AD Cases Research Articles

Molecular Insight into the Crosstalk of UPS Components and Alzheimer's Disease.

The ubiquitin (Ub)-proteasome system (UPS) targets various cellular proteins for degradation. It has been found that defects in the UPS play a crucial role in the pathogenesis of Alzheimer's disease (AD), as the existence of Ub immunoreactivity in AD-linked neuronal inclusions, including neurofibrillary tangles, is observed in all types of AD cases. Current investigations have shown that components of the UPS can be connected with the early stage of AD, which is characterized by synaptic dysfunction, and to the late phases of the disease, marked by neurodegeneration. Although the significance of UPS in the pathogenesis of AD has been emphasized, targeted treatment at the main components of these pathways has a great perspective in advancing new therapeutic interventions for AD. In this review, we emphasize the relationship between UPS and AD pathology. We also represent the recent therapeutic advancements targeting UPS components in AD.

The coarse-grained plaque: a divergent A\u03b2 plaque-type in early-onset Alzheimer\u2019s disease

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque’s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque’s neuritic component (pTau, APP, PrPC), Aβ isoform composition (Aβ40, Aβ42, AβN3pE, pSer8Aβ), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aβ40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aβ40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

Multi-slice representational learning of convolutional neural network for Alzheimer\u2019s disease classification using positron emission tomography

BackgroundAlzheimer’s Disease (AD) is a degenerative brain disorder that often occurs in people over 65 years old. As advanced AD is difficult to manage, accurate diagnosis of the disorder is critical. Previous studies have revealed effective deep learning methods of classification. However, deep learning methods require a large number of image datasets. Moreover, medical images are affected by various environmental factors. In the current study, we propose a deep learning-based method for diagnosis of Alzheimer’s disease (AD) that is less sensitive to different datasets for external validation, based upon F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT).ResultsThe accuracy, sensitivity, and specificity of our proposed network were 86.09%, 80.00%, and 92.96% (respectively) using our dataset, and 91.02%, 87.93%, and 93.57% (respectively) using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. We observed that our model classified AD and normal cognitive (NC) cases based on the posterior cingulate cortex (PCC), where pathological changes occur in AD. The performance of the GAP layer was considered statistically significant compared to the fully connected layer in both datasets for accuracy, sensitivity, and specificity (p < 0.01). In addition, performance comparison between the ADNI dataset and our dataset showed no statistically significant differences in accuracy, sensitivity, and specificity (p > 0.05).ConclusionsThe proposed model demonstrated the effectiveness of AD classification using the GAP layer. Our model learned the AD features from PCC in both the ADNI and Severance datasets, which can be seen in the heatmap. Furthermore, we showed that there were no significant differences in performance using statistical analysis.

Molecular abnormalities in autopsied brain tissue from the inferior horn of the lateral ventricles of nonagenarians and Alzheimer disease patients

BackgroundThe ventricular system plays a vital role in blood-cerebrospinal fluid (CSF) exchange and interstitial fluid-CSF drainage pathways. CSF is formed in the specialized secretory tissue called the choroid plexus, which consists of epithelial cells, fenestrated capillaries and the highly vascularized stroma. Very little is currently known about the role played by the ventricles and the choroid plexus tissue in aging and Alzheimer’s disease (AD).MethodsIn this study, we used our state-of-the-art proteomic platform, a liquid chromatography/mass spectrometry (LC-MS/MS) approach coupled with Tandem Mass Tag isobaric labeling to conduct a detailed unbiased proteomic analyses of autopsied tissue isolated from the walls of the inferior horn of the lateral ventricles in AD (77.2 ± 0.6 yrs), age-matched controls (77.0 ± 0.5 yrs), and nonagenarian cases (93.2 ± 1.1 yrs).ResultsIngenuity pathway analyses identified phagosome maturation, impaired tight-junction signaling, and glucose/mannose metabolism as top significantly regulated pathways in controls vs nonagenarians. In matched-control vs AD cases we identified alterations in mitochondrial bioenergetics, oxidative stress, remodeling of epithelia adherens junction, macrophage recruitment and phagocytosis, and cytoskeletal dynamics. Nonagenarian vs AD cases demonstrated augmentation of oxidative stress, changes in gluconeogenesis-glycolysis pathways, and cellular effects of choroidal smooth muscle cell vasodilation. Amyloid plaque score uniquely correlated with remodeling of epithelial adherens junctions, Fc γ-receptor mediated phagocytosis, and alterations in RhoA signaling. Braak staging was uniquely correlated with altered iron homeostasis, superoxide radical degradation and phagosome maturation.ConclusionsThese changes provide novel insights to explain the compromise to the physiological properties and function of the ventricles/choroid plexus system in nonagenarian aging and AD pathogenesis. The pathways identified could provide new targets for therapeutic strategies to mitigate the divergent path towards AD.

RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies.

Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X‐linked Parkinson’s disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha‐Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post‐mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer’s disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co‐localized with beta‐amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B‐associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co‐aggregation of RAB39B with Aβ in plaques suggests that age‐associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases.

Chromatic Pupillometry Findings in Alzheimer’s Disease

Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mild-moderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.

Association between periodontitis and Alzheimer's disease and its impact on the self-perceived oral health status: a case-control study.

To test the hypothesis that periodontitis is associated with AD and search whether periodontal and other variables would negatively impact the oral health-related quality of life (OHRQoL) perception. Oral examinations and interview on self-perceived oral health status (Geriatric Oral Health Assessment Index (GOHAI) questionnaire (higher score corresponds to better perceived oral status)) were carried out and socio-demographic data were collected from outpatients with mild to moderate AD (cases, n = 50) and from their age- and sex-matched family caregivers (controls, n = 52). Full-mouth periodontal examination was performed. Significance of differences between groups was sought by chi-square, Student's t, or the Mann-Whitney test. The association between the variables periodontitis, probing depth (PD) ≥ 5 mm, and clinical attachment loss (CAL) ≥ 5 mm with the variable group was tested in binary logistic regression models (LRMs). LRMs were used to test the association of oral findings, demographics, and group with GOHAI. Cases had fewer teeth and greater CAL than controls. Cases had a superior percentage of sites with plaque, calculus, and bleeding on probing than controls. Cases had greater GOHAI scores than controls. Periodontitis was a variable most likely associated with AD (OR = 11.08, p < 0.001). None of the oral findings or demographics, but group, was associated with GOHAI (OR = 14.45, p < 0.001). Periodontitis is associated with AD, but not with patients' OHRQoL. Health care professionals must be aware that AD patients should have a periodic thorough oral examination and preventive intervention aiming at their welfare and maintenance of a pain-free functional dentition.

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-\u03b2 plaques in Alzheimer\u2019s disease

Specificity and sensitivity of positron emission tomography (PET) radiopharmaceuticals targeting fibrillar amyloid-β (Aβ) deposits is high for detection of neuritic Aβ plaques, a mature form of Aβ deposits which often have dense Aβ core (i.e., cored plaques). However, imaging-to-autopsy validation studies of amyloid PET radioligands have identified several false positive cases all of which had mainly diffuse Aβ plaques (i.e., plaques without neuritic pathology or dense amyloid core), and high amyloid PET signal was reported in the striatum where diffuse plaques predominate in Alzheimer’s disease (AD). Relative contributions of different plaque types to amyloid PET signal is unclear, particularly in neocortical areas where they are intermixed in AD. In vitro binding assay and autoradiography were performed using [3H]flutemetamol and [3H]Pittsburgh Compound-B (PiB) in frozen brain homogenates from 30 autopsy cases including sporadic AD and non-AD controls with a range of brain Aβ burden and plaque density. Fixed tissue sections of frontal cortex and caudate from 10 of the AD cases were processed for microscopy using fluorescent derivatives of flutemetamol (cyano-flutemetamol) and PiB (cyano-PiB) and compared to Aβ immunohistochemistry and pan-amyloid (X-34) histology. Using epifluorescence microscopy, percent area coverage and fluorescence output values of cyano-PiB- and cyano-flutemetamol-labeled plaques in two-dimensional microscopic fields were then calculated and combined to obtain integrated density measurements. Using confocal microscopy, we analysed total fluorescence output of the entire three-dimensional volume of individual cored plaques and diffuse plaques labeled with cyano-flutemetamol or cyano-PiB. [3H]Flutemetamol and [3H]PiB binding values in tissue homogenates correlated strongly and their binding pattern in tissue sections, as seen on autoradiograms, overlapped the pattern of Aβ-immunoreactive plaques on directly adjacent sections. Cyano-flutemetamol and cyano-PiB fluorescence was prominent in cored plaques and less so in diffuse plaques. Across brain regions and cases, percent area coverage of cyano-flutemetamol-labeled plaques correlated strongly with cyano-PiB-labeled and Aβ-immunoreactive plaques. For both ligands, plaque burden, calculated as percent area coverage of all Aβ plaque types, was similar in frontal cortex and caudate regions, while integrated density values were significantly greater in frontal cortex, which contained both cored plaques and diffuse plaques, compared to the caudate, which contained only diffuse plaques. Three-dimensional analysis of individual plaques labeled with either ligand showed that total fluorescence output of a single cored plaque was equivalent to total fluorescence output of approximately three diffuse plaques of similar volume. Our results indicate that [18F]flutemetamol and [11C]PiB PET signal is influenced by both diffuse plaques and cored plaques, and therefore is likely a function of plaque size and density of Aβ fibrils in plaques. Brain areas with large volumes/frequencies of diffuse plaques could yield [18F]flutemetamol and [11C]PiB PET retention levels comparable to brain regions with a lower volume/frequency of cored plaques.

Phosphorylated A\u03b2 peptides in human Down syndrome brain and different Alzheimer\u2019s-like mouse models

The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer’s disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct age-dependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.

Clinical profile of Alzheimer’s patients: A multihospital based study done in India

Objectives. To find out the risk factors, clinical features, co-morbid conditions and management practices among AD patients. Materials and methods. This study was conducted at three major tertiary care hospitals in Mangalore city of south India. Medical records of confirmed cases of AD over the recent 10 years were analyzed. A semi-structured proforma was used for data collection. Outcomes. Mean age of the 55 AD patients was 81.1±7.6 years. The mean age at diagnosis was 75.95±7.95 years. The age at the onset of AD in 14 (25.5%) patients was from 76 to 80 years. Early onset AD (≤ 65 years) was reported among 9 (16.4%) patients. 35 (63.6%) patients were males and 37 (67.3%) were from urban area. Family history of AD was present among 2 (3.6%) patients. History of depression and traumatic brain injury was present among 5 (9.1%) and 4 (7.3%) patients respectively. History of consumption of alcohol and smoking was present in 9 (16.4%) and 7 (12.7%) patients respectively. Clinical features such as disorientation and recent memory loss was present among 39 (70.9%) and 38 (69.1%) patients respectively. Donepezil was used for the management of AD in 44 (80%) of patients. Non-pharmacological methods like physiotherapy were recommended in 21 (38.2%) AD patients. Conclusions. Considering the varied problems faced by the Alzheimer’s affected patients in terms of co-morbidities and clinical presentation, a multidisciplinary approach for the management of AD is suggested. More non-pharmacologic methods need to be introduced at this setting.

Synaptic Loss, ER Stress and Neuro-Inflammation Emerge Late in the Lateral Temporal Cortex and Associate with Progressive Tau Pathology in Alzheimer\u2019s Disease

The complex multifactorial nature of AD pathogenesis has been highlighted by evidence implicating additional neurodegenerative mechanisms, beyond that of amyloid-β (Aβ) and tau. To provide insight into cause and effect, we here investigated the temporal profile and associations of pathological changes in synaptic, endoplasmic reticulum (ER) stress and neuro-inflammatory markers. Quantifications were established via immunoblot and immunohistochemistry protocols in post-mortem lateral temporal cortex (n = 46). All measures were assessed according to diagnosis (non-AD vs. AD), neuropathological severity (low (Braak ≤ 2) vs. moderate (3–4) vs. severe (≥ 5)) and individual Braak stage, and were correlated with Aβ and tau pathology and cognitive scores. Postsynaptic PSD-95, but not presynaptic synaptophysin, was decreased in AD cases and demonstrated a progressive decline across disease severity and Braak stage, yet not with cognitive scores. Of all investigated ER stress markers, only phospho-protein kinase RNA-like ER kinase (p-PERK) correlated with Braak stage and was increased in diagnosed AD cases. A similar relationship was observed for the astrocytic glial fibrillary acidic protein (GFAP); however, the associated aquaporin 4 and microglial Iba1 remained unchanged. Pathological alterations in these markers preferentially correlated with measures of tau over those related to Aβ. Notably, GFAP also correlated strongly with Aβ markers and with all assessments of cognition. Lateral temporal cortex-associated synaptic, ER stress and neuro-inflammatory pathologies are here determined as late occurrences in AD progression, largely associated with tau pathology. Moreover, GFAP emerged as the most robust indicator of disease progression, tau/Aβ pathology, and cognitive impairment.

Targeted mass spectrometry to quantify brain-derived cerebrospinal fluid biomarkers in Alzheimer\u2019s disease

IntroductionAlzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline. Protein biomarkers of AD brain pathology, including β-amyloid and Tau, are reflected in cerebrospinal fluid (CSF), yet the identification of additional biomarkers linked to other brain pathophysiologies remains elusive. We recently reported a multiplex tandem-mass tag (TMT) CSF proteomic analysis of nearly 3000 proteins, following depletion of highly abundant proteins and off-line fractionation, across control and AD cases. Of these, over 500 proteins were significantly increased or decreased in AD, including markers reflecting diverse biological functions in brain. Here, we use a targeted mass spectrometry (MS) approach, termed parallel reaction monitoring (PRM), to quantify select CSF biomarkers without pre-depletion or fractionation to assess the reproducibility of our findings and the specificity of changes for AD versus other causes of cognitive impairment.MethodWe nominated 41 proteins (94 peptides) from the TMT CSF discovery dataset, representing a variety of brain cell-types and biological functions, for label-free PRM analysis in a replication cohort of 88 individuals that included 20 normal controls, 37 clinically diagnosed AD cases and 31 cases with non-AD cognitive impairment. To control for technical variables, isotopically labeled synthetic heavy peptide standards were added into each of the 88 CSF tryptic digests. Furthermore, a peptide pool, representing an equivalent amount of peptide from all samples, was analyzed (n = 10) across each batch. Together, this approach enabled us to assess both the intra- and inter-sample differences in peptide signal response and retention time.ResultsDespite differences in sample preparation, quantitative MS approaches and patient samples, 25 proteins, including Tau, had a consistent and significant change in AD in both the discovery and replication cohorts. Validated CSF markers with low coefficient of variation included the protein products for neuronal/synaptic (GDA, GAP43, SYN1, BASP1, YWHAB, YWHAZ, UCHL1, STMN1 and MAP1B), glial/inflammation (SMOC1, ITGAM, CHI3L1, SPP1, and CHIT1) and metabolic (PKM, ALDOA and FABP3) related genes. Logistical regression analyses revealed several proteins with high sensitivity and specificity for classifying AD cases from controls and other non-AD dementias. SMOC1, YWHAZ, ALDOA and MAP1B emerged as biomarker candidates that could best discriminate between individuals with AD and non-AD cognitive impairment as well as Tau/β-amyloid ratio. Notably, SMOC1 levels in postmortem brain are highly correlated with AD pathology even in the preclinical stage of disease, indicating that CSF SMOC1 levels reflect underlying brain pathology specific for AD.ConclusionCollectively these findings highlight the utility of targeted MS approaches to quantify biomarkers associated with AD that could be used for monitoring disease progression, stratifying patients for clinical trials and measuring therapeutic response.

Picornavirus Identified in Alzheimer's Disease Brains: A Pathogenic Path?

We investigated formalin-fixed postmortem brain tissue from the hippocampus region of 18 AD cases and 11 age-matched controls using a polyclonal antibody against Ljungan virus (LV) capsid protein 1. Evidence of a LV antigen was found in all AD cases but in none of the control specimens (p < 0.0001). The antibodies reacted with neurons and astrocytes and also showed distinct positive reaction in the amyloid/neuritic plaques. The possible role of an incompletely characterized picornavirus as the etiologic agent in AD open up the possibility of treatment with antiviral therapy directed against picornaviruses. The positive result of such treatment in a small number of patients is presented separately back to back to this report.

MATHEMATICAL MODELLING OF A TWO-STAGE ANAEROBIC DIGESTION PROCESS WITH HYDROGEN AND METHANE PRODUCTION USING ADM1

The aim of this study is to implement a mathematical model to simulate the dynamic behaviour of a two-stage anaerobic digestion process for simultaneous production of hydrogen and methane. The process is carried out in two connected continuously stirred bioreactors. The proposed model is developed by reducing the well known IWA Anaerobic Digester Model No 1 (ADM1). In the present study the original model concept was adapted and applied to replicate a two-stage process. The proposed model involves 13 ODEs for the 1st stage and 7 ODEs for the 2nd stage. The numerical coefficient values in the model are taken from specified literature and adapted to the case of wheat straw AD. Important input-output static characteristics and existence of maxima of the input-output static characteristics concerning the biohydrogen and biomethane production in function of the control variable (dilution rate) are presented. Supposing that both bioreactors are operating nearby these maxima the optimal ratio of the working volumes was obtained. Numerical simulations using a specially elaborated web-based software environment are presented to demonstrate the dynamic behavior of the model solutions.

Factors associated with development and distribution of granular/fuzzy astrocytes in neurodegenerative diseases.

Granular/fuzzy astrocytes (GFAs), a subtype of “aging‐related tau astrogliopathy,” are noted in cases bearing various neurodegenerative diseases. However, the pathogenic significance of GFAs remains unclear. We immunohistochemically examined the frontal cortex, caudate nucleus, putamen and amygdala in 105 cases composed of argyrophilic grain disease cases (AGD, N = 26), and progressive supranuclear palsy (PSP, N = 10), Alzheimer’s disease (AD, N = 20) and primary age‐related tauopathy cases (PART, N = 18) lacking AGD, as well as 31 cases bearing other various neurodegenerative diseases to clarify (i) the distribution patterns of GFAs in AGD, and PSP, AD and PART lacking AGD, (ii) the impacts of major pathological factors and age on GFA formation and (iii) immunohistochemical features useful to understand the formation process of GFAs. In AGD cases, GFAs consistently occurred in the amygdala (100%), followed by the putamen (69.2%) and caudate nucleus and frontal cortex (57.7%, respectively). In PSP cases without AGD, GFAs were almost consistently noted in all regions examined (90–100%). In AD cases without AGD, GFAs were less frequent, developing preferably in the putamen (35.0%) and caudate nucleus (30.0%). PART cases without AGD had GFAs most frequently in the amygdala (35.3%), being more similar to AGD than to AD cases. Ordered logistic regression analyses using all cases demonstrated that the strongest independent factor of GFA formation in the frontal cortex and striatum was the diagnosis of PSP, while that in the amygdala was AGD. The age was not significantly associated with GFA formation in any region. In GFAs in AGD cases, phosphorylation and conformational change of tau, Gallyas‐positive glial threads indistinguishable from those in tufted astrocytes, and the activation of autophagy occurred sequentially. Given these findings, AGD, PSP, AD and PART cases may show distinct distributions of GFAs, which may provide clues to predict the underlying processes of primary tauopathies.

White matter alterations in Alzheimer's disease without concomitant pathologies.

AimsMost individuals with AD neuropathological changes have co‐morbidities which have an impact on the integrity of the WM. This study analyses oligodendrocyte and myelin markers in the frontal WM in a series of AD cases without clinical or pathological co‐morbidities.MethodsFrom a consecutive autopsy series, 206 cases had neuropathological changes of AD; among them, only 33 were AD without co‐morbidities. WM alterations were first evaluated in coronal sections of the frontal lobe in every case. Then, RT‐qPCR and immunohistochemistry were carried out in the frontal WM of AD cases without co‐morbidities to analyse the expression of selected oligodendrocyte and myelin markers.ResultsWM demyelination was more marked in AD with co‐morbidities when compared with AD cases without co‐morbidities. Regarding the later, mRNA expression levels of MBP, PLP1, CNP, MAG, MAL, MOG and MOBP were preserved at stages I–II/0–A when compared with middle‐aged (MA) individuals, but significantly decreased at stages III–IV/0–C. This was accompanied by reduced expression of NG2 and PDGFRA mRNA, reduced numbers of NG2‐, Olig2‐ and HDAC2‐immunoreactive cells and reduced glucose transporter immunoreactivity. Partial recovery of some of these markers occurred at stages V–VI/B–C.ConclusionsThe present observations demonstrate that co‐morbidities have an impact on WM integrity in the elderly and in AD, and that early alterations in oligodendrocytes and transcription of genes linked to myelin proteins in WM occur in AD cases without co‐morbidities. These are followed by partial recovery attempts at advanced stages. These observations suggest that oligodendrocytopathy is part of AD.

Superradiance of a global monopole in Reissner\u2013Nordstr\xf6m(\u2013AdS) space-time

In this article, the behavior of a charged and massive scalar field around a global monopole swallowed by a Reissner–Nordström–Anti-de Sitter (RN–AdS) black hole is investigated by considering the Klein–Gordon equation in this geometry. The superradiance phenomenon and instability behavior of the black hole against charged scalar perturbations are studied for both an RN–AdS case and also for an RN black hole surrounded by a reflective mirror, i.e., the black hole bomb case. The effects of the monopole on these cases are discussed analytically and also with the help of several graphs in detail. The monopole charge affects the superradiance threshold frequency and also effects the instability time scale for both cases. The existence of global monopole makes these black holes more stable against superradiance instability.

Quadratic gravity and conformally coupled scalar fields

We construct black hole solutions in four-dimensional quadratic gravity, supported by a scalar field conformally coupled to quadratic terms in the curvature. The conformal matter Lagrangian is constructed with powers of traces of a conformally covariant tensor, which is defined in terms of the metric and a scalar field, and has the symmetries of the Riemann tensor. We find exact, neutral and charged, topological black hole solutions of this theory when the Weyl squared term is absent from the action functional. Including terms beyond quadratic order on the conformally covariant tensor, allows to have asymptotically de Sitter solutions, with a potential that is bounded from below. For generic values of the couplings we also show that static black hole solutions must have a constant Ricci scalar, and provide an analysis of the possible asymptotic behavior of both, the metric as well as the scalar field in the asymptotically AdS case, when the solutions match those of general relativity in vacuum at infinity. In this frame, the spacetime fulfils standard asymptotically AdS boundary conditions, and in spite of the non-standard couplings between the curvature and the scalar field, there is a family of black hole solutions in AdS that can be interpreted as localized objects. We also provide further comments on the extension of these results to higher dimensions.

Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier \u2013 phenotypic variability in autosomal dominant Alzheimer\u2019s disease

The discovery of mutations associated with familial forms of Alzheimer’s disease (AD), has brought imperative insights into basic mechanisms of disease pathogenesis and progression and has allowed researchers to create animal models that assist in the elucidation of the molecular pathways and development of therapeutic interventions. Position 717 in the amyloid precursor protein (APP) is a hotspot for mutations associated with autosomal dominant AD (ADAD) and the valine to isoleucine amino acid substitution (V717I) at this position was among the first ADAD mutations identified, spearheading the formulation of the amyloid cascade hypothesis of AD pathogenesis. While this mutation is well described in multiple kindreds and has served as the basis for the generation of widely used animal models of disease, neuropathologic data on patients carrying this mutation are scarce. Here we present the detailed clinical and neuropathologic characterization of an APP V717I carrier, which reveals important novel insights into the phenotypic variability of ADAD cases. While age at onset, clinical presentation and widespread parenchymal beta-amyloid (Aβ) deposition are in line with previous reports, our case also shows widespread and severe cerebral amyloid angiopathy (CAA). This patient also presented with TDP-43 pathology in the hippocampus and amygdala, consistent with limbic predominant age-related TDP-43 proteinopathy (LATE). The APOE ε2/ε3 genotype may have been a major driver of the prominent vascular pathology seen in our case. These findings highlight the importance of neuropathologic examinations of genetically determined AD cases and demonstrate striking phenotypic variability in ADAD cases.

White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer\u2019s disease rat model

BackgroundMetabolic syndrome, the development of which is associated with high-caloric Western diet (HCD) intake, represent a risk factor for mild cognitive impairment (MCI) and dementia including Alzheimer’s disease (AD) later in life. This study aimed to investigate the effect of diet-induced metabolic disturbances on white matter neuroinflammation and cognitive function in a transgenic (TG) Fischer 344 rat carrying a human β-amyloid precursor protein (APP) gene with Swedish and Indiana mutations (APP21 TG), a model of pre-AD and MCI.MethodsTG and wildtype (WT) rats received either a HCD with 40% kJ from fat supplemented with 20% corn syrup drink or a standard diet for 12 weeks. Body weight, caloric intake, and blood pressure were measured repeatedly. End-point changes in glucose and lipid metabolism were also assessed. Open field task was used for assessment of activity; Morris water maze was used to assess spatial learning and memory. Cerebral white matter microglia and astrocytes, hippocampal neurons, and neuronal synapses were examined using immunohistochemistry.ResultsRats maintained on the HCD developed significant obesity, visceral adiposity, dyslipidemia, and hyperinsulinemia, but did not become hypertensive. Impaired glucose tolerance was observed only in WT rats on the HCD. Total microglia number, activated OX-6+ microglia, as well as GFAP+ astrocytes located predominantly in the white matter were greater in the APP21 TG rat model in comparison to WT rats. HCD-driven metabolic perturbations further exacerbated white matter microgliosis and microglia cell activation in the APP21 TG rats and led to detectable changes in spatial reference memory in the comorbid prodromal AD and metabolic syndrome group compared to WT control rats. Neuronal density in the CA1 subregion of the hippocampus was not different between the experimental groups. Synaptic density in the CA1 and CA3 hippocampal subregions was lower in the TG rats compared to WT rats; however, there was no additional effect of the co-morbidity on this measure.ConclusionsThese results suggest that white matter neuroinflammation might be one of the possible processes of early interaction of metabolic syndrome with MCI and pre-AD and could be one of the early brain pathologies contributing to cognitive deficits observed in mild cognitive impairment and dementia, including AD cases.