White matter hyperintensities and the surrounding normal appearing white matter are associated with water channel disruption in the oldest old.

Introduction: Age-related magnetic resonance imaging (MRI) T2 white matter hyperintensities (WMHs) are common and associated with neurological decline. We investigated the histopathological underpinnings of MRI WMH and surrounding normal appearing white matter (NAWM), with a focus on astroglial phenotypes.

Methods: Brain samples from 51 oldest old Oregon Alzheimer's Disease Research Center participants who came to autopsy underwent post mortem (PM) 7 tesla MRI with targeted histopathological sampling of WMHs and NAWM.

Role of platelet count in a murine stasis model of deep vein thrombosis.

Platelets are core components of thrombi but their effect on thrombus burden during deep vein thrombosis (DVT) has not been fully characterized. We examined the role of thrombopoietin-altered platelet count on thrombus burden in a murine stasis model of DVT. To modulate platelet count compared to baseline, CD1 mice were pretreated with thrombopoietin antisense oligonucleotide (THPO-ASO, 56% decrease), thrombopoietin mimetic (TPO-mimetic, 36% increase), or saline (within 1%).

Elevated α5 integrin expression on myeloid cells in motor areas in amyotrophic lateral sclerosis is a therapeutic target.

Amyotrophic lateral sclerosis (ALS) is a fatal disease affecting upper and lower motor neurons. Microglia directly interact with motor neurons and participate in the progression of ALS. Single-cell mass cytometry (CyTOF) analysis revealed prominent expression of α5 integrin in microglia and macrophages in a superoxide dismutase-1 G93A mouse model of ALS (SOD1).

Preserved autophagy in cognitively intact non-demented individuals with Alzheimer's neuropathology.

Introduction: Growing evidence supports that dysfunctional autophagy, the major cell mechanism responsible for removing protein aggregates and a route of clearance for Tau in healthy neurons, is a major finding in demented Alzheimer's disease (AD) patients. However, the association of autophagy with maintenance of cognitive integrity in resilient individuals who have AD neuropathology but remain non-demented (NDAN) has not been evaluated.

Methods: Using post mortem brain samples from age-matched healthy control, AD, and NDAN subjects, we evaluated autophagy in relation to Tau pathology using Western blot, immunofluorescence and RNA-seq.

Targeted Transcriptional Analysis of IgA Vasculitis, IgA Nephropathy, and IgA-Dominant Infection-Related Glomerulonephritis Reveals Both Distinct and Overlapping Immune Signatures.

Key Points: Skin IL-9, calprotectin, and KIR gene expression may be predictive of subsequent kidney involvement in patients with IgAV. Histologically similar patients with IgAN, IgAV, and IgA-IRGN can be distinguished by their immune transcriptomes. Kidney biopsies from patients with IgA-IRGN are enriched for transcripts involved in granulocyte chemotaxis.

Aggregated Alpha-Synuclein Inclusions within the Nucleus Predict Impending Neuronal Cell Death in a Mouse Model of Parkinsonism.

Alpha-synuclein (aSyn) is a 14 kD protein encoded by the SNCA gene that is expressed in vertebrates and normally localizes to presynaptic terminals and the nucleus. aSyn forms pathological intracellular aggregates that typify a group of important neurodegenerative diseases called synucleinopathies. Previous work in human tissue and model systems indicates that some of these aggregates can be intranuclear, but the significance of aSyn aggregation within the nucleus is not clear.

Serine ether glycerophospholipids: Decrements in the frontal cortex associated with mild cognitive impairment and Alzheimer's disease.

Ether glycerophospholipids (GPL) are involved in membrane fluidity and fusion. Vinyl-ether GPL are also conjectured to provide antioxidant capacity in the brain. The roles of these lipids in the processes involved in the development of dementia are not understood but choline and ethanolamine vinyl-ether GPL (i.

TREM2-induced activation of microglia contributes to synaptic integrity in cognitively intact aged individuals with Alzheimer's neuropathology.

The existence of individuals who remain cognitively intact despite presenting histopathological signs of Alzheimer's disease (AD), here referred to as "Nondemented with AD neuropathology" (NDAN), suggests that some mechanisms are triggered to resist cognitive impairment. Exposed phosphatidylserine (ePS) represents a neuronal "eat-me" signal involved in microglial-mediated phagocytosis of damaged synapses. A possible mediator of this process is TREM2, a microglial surface receptor activated by ligands including PS.

Human Brain Lipidomics: Investigation of Formalin Fixed Brains.

Human brain lipidomics have elucidated structural lipids and lipid signal transduction pathways in neurologic diseases. Such studies have traditionally sourced tissue exclusively from brain bank biorepositories, however, limited inventories signal that these facilities may not be able to keep pace with this growing research domain. Formalin fixed, whole body donors willed to academic institutions offer a potential supplemental tissue source, the lipid profiles of which have yet to be described.

Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid β plaque formation in mice.

Background: Slowed clearance of amyloid β (Aβ) is believed to underlie the development of Aβ plaques that characterize Alzheimer's disease (AD). Aβ is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs Aβ clearance, and promotes Aβ plaque formation.

Human Brain Lipidomics: Pilot Analysis of the Basal Ganglia Sphingolipidome in Parkinson's Disease and Lewy Body Disease.

Sphingolipids constitute a complex class of bioactive lipids with diverse structural and functional roles in neural tissue. Lipidomic techniques continue to provide evidence for their association in neurological diseases, including Parkinson's disease (PD) and Lewy body disease (LBD). However, prior studies have primarily focused on biological tissues outside of the basal ganglia, despite the known relevancy of this brain region in motor and cognitive dysfunction associated with PD and LBD.

Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling.

Clinical symptoms correlate with underlying neurodegenerative changes in the vast majority of people. However, an intriguing group of individuals demonstrate neuropathologic changes consistent with Alzheimer disease (AD) yet remain cognitively normal (termed "resilient"). Previous studies have reported less overall neuronal loss, less gliosis, and fewer comorbidities in these individuals.

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study.

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged.

The Genome-Wide Binding Profile for Human RE1 Silencing Transcription Factor Unveils a Unique Genetic Circuitry in Hippocampus.

Early studies in mouse neurodevelopment led to the discovery of the RE1 Silencing Transcription Factor (REST) and its role as a master repressor of neuronal gene expression. Recently, REST was reported to also repress neuronal genes in the human adult brain. These genes were found to be involved in pro-apoptotic pathways; and their repression, associated with increased REST levels during aging, were found to be neuroprotective and conserved across species.

MRI characteristics of Japanese macaque encephalomyelitis: Comparison to human diseases.

Background And Purpose: To describe MRI findings in Japanese macaque encephalomyelitis (JME) with emphasis on lesion characteristics, lesion evolution, normal-appearing brain tissue, and similarities to human demyelinating disease.

Methods: MRI data were obtained from 114 Japanese macaques, 30 presenting neurological signs of JME. All animals were screened for presence of T -weighted white matter signal hyperintensities; animals with behavioral signs of JME were additionally screened for contrast-enhancing lesions.

Human Brain Lipidomics: Utilities of Chloride Adducts in Flow Injection Analysis.

Ceramides have been implicated in a number of disease processes. However, current means of evaluation with flow infusion analysis (FIA) have been limited primarily due to poor sensitivity within our high-resolution mass spectrometry lipidomics analytical platform. To circumvent this deficiency, we investigated the potential of chloride adducts as an alternative method to improve sensitivity with electrospray ionization.

Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914).

Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer's Neuropathology.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration in the cerebral cortex, histopathologically hallmarked by amyloid β (Aβ) extracellular plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. Correlation between these pathologic features and dementia has been challenged by the emergence of "nondemented with Alzheimer's neuropathology" (NDAN) individuals, cognitively intact despite displaying pathologic features of AD. The existence of these subjects suggests that some unknown mechanisms are triggered to resist Aβ-mediated detrimental events.

Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy.

It is necessary to develop an understanding of the specific mechanisms involved in alpha-synuclein aggregation and propagation to develop disease modifying therapies for age-related synucleinopathies, including Parkinson's disease and Dementia with Lewy Bodies. To adequately address this question, we developed a new transgenic mouse model of synucleinopathy that expresses human A53T SynGFP under control of the mouse prion protein promoter. Our characterization of this mouse line demonstrates that it exhibits several distinct advantages over other, currently available, mouse models.

4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN.

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase.

Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders.

Alpha-synuclein is a presynaptic protein that forms abnormal cytoplasmic aggregates in Lewy body disorders. Although nuclear alpha-synuclein localization has been described, its function in the nucleus is not well understood. We demonstrate that alpha-synuclein modulates DNA repair.

Astrocyte dysfunction and neurovascular impairment in neurological disorders: Correlation or causation?

The neurovascular unit, consisting of neurons, astrocytes, and vascular cells, has become the focus of much discussion in the last two decades and emerging literature now suggests an association between neurovascular dysfunction and neurological disorders. In this review, we synthesize the known and suspected contributions of astrocytes to neurovascular dysfunction in disease. Throughout the brain, astrocytes are centrally positioned to dynamically mediate interactions between neurons and the cerebral vasculature, and play key roles in blood-brain barrier maintenance and neurovascular coupling.