Abstract Body

The defining neuropathological features of Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and hyperphosphorylated tau (tau) in the form of neurofibrillay tangles and neuropil threads while Lewy body diseases (LBD) are characterised by Lewy bodies and Lewy neurites composed of α-synuclein (α-syn) depositions. However, over 90% of clinical LBD cases show AD type pathology in addition to Lewy pathology and AD cases often show additional Lewy pathology.

True mixed dementia is diagnosed if the severity of both Lewy and AD pathology is so severe that each could be the neuropathological correlate of clinical dementia. Using quantitative measures on the burden of Aβ, tau and, α-syn in such mixed AD/LBD cases we found that both the amount and the topographical distribution of pathological protein aggregates differed between clinical AD and DLB phenotypes. In particular the distribution of tau in in clinical AD cases in such mixed AD/DLB cases was similar to the one observed in pure AD cases without Lewy pathology, while clinical DLB cases had comparatively less hippocampal tau.

Large scale clinico-pathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed AD/LBD pathology.

Abstract Body

Alzheimer’s disease (AD) is neuropathologically characterized by the presence of amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques consist of extracellular amyloid β-protein (Aβ) deposits. NFTs are intraneuronal aggregates of abnormal phosphorylated τ-protein. In addition, cerebral amyloid angiopathy (CAA), granulovacuolar degeneration (GVD) and cytoplasmic aggregates of TDP-43 are found in brains of AD patients. CAA can cause microbleeds, hemorrhages, infarcts and microinfarcts that can contribute to cognitive decline. GVD contains the active necrosome complex. Accordingly, it is tempting to speculate that GVD contributes to neuronal cell death in AD. Here, the density of neurons in GVD-affected regions inversely correlates with the percentage of neurons exhibiting necrosome-positive GVD. TDP-43 lesions are not seen in every AD case and show different types of distribution depending on the antibodies used for detection, suggesting that TDP-43 aggregates in AD show a spectrum from frontotemporal lobar degeneration (FTLD-TDP)-like features to age and AD-related aggregates that have been suggested to represent a limbic-associated age-related TDP-43 encephalopathy (LATE). The contribution of TDP-43 pathology and CAA may have significant impact on the clinical picture of patients and explain variabilities among patients with similar Aβ and τ biomarker status. End-of-life studies for amyloid and τ-PET have shown that τ-changes can be detected in symptomatic AD cases whereas preclinical stages of AD can be better picked up with amyloid biomarkers (amyloid PET). However, a large part of the preclinical AD cases that can be identified neuropathologically drop clinical attention today similar to TDP-43 pathology, CAA and GVD.

Abstract Body

Aims: Associated microvascular pathology has been described in many patients with dementing neurodegenerative disorders including Alzheimer’s disease, Lewy Body dementia, Primary progressive aphasia and frontotemporal dementia. In order to determine the contribution of microvascular pathology to age related cognitive changes we performed several series of autopsy studies.

Methods: Radiopathological and clinicopathological correlations in hospitalized elderly with an average age of 85 years.

Results: Cortical microinfarcts (CMI) were the vascular lesion most closely related to the presence of dementia in this population, representing up to 36% of the clinical variability in cognitive function.

In mixed cases, two relatively simple pathological hallmarks, neurofibrillary tangles (NFT) and CMI, were the most potent correlates of dementia; using a microscopic ischemic score for CMI and Braak NFT staging, we were able to account for 50% of the variability in dementia prevalence. CMI are particularly common in the elderly although many may remain undetected with standard brain autopsy procedures. Using a stereological approach were able to identify CMI in over half of the examined older brains.

Although some studies have been able to identify large CMI on 3 or 7 Tesla MRI, radiopathological correlations in our series indicate that the vast majority of CMI are smaller than 500 microns and cannot be seen on ante-mortem or post-mortem sequences.

Conclusion: Studies in older people with dementia should take into account the frequent occurrence of vascular pathology and its important contribution to cognitive changes in this population. CMI are rarely seen on neuroimaging but their hidden presence may affect therapeutic interventions in old age cognitive disorders.

Aims

It is of great importance to get a better understanding of the heterogeneity within Alzheimer’s disease (AD). Here, we want to give an update on where we stand today, present new findings and give some future directions.

Methods

We have recently performed a review and meta-analysis summarizing the findings to date [1]. Our conclusions based on where we stand today were: 1) We need a framework that will aid with hypothesis formation, study design, interpretation of results, and understanding mechanisms in future subtype studies 2) To separate distinct subtypes of disease from disease staging, longitudinal information needs to be incorporated in models. 3) There is a need to harmonize subtyping methods across studies to increase generalizability and to compare results reliably.

Results

Our framework looks at the heterogeneity in AD along the two axis, typicality and severity. Individual subjects are positioned within this two-dimensional space in relation to risk factors, protective factors, and concomitant non-AD brain pathologies. Longitudinal subtyping data are presented and results from studies comparing subtyping methods.

Conclusions

To get a better understanding of the complexity and heterogeneity in AD will result in more personalized medicine in the future and opportunities for successful drug trials so we can finally find treatment approaches for such a complex and multifaceted disease like AD.

1. Ferreira, D., A. Nordberg, and E. Westman, Biological subtypes of Alzheimer disease: A systematic review and meta-analysis. Neurology, 2020. 94(10): p. 436-448.

Aims

Alzheimer’s disease (AD) is characterized by cortical atrophy on MRI and abnormal depositions of amyloid-beta, p-tau and inflammation pathologically. However, the relative contribution of these pathological hallmarks to cortical atrophy, widely used as MRI biomarker in AD, is yet to be defined. The aim of this study is to determine the independent and combined contributions of the pathological hallmarks to cortical thickness in AD descents.

Methods

Twenty pathologically confirmed AD donors and ten age-matched controls underwent post-mortem in-situ 3T 3DT1 MRI, from which cortical thickness was calculated with Freesurfer. Upon subsequent autopsy, 12 cortical regions from the right and 9 from the left hemisphere were dissected and immunostained for amyloid-beta, p-tau, CD68 and C4b complement, and area %load was calculated. MRI-pathology associations were assessed with linear mixed models.

Results

A region-wide positive association between amyloid-beta load and cortical thickness was found in AD cases (r=0.17,p=0.012). In contrast, region-specific negative associations between p-tau and cortical thickness were found in frontal (r=-0.91,p<0.001), parietal (r=-0.71,p<0.001) and medial temporal regions (r=-0.89,p<0.001). CD68 load contributed to the correlation with cortical thickness in the parietal region even when controlling for p-tau (r=-0.55,p=0.048).

Conclusions

Our results show that amyloid-beta and p-tau burden contribute to cortical thickness differently: while amyloid-beta contributes to a cortical thickening diffusely, p-tau strongly contributes to cortical thinning in specific regions. Moreover, reactive microglia load contributes to cortical thinning in the inferior parietal gyrus, independently of the underlying pathology.

Aims

Post-mortem work has shown local accumulation of amyloid-beta, p-tau in the nucleus basali of Meynert (NbM), which leads to cholinergic deficiency in Alzheimer’s disease (AD). In MRI, NbM volume loss and microstructural alterations have been reported in AD. We aim to investigate the effect of neuropathological hallmarks in the NbM on MRI-measured NbM volume and structural connectivity in AD.

Methods

Twenty AD and eleven age- and gender-matched non-neurological control donors underwent post-mortem in-situ 3T MRI: T1-w for NbM delineation and DTI (fractional anisotropy, FA, and mean diffusivity, MD) for quantifying the integrity of the NbM and the projections. NbM sections of 20 μm were immunohistochemically stained for ChAT, amyloid-beta, and p-tau, and analyzed with ImageJ for their area %-load. Group comparisons were assessed using non-parametric tests and MRI-pathology associations with linear mixed models.

Results

AD cases showed lower NbM volume (p=0.003) and higher MD (p=0.003), as well as higher amyloid-beta (p=0.003) and p-tau (p=0.004) load than controls. In addition, AD cases showed higher MD in frontal (p=0.017) and temporal (p=0.039) projections.

For MRI-pathology associations in combined groups, NbM atrophy associated with less ChAT load (r=0.58,p=0.005), and lower FA associated with higher amyloid-beta load (r=0.47,p=0.032) in the NbM. MD of parietal and temporal projections associated with NbM ChAT load (r=0.44,p=0.013;r=0.3,p=0.007), and FA of temporal projections (r=0.26,p=0.029) with NbM p-tau load.

Conclusions

Our results indicate that cholinergic degeneration due to AD pathology is not restricted to the NbM, but further impacts its projections to the cortex, which can be captured by diffusion MRI.

Aims

Interrogation of Alzheimer’s disease (AD) in the neurosensory retina, a CNS organ easily accessible for noninvasive imaging, is undertaken to improve early AD detection and monitoring. Here, we sought to identify and characterize retinal vascular molecular and cellular parameters that appear to play a prominent role in early brain AD-related pathogenesis and further associate with cognitive decline.

Methods

We comprehensively evaluated microvascular degeneration, pericyte integrity, platelet-derived growth factor receptor-β (PDGFRβ) expression, vascular amyloidosis, and molecular pathways related to the blood-retinal barrier (BRB) in postmortem retinas from mild cognitively impaired (MCI) and AD patients compared with age- and sex-matched cognitively normal controls (n=62 subjects). Retinal cross-sections and isolated vascular network from predefined retinal regions were analyzed. Retinal vascular parameters were correlated with brain pathology.

Results

We revealed early, progressive and substantial decreases in vascular PDGFRβ expression and pericyte numbers in the retina of MCI and AD patients that were linked to retinal vascular Aβ₄₀ and Aβ₄₂ burden. Decreased vascular low-density lipoprotein receptor-related protein 1 (LRP1) and an early increase in pericyte apoptosis were also detected in MCI and AD retinas. Mapping of PDGFRβ and Aβ₄₀ levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, significant correlations were found between retinal vascular abnormalities and cerebral amyloid angiopathy and cognitive status.

Conclusions

The identification of early vascular PDGFRβ deficiency, pericyte loss, and tight-junction disruptions along with vascular amyloidosis in the AD retina implies a compromised BRB integrity and provides new targets for AD diagnosis and therapy.