Clinical, neuropathological, and molecular characteristics of rapidly progressive dementia with Lewy bodies: a distinct clinicopathological entity?

Abstract

Background: The term rapidly progressive dementia (RPD) with Lewy bodies (rpDLB) is used for DLB patients who develop a rapidly progressive neurological syndrome and have reduced survival. Here, we characterise the clinical, neuropathological, and molecular characteristics of a large rpDLB neuropathological series.

Methods: We included all RPD patients with a disease duration < 4 years submitted to our prion disease referral centre between 2003 and 2022 who showed Lewy body pathology (LBP) in limbic or neocortical stages as primary neuropathological diagnosis, had no systemic condition justifying the rapid deterioration and were previously neurologically unimpaired. Clinical features were retrieved and compared with Creutzfeldt-Jakob disease (CJD) and rapidly progressive Alzheimer's disease (rpAD) cohorts. Neuropathological and genetic (whole exome sequencing, APOE genotyping, and C9orf72 repeat expansion analysis) characteristics of rpDLB patients were systematically investigated. We scored semi-quantitatively the LBP load and performed a α-synuclein (αSyn) RT-QuIC seeding amplification assay (SAA) on cerebrospinal fluid (CSF) and tenfold serially diluted brain homogenates from different brain areas in rpDLB patients and typical long-lasting Lewy body disease (LBD) with dementia patients as control group.

Results: RpDLB patients were older (p = 0.047) and presented more cognitive fluctuations (p = 0.005), visual hallucinations (p = 0.020), neuropsychiatric symptoms (p = 0.006) and seizures (p = 0.032), and fewer cerebellar (p < 0.001) and visual (p = 0.004) signs than CJD ones. Delirium onset was more common than in both CJD (p < 0.001) and rpAD (p = 0.008). Atypical LBD signs (pyramidal, myoclonus, akinetic mutism) were common. All tested patients were positive by CSF αSyn SAA. Concomitant pathologies were common, with only four cases showing relatively "pure" LBP. LBP load and αSyn seeding activity measured through αSyn RT-QuIC SAA were not significantly different between rpDLB patients and typical LBD. We found a likely pathogenic variant in GBA in one patient.

Conclusions: Our results indicate that: 1) rpDLB exhibits a distinct clinical signature (2) CSF αSyn SAA is a reliable diagnostic test; 3) rpDLB is a heterogeneous neuropathological entity that can be underlain by both widespread pure LBP, or multiple copathologies 4) rpDLB is likely not sustained by distinct αSyn conformational strains; 5) genetic defects may, at least occasionally, contribute to the poor prognosis in these patients.

Keywords: Alpha-synuclein; Alzheimer’s disease; Delirium; GBA; Lewy body disease; Parkinson’s disease; Prion disease; RT-QuIC; Rapidly progressive dementia; Seeding amplification assay.

Fig. 1

Main histopathological features of rpDLB cases. LPB showed typical morphology, with varying amounts of αSyn-immunoreactive LBs and LNs (a-d). Brainstem-type LBs and LNs in the medulla oblongata (a), substantia nigra (bi-bii), and basal forebrain (c) and cortical-type LBs and LNs in the amygdala (d) of case #22. High magnification image of an LB (c): αSyn immunoreactivity is prominent in the halo and peripheral portion of the core of brainstem-type LBs [1]. P-tau immunoreactive neuritic plaques in the frontal cortex of patient #21 (e), who presented high-grade AD neuropathological changes. Type 1 CAA copathology in the occipital cortex of patient #7 (f). Immunohistochemistry for αSyn (LB509) (a-d), p-tau (AT8) (e), and Aβ (4G8) (f). Abbreviations: αSyn, α-synuclein; AD, Alzheimer’s disease; CAA, cerebral amyloid angiopathy; LBP, Lewy body pathology; LN, Lewy neurites; p-tau, phosphorylated tau; Aβ, amyloid-beta

Fig. 2

LB score in different brain areas and correlation with NP score. (a) Mean LB score of rpDLB patients and controls in different brain areas. Error bars represent standard deviation. (b) Correlation plot of the LB score and NP score (r=-0.42, p = 0.046). Linear regression line and relative confidence interval were applied to the plot. Abbreviations: AMG, amygdala; CIN, cingulate gyrus; CTRL, controls; EC, entorhinal cortex; FC, frontal cortex; HYP, hypothalamus; HIPP, hippocampus; LB, Lewy-body; MED, medulla oblongata; NP, neuropathology; PO, pons; SN, substantia nigra; TC, temporal cortex

Fig. 3

Quantification of αSyn seeding activity in brain homogenates. Mean SD₅₀ score of rpDLB patients and controls in different brain areas. Error bars represent standard deviation. Abbreviations: AMG, amygdala; CTRL, controls; FC, frontal cortex; MED, medulla oblongata; SD, seeding dose; SN, substantia nigra