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

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

doi:10.1371/journal.pone.0217566

Abstract

BackgroundNeuropathology 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.MethodsSubjects 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.ResultsLinear 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).ConclusionsThe 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.

Highlights

Dementia due to AD (ADD) is frequently associated with comorbid pathologies that could affect clinical presentation, the rate of clinical progression, and response to investigational or approved treatments
If it resulted in an altered clinical disease progression rate and was not responsive to therapies directed at the “primary” pathology, it could have a significant impact on the response to such therapies
A number of autopsy-validated studies have indicated that cognitive decline is faster in elderly subjects dying with ADD, or any AD neuropathology, who have unspecified Lewy body disease (LBD) [3;34,35,36,37] but it is unclear whether or not these results may be driven primarily by DLB subjects with neuropathologically-severe LBD, as disease duration is reportedly shorter in this group [28;38]

Summary

Introduction

Dementia due to AD (ADD) is frequently associated with comorbid pathologies that could affect clinical presentation, the rate of clinical progression, and response to investigational or approved treatments. The presence of comorbid and heterogeneous neuropathology would be a moot point if it had little or no clinical effect, or if it were only secondarily generated by the primary pathology If it resulted in an altered clinical disease progression rate and was not responsive to therapies directed at the “primary” pathology, it could have a significant impact on the response to such therapies. 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. 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

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Results

Conclusion