title: Neuropathologically mixed Alzheimer's and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes.
abstract: Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Our study group consisted of 28 cases (mean age, 76.11 SE: ±1.29 years; m:f, 17:11) of which 19 were neuropathologically diagnosed as mixed AD/DLB. Clinically, 8 mixed AD/DLB cases were diagnosed as AD (cAD), 8 as DLB (cDLB) and 3 as PDD (cPDD). In addition, we investigated cases that were both clinically and neuropathologically diagnosed as either AD (pure AD; n = 5) or DLB/neocortical LBD (pure DLB; n = 4). Sections from neocortical, limbic and subcortical areas were stained with antibodies against HP-τ, Aβ and α-syn. The area covered by immunopositivity was measured using image analysis. cAD cases had higher HP-τ loads than both cDLB and cPDD and the distribution of HP-τ in cAD was similar to the one observed in pure AD whilst cDLB showed comparatively less hippocampal HP-τ load. cPDD cases showed lower HP-τ and Aβ loads and higher α-syn loads. Here, we show that in neuropathologically mixed AD/DLB cases both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Large-scale clinicopathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed pathology.
authors.affiliation: Institute of Neuroscience and Institute for Ageing, Newcastle University, Campus for Ageing and Vitality, NE4 5PL, Newcastle upon Tyne, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Walker
authors.forename: Kirsty E
authors.initials: KE
authors.lastname: McAleese
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Thomas
authors.forename: Mary
authors.initials: M
authors.lastname: Johnson
authors.forename: Carmen
authors.initials: C
authors.lastname: Martin-Ruiz
authors.forename: Craig
authors.initials: C
authors.lastname: Parker
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Colloby
authors.forename: Kurt
authors.initials: K
authors.lastname: Jellinger
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D015897:Comorbidity; D003704:Dementia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D066329:Protein Aggregates; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008869:Microtubule-Associated Proteins; D066329:Protein Aggregates; D051844:alpha-Synuclein; D016875:tau Proteins