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimer’s disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimer’s disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course. Methods Subjects with dementia included those with “pure” ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination. Results Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group (β = -0.69, 95% CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not (β = -0.30, 95% CI: -0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66% and 2.1%, respectively, had been diagnosed with LBD at any point during their clinical course. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013). Conclusions The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success.

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