Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias

Abstract

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein-positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.

Amyloid-β deposition and regional grey matter atrophy rates in dementia with Lewy bodies

“…Furthermore, since PiB imaging does not distinguish between amyloid-b deposition of diffuse more than neuritic plaques (Kantarci et al, 2012c), it is also not known whether this distinction may make a difference in the effects of amyloid protein aggregation in DLB, and may contribute to some of this variability. Overall our findings are in agreement with the hypothesis that patients with probable DLB with concomitant underlying Alzheimer's disease pathology could show a more aggressive clinical phenotype of the disease with increased atrophy rates and functional decline (Nelson et al, 2009;Clinton et al, 2010;Gomperts et al, 2012;De Beer et al, 2015;Ferman et al, 2015;Graff-Radford et al, 2015;Howlett et al, 2015).…”

“…In the Lewy bodies disease spectrum of disorders, autopsy studies highlighted that co-occurrence of amyloid-b plaques and phosphorylated tau together with -synuclein deposition are associated with greater cognitive decline (Kraybill et al, 2005;Nelson et al, 2009;Ferman et al, 2015;Howlett et al, 2015), and shorter survival (Kotzbauer et al, 2012;Graff-Radford et al, 2015) .…”

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

“…Not all patients had tissues available for all brain regions and analyses. Assessment and diagnostic criteria have been previously described [6].…”

“…As in AD, cholinesterase inhibitors provide symptomatic benefits, but efforts to develop disease modifying therapies are at a much earlier stage. Previous pathological studies have suggested that the burden of synuclein pathology is associated with cognitive decline, and that concurrent AD pathology may also contribute [6]. However, this only explains a minority of the variance, and a better understanding of disease substrates is needed for targeted drug discovery and to enable better monitoring of disease progression.…”

“…Less is known regarding the role of synaptic dysfunction in PDD and DLB [6,13,14], but synaptic alterations have been demonstrated in Parkinson`s disease [15] and preliminary studies have indicated early synaptic changes in DLB/PDD. Consistent with our hypothesis that synaptic dysfunction may be particularly important in DLB/PDD, structural imaging studies indicate that brain atrophy is less pronounced in DLB and PDD compared to AD [16] despite the more severe disease course [17,18].…”