Accumulation of multiple neurodegenerative disease-related proteins in familial frontotemporal lobar degeneration associated with granulin mutation.

In 2006, mutations in the granulin gene were identified in patients with familial Frontotemporal Lobar Degeneration. Granulin transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin protein. Granulin mutations were initially found in tau-negative patients, though recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer's disease and corticobasal degeneration.

Changes in CD200 and intercellular adhesion molecule-1 (ICAM-1) levels in brains of Lewy body disorder cases are associated with amounts of Alzheimer's pathology not α-synuclein pathology.

Enhanced inflammation has been associated with Alzheimer's disease (AD) and diseases with Lewy body (LB) pathology, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). One issue is whether amyloid and tangle pathology, features of AD, or α-synuclein LB pathology have similar or different effects on brain inflammation. An aim of this study was to examine if certain features of inflammation changed in brains with increasing LB pathology.

Whole transcriptome profiling of the human hippocampus suggests an involvement of the KIBRA rs17070145 polymorphism in differential activation of the MAPK signaling pathway.

The rs17070145-T variant of the WWC1 gene, coding for the KIBRA protein, has been associated with both increased episodic memory performance and lowered risk for late onset Alzheimer's disease, although the mechanism behind this protective effect has not been completely elucidated. To achieve a better understanding of the pathways modulated by rs17070145 and its associated functional variant(s), we used laser capture microdissection (LCM) and RNA-sequencing to investigate the effect of rs17070145 genotypes on whole transcriptome expression in the human hippocampus (HP) of 22 neuropathologically normal individuals, with a specific focus on the dentate gyrus (DG) and at the pyramidal cells (PC) of CA1 and CA3 sub-regions. Differential expression analysis of RNA-seq data within the HP based on the rs17070145 genotype revealed an overexpression of genes involved in the MAPK signaling pathway, potentially driven by the T/T genotype.

A nutritional supplement containing lactoferrin stimulates the immune system, extends lifespan, and reduces amyloid peptide toxicity in .

Lactoferrin is a highly multifunctional glycoprotein involved in many physiological functions, including regulation of iron absorption and immune responses. Moreover, there is increasing evidence for neuroprotective effects of lactoferrin. We used as a model to test the protective effects, both on phenotype and transcriptome, of a nutraceutical product based on lactoferrin liposomes.

Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes.

Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis. Although it remains unknown why PGRN deficiency causes neurodegenerative diseases, there is increasing evidence that PGRN is implicated in lysosomal functions. Here, we show PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes.

The Search for a Peripheral Biopsy Indicator of α-Synuclein Pathology for Parkinson Disease.

The neuropathological hallmark of Parkinson disease (PD) is abnormal accumulation of α-synuclein (α-syn). Demonstrating pathological α-syn in live patients would be useful for identifying and monitoring PD patients. To date, however, imaging and biofluid approaches have not permitted premortem assessment of pathological α-syn.

A Quantitative Analysis of Brain Soluble Tau and the Tau Secretion Factor.

Neurofibrillary tangles (NFTs) represent products of insoluble tau protein in the brains of patients with Alzheimer disease (AD). The cerebrospinal fluid (CSF) tau level is a biomarker in AD diagnosis. The soluble portion of tau protein in brain parenchyma is presumably the source for CSF tau but this has not previously been quantified.

Comparison of neuropathology in Parkinson's disease subjects with and without deep brain stimulation.

Background: The aim of this postmortem study was to compare, in Parkinson's disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN-DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha-synuclein density within the SN and other brain regions.

Methods: PD subjects were identified from the Arizona Study of Aging and Neurodegenerative Disorders database (STN-DBS = 11, non-DBS = 156). Pigmented neuron loss scores within the substantia nigra as well as alpha-synuclein density scores within the substantia nigra and 9 other brain regions were compared, the latter individually and in summary as the Lewy body brain load score.

Multicenter Assessment of Immunohistochemical Methods for Pathological Alpha-Synuclein in Sigmoid Colon of Autopsied Parkinson's Disease and Control Subjects.

Background: Conflicting results from studies of Lewy-type α-synucleinopathy (LTS) in colonic biopsies of subjects with Parkinson's disease (PD) prompted a two-part multicenter assessment. The first assessment, now published (Acta Neuropathol Commun 4 : 35, 2016), examined archived colonic biopsies and found that none of the tested methods was adequately sensitive or specific.

Objective: As the amount of nervous tissue in typical colonic biopsies may be insufficient, and the clinical diagnosis of PD not completely accurate, the objective of the current study was to use instead full-thickness sections of sigmoid colon from autopsy-proven PD and normal subjects.

Chemical and neuropathological analyses of an Alzheimer's disease patient treated with solanezumab.

Introduction: Based on the amyloid cascade hypothesis of Alzheimer's disease (AD) pathogenesis, a series of clinical trials involving immunotherapies have been undertaken including infusion with the IgG1 monoclonal anti-Aβ antibody solanezumab directed against the middle of the soluble Aβ peptide. In this report, we give an account of the clinical history, psychometric testing, gross and microscopic neuropathology as well as immunochemical quantitation of soluble and insoluble Aβ peptides and other proteins of interest related to AD pathophysiology in a patient treated with solanezumab.

Materials And Methods: The solanezumab-treated AD case (SOLA-AD) was compared to non-demented control (NDC, n = 5) and non-immunized AD (NI-AD, n = 5) subjects.

Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies.

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

Multiplex immunoassay characterization and species comparison of inflammation in acute and non-acute ischemic infarcts in human and mouse brain tissue.

This study provides a parallel characterization of the cytokine and chemokine response to stroke in the human and mouse brain at different stages of infarct resolution. The study goal was to address the hypothesis that chronic inflammation may contribute to stroke-related dementia. We used C57BL/6 and BALB/c mice to control for strain related differences in the mouse immune response.

Bilayer of Terbium Double-Decker Single-Molecule Magnets.

We report a low-temperature scanning tunneling microscopy and spectroscopy study of the structural and electronic properties of a bilayer of terbium double-decker (bis(phthalocyaninato)terbium(III), TbPc) molecules on Au(111) at 5 K. The TbPc molecules are found to adsorb flat on top of a first compact TbPc monolayer on Au(111), forming a square-like packing similar to the underlying first layer. Their frontier-orbital electronic structure, measured by tunneling conductance spectroscopy, clearly differs from that of the underlying first monolayer.

Mitochondrial DNA Rearrangement Spectrum in Brain Tissue of Alzheimer's Disease: Analysis of 13 Cases.

Background: Mitochondrial dysfunction may play a central role in the pathologic process of Alzheimer's disease (AD), but there is still a scarcity of data that directly links the pathology of AD with the alteration of mitochondrial DNA. This study aimed to provide a comprehensive assessment of mtDNA rearrangement events in AD brain tissue.

Patients And Methods: Postmortem frozen human brain cerebral cortex samples were obtained from the Banner Sun Health Research Institute Brain and Body Donation Program, Sun City, AZ.

Gender Differences in Alzheimer Disease: Brain Atrophy, Histopathology Burden, and Cognition.

Multiple studies suggest that females are affected by Alzheimer disease (AD) more severely and more frequently than males. Other studies have failed to confirm this and the issue remains controversial. Difficulties include differences in study methods and male versus female life expectancy.

Clinical leishmaniasis in dogs living in the UK.

Objectives: To investigate the prevalence of leishmaniasis in dogs in the UK and to describe clinical presentation, clinicopathological abnormalities, therapeutic protocols and outcome in this non-endemic country.

Materials And Methods: Medical records of dogs diagnosed with leishmaniasis at seven referral centres in the UK were retrospectively reviewed.

Results: The prevalence was between 0·007 and 0·04% with a higher number of cases in southern England.

Cuttlefish Ink Melanin Encapsulated in Nanolipid Bubbles and Applied Through a Micro-Needling Procedure Easily Stains White Hair Facilitating Photoepilation.

Background: Photothermolysis of unwanted hair depends on the presence of melanin in the hair follicle as the chromophore, but is not effective in patients with non-pigmented, melanin-sparse hair shafts and follicles. This split-scalp, double-blind study was to monitor the efficacy of melanin bound in nanosomes to inject exogenous melanin into the hair follicles thus potentiating successful photothermolysis.


Material And Methods: Twelve patients, phototypes II-III, with white or very fair hair, were treated with a compound containing melanin encapsulated in nanosomes (Melaser) together with a fluorescent marker.

Characterization of RNA isolated from eighteen different human tissues: results from a rapid human autopsy program.

Many factors affect the integrity of messenger RNA from human autopsy tissues including postmortem interval (PMI) between death and tissue preservation and the pre-mortem agonal and disease states. In this communication, we describe RNA isolation and characterization of 389 samples from 18 different tissues from elderly donors who were participants in a rapid whole-body autopsy program located in Sun City, Arizona ( www.brainandbodydonationprogram.

Altered Expression Patterns of Inflammation-Associated and Trophic Molecules in Substantia Nigra and Striatum Brain Samples from Parkinson's Disease, Incidental Lewy Body Disease and Normal Control Cases.

Evidence of inflammation has been consistently associated with pathology in Parkinson's disease (PD)-affected brains, and has been suggested as a causative factor. Dopaminergic neurons in the substantia nigra (SN) pars compacta, whose loss results in the clinical symptoms associated with PD, are particularly susceptible to inflammatory damage and oxidative stress. Inflammation in the striatum, where SN dopaminergic neurons project, is also a feature of PD brains.

Peripheral Synucleinopathy in Early Parkinson's Disease: Submandibular Gland Needle Biopsy Findings.

Introduction: Finding a peripheral tissue biopsy site to diagnose early PD would be of value for clinical care, biomarker validation, and as research enrollment criteria. Whereas autopsy and advanced PD studies suggest that the submandibular gland is an important biopsy site, there are no studies in early PD. The aim of this study was to determine whether needle biopsy of the submandibular gland reveals Lewy type alpha-synucleinopathy in early PD.

Prevalence of Submandibular Gland Synucleinopathy in Parkinson's Disease, Dementia with Lewy Bodies and other Lewy Body Disorders.

Background: Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson's disease (PD).

Phosphatidylcholine liposomes as carriers to improve topical ascorbic acid treatment of skin disorders.

Liposomes have been intensively investigated as carriers for different applications in dermatology and cosmetics. Ascorbic acid has potent antioxidant and anti-inflammatory properties preventing photodamage of keratinocytes; however, due to its instability and low skin penetration, an appropriate carrier is mandatory to obtain desirable efficacy. The present work investigates the ability of a specific ascorbate phosphatidylcholine (PC) liposome to overcome the barrier of the stratum corneum and deliver the active agent into the dermis to prevent photodamage.

Nanoliposomes protect against human arteriole endothelial dysfunction induced by β-amyloid peptide.

We tested whether nanoliposomes containing phosphatidylcholine, cholesterol and phosphatidic acid (NLPA) prevent β-amyloid 1-42 (Aβ42) fibrillation and Aβ42-induced human arteriole endothelial dysfunction. NLPA abolished Aβ42 fibril formation (thioflavin-T fluorescence/electron microscopy). In ex-vivo human adipose and leptomeningeal arterioles, Aβ42 impaired dilator response to acetylcholine that was reversed by NLPA; this protection was abolished by L-NG-nitroarginine methyl ester.