Cerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer’s disease (AD) pathology, i.e. hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) deposition. WML seen in AD have a posterior predominance compared to non-demented individuals but it is unclear whether the pathological and molecular signatures of WML differ between these two groups. We investigated differences in the composition and aetiology of parietal WML from AD and non-demented controls. Parietal WML tissue from 55 human post-mortem brains (AD, n = 27; non-demented controls, n = 28) were quantitatively assessed for axonal loss and demyelination, as well as for cortical HPτ and Aβ burden and SVD. Biochemical assessment included Wallerian degeneration protease calpain and the myelin-associated glycoprotein (MAG) to proteolipid protein (PLP) ratio (MAG:PLP) as a measure of hypoperfusion. WML severity was associated with both axonal loss and demyelination in AD, but only with demyelination in controls. Calpain was significantly increased in WML tissue in AD, whereas MAG:PLP was significantly reduced in controls. Calpain levels were associated with increasing amounts of cortical AD-pathology but not SVD. We conclude that parietal WML seen in AD differ in their pathological composition and aetiology compared to WML seen in aged controls: WML seen in AD may be associated with Wallerian degeneration that is triggered by cortical AD-pathology, whereas WML in aged controls are due to ischaemia. Hence, parietal WML as seen on MRI should not invariably be interpreted as a surrogate biomarker for SVD as they may be indicative of cortical AD-pathology, and therefore, AD should also be considered as the main underlying cause for cognitive impairment in cases with parietal WML.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1738-2) contains supplementary material, which is available to authorized users.
Intracellular inclusions consisting of TAR DNA binding protein-43 (TDP-43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP-43 in AD staging scheme. This scheme has not been applied to the assessment of TDP-43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP-43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls. One hundred and nineteen human post-mortem brains were included, neuropathologically diagnosed as AD: 46, DLB: 15, Mx AD/DLB: 19 and aged controls: 39. Paraffin sections inclusive of the amygdala, hippocampus, striatum and neocortex were immunohistochemically stained with antibodies against phosphorylated TDP-43 and staged according to the TDP-43 in AD staging scheme. TDP-43 pathology was present in all groups: AD: 73.9%, DLB: 33.3%, Mx AD/DLB: 52.6% and controls: 17.9%. Prevalence of TDP-43 pathology was significantly higher in AD and Mx AD/DLB compared to controls. In controls, higher age at death was associated with prevalence of TDP-43 pathology and higher TDP-43 in AD stage, suggesting that this type of TDP-43 pathology may partly be an age-associated phenomenon. Significantly higher prevalence of TDP-43 pathology in the AD group indicates that AD pathology possibly triggers and aggravates TDP-43 pathology. The validity of the TDP-43 in AD staging scheme is not limited to AD and should be applied to assess TDP-43 pathology in post mortem brains of aged individuals to further elucidate the role of TDP-43 pathology in age associated neurodegeneration.
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.
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