Lewy body pathology in Alzheimer's disease: A clinicopathological prospective study

Savica, Rodolfo; Beach, Thomas G.; Hentz, Joseph G.; Sabbagh, Marwan N.; Serrano, Geidy E.; Sue, Lucia I.; Dugger, Brittany N.; Shill, Holly A.; Driver‐Dunckley, Erika; Caviness, John N.; Mehta, Shyamal H.; Jacobson, Sandra A.; Belden, Christine M.; Davis, Kathryn; Zamrini, Edward; Shprecher, David; Adler, Charles H.

doi:10.1111/ane.13028

Cited by 37 publications

(30 citation statements)

References 25 publications

(48 reference statements)

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“…Unfortunately, more sophisticated neuropsychological tests often cannot be performed in subjects with advanced dementia and so the sample size is much reduced. In a reduced subject set with full neuropsychological test battery results, we previously reported that AD-LB and ADD subjects differed only on depression and Trail-Making A scores [53].…”

Section: Discussionmentioning

confidence: 95%

“…These "AD-LB" cases are most often clinically silent [1] and diagnosed as probable ADD. We have previously reported that AD-LB subjects, as compared to ADD subjects without LBD, depression and Trail-Making Test A scores correlate significantly with LBD pathology but that other neuropsychological variables are not significantly different [53]. This study seeks to determine whether clinical disease progression differs in AD subjects with and without LBD.…”

Section: Introductionmentioning

confidence: 96%

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Faster Cognitive Decline in Dementia due to Alzheimer Disease with Clinically Undiagnosed Lewy Body Disease

Beach

Malek‐Ahmadi

Zamrini

et al. 2019

Preprint

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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. 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. 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. 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. 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 3 Faster Decline with Unsuspected Lewy Bodies (0.013). 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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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 96%

Faster Cognitive Decline in Dementia due to Alzheimer Disease with Clinically Undiagnosed Lewy Body Disease

Beach

Malek‐Ahmadi

Zamrini

et al. 2019

Preprint

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“…These "AD-LB" cases are most often clinically silent [24] and diagnosed as probable ADD. We have recently reported that even in these AD-LB subjects without neocortical disease, as compared to ADD subjects without any LBD, that depression and Trail-Making Test A scores correlate significantly with LBD pathology, and the global rate of cognitive decline is more rapid than in either AD-DLB or ADD without LBD [41,120], even after adjustment for AD pathology severity. These data suggest that accompanying LBD is a "state" biomarker of a more clinically severe form of AD.All the other ADD comorbidities increase in prevalence with age, suggesting that they are primarily agedependent, or at least co-dependent on both AD and age (Figure 1).…”

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confidence: 86%

Alzheimer’s Disease Neuropathological Comorbidities Are Common in the Younger-Old

Beach

Malek‐Ahmadi

2020

Preprint

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Clinicopathological studies have demonstrated that Alzheimer's disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the presence and rate of cognitive decline in aging and ADD. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown. We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer's Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer's Association (NIA-AA) intermediate or high AD Neuropathological Change (ADNC) levels, excluding those with known autosomal dominant AD-related mutations. Subjects were divided into age-atdeath categories for analysis: under 60, 60-69, 70-79, 80-89, 90-99 and 100 or over. Confirmatory of earlier reports, ADD histopathology is less severe with advancing age, effectively increasing the relative contribution of comorbidities, most of which rise in prevalence with age. Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where "pure" ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20% in the 70s and beyond. Comorbidity rates for some pathologies, especially LBD, are high even in subjects in their 60s and 70s, at nearly 60%, but for most others, their prevalence increases with age. TDP-43 pathology affects more than 35% of ADD subjects 80 and over while microscopic infarcts reach this rate a decade later. Gross infarcts rise more slowly and affect fewer subjects but still involve 15-20% of ADD after age 80. White matter rarefaction may be underestimated in the NACC database but is present in almost 70% of centenarians with ADD. Effective clinical trials depend on accurate estimates of required subject numbers, which are dependent on observed effect size and clinical response variability. Comorbidities are likely to affect both, leading to lower probability of clinical trial success. Stratifying ADD clinical trial analyses by presence and types of accompanying comorbidities might identify subgroups with higher effect sizes and greater clinical response rates, but accurate in-vivo diagnostic methods for most comorbidities are still lacking. Neuropathological studies are increasingly demonstrating that Alzheimer's disease dementia (ADD) is most often not the sole brain pathology in those that die and are autopsied, but is very likely to be accompanied by comorbid neurodegenerative and cerebrovascular disease. Comorbidities are likely to alter the presence and rate of ...

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“…Mixed pathologies are not infrequent in senile cases [15] , especially AD mixed with various types of vascular lesions [16] , or DLB with concomitant AD pathology [17] . Such mixed pathologies may modify the clinical presentation [18,19] and the rate of disease progression [20] . In addition, some patients present very early, in a symptomatic but pre-dementia stage [mild cognitive impairment (MCI) and MCI due to AD] [21] .…”

Section: Why Do We Need Biomarkers?mentioning

confidence: 99%

Cerebrospinal fluid biomarkers for cognitive disorders. An introductory overview

Paraskevas¹

2020

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The core (established) cerebrospinal fluid biomarkers of Alzheimer's disease (AD), namely amyloid-beta peptide, total tau protein and phospho-tau protein, have become a part of the diagnostic workup of patients with cognitive disorders in many specialized centers, especially for ambiguous cases. Combined, these biomarkers can identify the presence or absence of an AD biochemical process with sensitivities and specificities approaching or exceeding 90% in both dementia and pre-dementia stages of AD. Thus, they have been incorporated in various sets of research or clinical diagnostic criteria and recommendations. Results that are atypical, incompatible with AD, or inconclusive may occur, necessitating the use of other cerebrospinal fluid or imaging biomarkers.

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Lewy body pathology in Alzheimer's disease: A clinicopathological prospective study

Abstract: Our study suggests that the presence (or absence) of LTS influences motor and non-motor clinical findings in AD patients. These findings may lead to biomarkers that allow for more targeted treatment of AD.

Cited by 37 publications

References 25 publications

Faster Cognitive Decline in Dementia due to Alzheimer Disease with Clinically Undiagnosed Lewy Body Disease

Faster Cognitive Decline in Dementia due to Alzheimer Disease with Clinically Undiagnosed Lewy Body Disease

Alzheimer’s Disease Neuropathological Comorbidities Are Common in the Younger-Old

Cerebrospinal fluid biomarkers for cognitive disorders. An introductory overview

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