Cognitive Profile and Markers of Alzheimer Disease–Type Pathology in Patients With Lewy Body Dementias

Abstract

ObjectiveTo determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)–type copathology are more impaired on confrontation naming than those without likely AD-type copathology.MethodsWe selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid1-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD − AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD − AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes.ResultsPatients with LBD + AD performed worse on BNT than patients with LBD − AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = −0.28, p < 0.05) and p-tau (ρ = −0.26, p = 0.05) but not Aβ42 (p > 0.1).ConclusionMarkers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

Parkinson’s Disease Dementia: Synergistic Effects of Alpha-Synuclein, Tau, Beta-Amyloid, and Iron

“…Although most evidence has indicated an α-syn pathology in the development of PDD, there is a notable heterogeneity in symptomatology and timing of dementia between PDD cases. An increasing number of studies have shown that LBs, AD-type pathology, and iron dysmetabolism appear to contribute to the emergence of PDD (Smith et al, 2019 ; Kouli et al, 2020 ; Howard et al, 2021 ). It is possible that α-syn is transmitted from degenerating neurons into neighboring neurons and non-neuronal cells; indeed, α-syn aggregates have been found in the SN, the nucleus basalis of Meynert, cerebral cortex, locus coeruleus, cranial nerve motor nuclei, and locus coeruleus (Braak et al, 2006 ; Brundin and Melki, 2017 ).…”

“…The combination of LBs and AD-type pathology is considered to have a strong pathological association with PDD (Irwin et al, 2013 ). Clinical studies have shown that PDD is associated with severe α-syn pathology in the hippocampus and entorhinal and occipitotemporal cortexes, and Aβ pathology and tau pathology in the striatum (Smith et al, 2019 ; Kouli et al, 2020 ; Howard et al, 2021 ). The combination of LBs, Aβ, and tau pathologies has a strong correlation with the pathology in patients with PDD (Compta et al, 2011 ).…”

Are Parkinson’s Disease Patients the Ideal Preclinical Population for Alzheimer’s Disease Therapeutics?

“…That is, PD patients with aSyn pathology found not only in the brainstem but also throughout the limbic system and cortex are more likely to have cognitive impairment than PD patients with less extensive aSyn pathology [ 46 ]. People with PD and concomitant AD have more severe motor dysfunction, a higher burden of depression, faster rate of cognitive progression, shorter interval from motor to cognitive symptom onset, impaired language performance, higher rate of nursing home admittance, and higher mortality risk, compared to PD patients without AD pathology [ 46 , 47 , 48 ]. Specifically, temporal lobe tau burden has been independently associated with antemortem deficits in confrontation naming [ 40 , 49 ].…”

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium

“…Evidence suggests that these Alzheimer markers likely reflect concomitant Alzheimer pathological process along with the Lewy body disease. Specifically, AD biomarkers in DLB (DLB-AD) are associated with increased age, female sex, increased APOE ε4 genotype, decreased memory, increased delusions and hallucinations, less REM-behavior sleep disorder and parkinsonism, worse language performance, faster progression, increased temporal thinning and tau pathology, and greater risk of institutionalization and mortality (2)(3)(4)(24)(25)(26)(27)(28). These findings are corroborated by post-mortem clinicopathologic studies showing that AD pathologic features (neuritic plaques and also tangles) in cases clinically defined as "probable DLB" are associated with an atypical "Alzheimerized" clinical presentation (e.g.…”