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Introduction: Imaging studies indicated basal forebrain reduction in primary progressive aphasia (PPA), which might be a candidate marker for cholinergic treatment. Nucleus basalis of Meynert (nbM) neuronal loss has been reported, but a systematic quantitative neuropathological assessment including the three clinical PPA variants is lacking., Methods: Quantitative assessment of neuronal density and pathology was performed on nbM tissue of 47 cases: 15 PPA, constituting the different clinicopathological phenotypes, 14 Alzheimer's disease (AD), and 18 cognitively normals., Results: Group-wise, reduced nbM neuronal density was restricted to AD. At the individual level, semantic variant PPA with underlying AD neuropathological change (ADNC) had lower neuronal densities, while those with frontotemporal lobar degeneration (FTLD) transactive response DNA binding protein 43 kDa (TDP-43) type C pathology were unaffected. Higher Braak stages and increased numbers of nbM-related pretangles were associated with nbM neuronal loss., Discussion: nbM neuronal loss in PPA is related to ADNC. This study cautions against overinterpreting MRI-based basal forebrain volumes in non-AD PPA as neuronal loss., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The tau protein (τ) is one of the two hallmark proteins of Alzheimer's disease (AD) together with the amyloid β protein (Aβ). In contrast to Aβ, abnormally phosphorylated τ (p-τ) can also be found in non-AD tauopathies. In AD, p-τ is the main component of intraneuronal neurofibrillary tangles, which result from aggregation of abnormally phosphorylated and folded τ. In this review, we discuss the role of p-τ pathology in Alzheimer's disease considering neuropathological, biochemical, cellular, animal model, and clinical findings. We discuss the relationship between p-τ and other AD-related proteins such as Aβ and transactive response DNA-binding protein 43 (TDP-43). In light of the current state of knowledge, we conclude that p-τ aggregation known as primary age-related tauopathy (PART) may represent a prerequisite for the development of AD rather that a downstream effect of Aβ toxicity. However, Aβ as well as TDP-43 pathology appear to accelerate accumulation and propagation of p-τ pathology once initiated, ultimately leading to the full-blown picture of AD. In this context, τ seeds can induce granulovacuolar degeneration (GVD), AD-typical lesions in which the activated necrosome - required for the execution of necroptosis, a programmed form of cell death - can be found. Moreover, necrosome-exhibiting GVD is associated with a decreased neuronal density. Thus, we speculate that p-τ pathology is a major driver for neuron loss in AD via GVD-mediated necroptosis. Overall, p-τ seems to play a central role in AD as it appears to constitute a prerequisite for AD development which can then be accelerated by co-factors. This would fit in a probabilistic model of AD, in which the presence and severity of the respective co-factors such as Aβ, TDP-43, and others contribute separately to AD pathogenesis as probabilistic factors with a certain weight., Competing Interests: Conflicts of interest DRT received speaker honorary from Novartis Pharma AG (Switzerland) and Biogen (USA), travel reimbursement from GE-Healthcare (UK) and UCB (Belgium) and collaborated with Novartis Pharma AG (Switzerland), Probiodrug (Germany), GE-Healthcare (UK), and Janssen Pharmaceutical Companies (Belgium)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: End-of-life studies have validated the binary visual reads of 18 F-labeled amyloid PET tracers as an accurate tool for the presence or absence of increased neuritic amyloid plaque density. In this study, the performance of a support vector machine (SVM)-based classifier will be tested against pathological ground truths and its performance determined in cognitively healthy older adults., Methods: We applied SVM with a linear kernel to an 18 F-Flutemetamol end-of-life dataset to determine the regions with the highest feature weights in a data-driven manner and to compare between two different pathological ground truths: based on neuritic amyloid plaque density or on amyloid phases, respectively. We also trained and tested classifiers based on the 10% voxels with the highest amplitudes of feature weights for each of the two neuropathological ground truths. Next, we tested the classifiers' diagnostic performance in the asymptomatic Alzheimer's disease (AD) phase, a phase of interest for future drug development, in an independent dataset of cognitively intact older adults, the Flemish Prevent AD Cohort-KU Leuven (F-PACK). A regression analysis was conducted between the Centiloid (CL) value in a composite volume of interest (VOI), as index for amyloid load, and the distance to the hyperplane for each of the two classifiers, based on the two pathological ground truths. A receiver operating characteristic analysis was also performed to determine the CL threshold that optimally discriminates between neuritic amyloid plaque positivity versus negativity, or amyloid phase positivity versus negativity, within F-PACK., Results: The classifiers yielded adequate specificity and sensitivity within the end-of-life dataset (neuritic amyloid plaque density classifier: specificity of 90.2% and sensitivity of 83.7%; amyloid phase classifier: specificity of 98.4% and sensitivity of 84.0%). The regions with the highest feature weights corresponded to precuneus, caudate, anteromedial prefrontal, and also posterior inferior temporal and inferior parietal cortex. In the cognitively normal cohort, the correlation coefficient between CL and distance to the hyperplane was -0.66 for the classifier trained with neuritic amyloid plaque density, and -0.88 for the classifier trained with amyloid phases. This difference was significant. The optimal CL cut-off for discriminating positive versus negative scans was CL = 48-51 for the different classifiers (area under the curve (AUC) = 99.9%), except for the classifier trained with amyloid phases and based on the 10% voxels with highest feature weights. There the cut-off was CL = 26 (AUC = 99.5%), which closely matched the CL threshold for discriminating phases 0-2 from 3-5 based on the end-of-life dataset and the neuropathological ground truth., Discussion: Among a set of neuropathologically validated classifiers trained with end-of-life cases, transfer to a cognitively normal population works best for a classifier trained with amyloid phases and using only voxels with the highest amplitudes of feature weights., (© 2022. The Author(s).)

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in App NL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes., Competing Interests: Declaration of interests B.D.S. is the Bax-Vanluffelen Chair for Alzheimer’s Disease and is supported by the Opening the Future campaign and Mission Lucidity of KU-Leuven. D.R.T. received speaker honorarium from Biogen (USA), and collaborated with GE-Healthcare (UK), Novartis Pharma Basel (Switzerland), Probiodrug (Germany), and Janssen Pharmaceutical Companies (Belgium)., (Copyright © 2022. Published by Elsevier Inc.)

Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly. Using structure-based thermodynamic calculations and extensive experimental validation, we performed a comprehensive exploration of the defining role of sequence promiscuity in amyloid interactions. Using tau as a model system we demonstrate that proteins with local sequence homology to tau amyloid nucleating regions can modify fibril nucleation, morphology, assembly and spreading of aggregates in cultured cells. Depending on the type of mutation such interactions inhibit or promote aggregation in a manner that can be predicted from structure. We find that these heterotypic amyloid interactions can result in the subcellular mis-localisation of these proteins. Moreover, equilibrium studies indicate that the critical concentration of aggregation is altered by heterotypic interactions. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and we discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression., (© 2022. The Author(s).)

The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD., (© 2021. Springer Nature Limited.)

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected., Competing Interests: Declaration of interests T.D.H., A.N., L.P., and J.W.R. are employees and stockholders at NanoString Technologies, Inc., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α 1 -antitrypsin (α 1 AT), a highly abundant circulating serine protease inhibitor. Here, we report that α 1 AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α 1 AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α 1 AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α 1 AT-containing drugs has prospects for the therapy of COVID-19.

An amendment to this paper has been published and can be accessed via the original article.

The deposition of the amyloid β-protein (Aβ) in senile plaques is one of the histopathological hallmarks of Alzheimer's disease (AD). Aβ-plaques arise first in neocortical areas and, then, expand into further brain regions in a process described by 5 phases. Since it is possible to identify amyloid pathology with radioactive-labeled tracers by positron emission tomography (PET) the question arises whether it is possible to distinguish the neuropathological Aβ-phases with amyloid PET imaging. To address this question we reassessed 97 cases of the end-of-life study cohort of the phase 3 [ 18 F]flutemetamol trial (ClinicalTrials.gov identifiers NCT01165554, and NCT02090855) by combining the standardized uptake value ratios (SUVRs) with pons as reference region for cortical and caudate nucleus-related [ 18 F]flutemetamol-retention. We tested them for their prediction of the neuropathological pattern found at autopsy. By defining threshold levels for cortical and caudate nucleus SUVRs we could distinguish different levels of [ 18 F]flutemetamol uptake termed PET-Aβ phase estimates. When comparing these PET-Aβ phase estimates with the neuropathological Aβ-phases we found that PET-Aβ phase estimate 0 corresponded with Aβ-phases 0-2, 1 with Aβ-phase 3, 2 with Aβ-phase 4, and 3 with Aβ-phase 5. Classification using the PET-Aβ phase estimates predicted the correct Aβ-phase in 72.16% of the cases studied here. Bootstrap analysis was used to confirm the robustness of the estimates around this association. When allowing a range of ± 1 phase for a given Aβ-phase correct classification was given in 96.91% of the cases. In doing so, we provide a novel method to convert SUVR-levels into PET-Aβ phase estimates that can be easily translated into neuropathological phases of Aβ-deposition. This method allows direct conclusions about the pathological distribution of amyloid plaques (Aβ-phases) in vivo. Accordingly, this method may be ideally suited to detect early preclinical AD-patients, to follow them with disease progression, and to provide a more precise prognosis for them based on the knowledge about the underlying pathological phase of the disease.

Neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTD), Lewy body disease (LBD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have in common that protein aggregates represent pathological hallmark lesions. Amyloid β-protein, τ-protein, α-synuclein, and TDP-43 are the most frequently aggregated proteins in these disorders. Although they are assumed to form disease-characteristic aggregates, such as amyloid plaques and neurofibrillary tangles in AD or Lewy bodies in LBD/PD, they are not restricted to these clinical presentations. They also occur in non-diseased individuals and can co-exist in the same brain without or with a clinical picture of a distinct dementing or movement disorder. In this review, we discuss the co-existence of these pathologies and potential additive effects in the human brain as well as related functional findings on cross-seeding and molecular interactions between these aggregates/proteins. We conclude that there is evidence for interactions at the molecular level as well as for additive effects on brain damage by multiple pathologies occurring in different functionally important neurons. Based upon this information, we hypothesize a cascade of events that may explain general mechanisms in the development of neurodegenerative disorders: (1) distinct lesions are a prerequisite for the development of a distinct disease (e.g., primary age-related tauopathy for AD), (2) disease-specific pathogenic events further trigger the development of a specific disease (e.g., Aβ aggregation in AD that exaggerate further Aβ and AD-related τ pathology), (3) the symptomatic disease manifests, and (4) neurodegenerative co-pathologies may be either purely coincidental or (more likely) have influence on the disease development and/or its clinical presentation.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

The diagnosis of vascular dementia (VaD) describes a group of various vessel disorders with different types of vascular lesions that finally contribute to the development of dementia. Most common forms of VaD in the elderly brain are subcortical vascular encephalopathy, strategic infarct dementia, and the multi infarct encephalopathy. Hereditary forms of VaD are rare. Most common is the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Sporadic forms of VaD are caused by degenerative vessel disorders such as atherosclerosis, small vessel disease (SVD) including small vessel arteriosclerosis, arteriolosclerosis, and lipohyalinosis, and cerebral amyloid angiopathy (CAA). Less frequently inflammatory vessel disorders and tumor-associated vessel lesions (e.g. angiocentric T-cell or angiotropic large cell lymphoma) can cause symptoms of dementia. Here, we review and discuss the impact of vessel disorders to distinct vascular brain tissue lesions and to the development of dementia in elderly individuals. The impact of coexisting neurodegenerative pathology in the elderly brain to VaD as well as the correlation between SVD and CAA expansion in the brain parenchyma with that of Alzheimer's disease (AD)-related pathology is highlighted. We conclude that "pure" VaD is rare and most frequently caused by infarctions. However, there is a significant contribution of vascular lesions and vessel pathology to the development of dementia that may go beyond tissue damage due to vascular lesions. Insufficient blood blow and alterations of the perivascular drainage mechanisms of the brain may also lead to a reduced protein clearance from extracellular space and subsequent increase of proteins in the brain parenchyma, such as the amyloid β-protein, and foster, thereby, the development of AD-related neurodegeneration. As such, it seems to be important for clinical practice to consider treatment of potentially coexisting AD pathology in cognitively impaired patients with vascular lesions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

An early role of amyloid-β peptide (Aβ) aggregation in Alzheimer's disease pathogenesis is well established. However, the contribution of intracellular or extracellular forms of Aβ to the neurodegenerative process is a subject of considerable debate. We here describe transgenic mice expressing Aβ1-40 (APP47) and Aβ1-42 (APP48) with a cleaved signal sequence to insert both peptides during synthesis into the endoplasmic reticulum. Although lower in transgene mRNA, APP48 mice reach a higher brain Aβ concentration. The reduced solubility and increased aggregation of Aβ1-42 may impair its degradation. APP48 mice develop intracellular Aβ lesions in dendrites and lysosomes. The hippocampal neuron number is reduced already at young age. The brain weight decreases during aging in conjunction with severe white matter atrophy. The mice show a motor impairment. Only very few Aβ1-40 lesions are found in APP47 mice. Neither APP47 nor APP48 nor the bigenic mice develop extracellular amyloid plaques. While intracellular membrane expression of Aβ1-42 in APP48 mice does not lead to the AD-typical lesions, Aβ aggregates develop within cells accompanied by considerable neurodegeneration.

The amyloid beta-protein (Abeta) is the main component of Alzheimer's disease-related senile plaques. Although Abeta is associated with the development of Alzheimer's disease, it has not been shown which forms of Abeta induce neurodegeneration in vivo and which types of neurons are vulnerable. To address these questions, we implanted DiI crystals into the left frontocentral cortex of APP23 transgenic mice overexpressing mutant human APP (amyloid precursor protein gene) and of littermate controls. Traced commissural neurons in layer III of the right frontocentral cortex were quantified in 3-, 5-, 11- and 15-month-old mice. Three different types of commissural neurons were traced. At 3 months of age no differences in the number of labelled commissural neurons were seen in APP23 mice compared with wild-type mice. A selective reduction of the heavily ramified type of neurons was observed in APP23 mice compared with wild-type animals at 5, 11 and 15 months of age, starting when the first Abeta-deposits occurred in the frontocentral cortex at 5 months. The other two types of commissural neurons did not show alterations at 5 and 11 months. At 15 months, the number of traced sparsely ramified pyramidal neurons was reduced in addition to that of the heavily ramified neurons in APP23 mice compared with wild-type mice. At this time Abeta-deposits were seen in the neo- and allocortex as well as in the basal ganglia and the thalamus. In summary, our results show that Abeta induces progressive degeneration of distinct types of commissural neurons. Degeneration of the most vulnerable neurons starts in parallel with the occurrence of the first fibrillar Abeta-deposits in the neocortex, that is, with the detection of aggregated Abeta. The involvement of additional neuronal subpopulations is associated with the expansion of Abeta-deposition into further brain regions. The vulnerability of different types of neurons to Abeta, thereby, is presumably related to the complexity of their dendritic morphology.