Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognized for its association with dementia. AIMS: This study investigated clinical and neuropathological differences between DLB and PDD. METHODS: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. RESULTS: CAA was more common in DLB than in PDD (P = 0.003). The severity of CAA was greater in DLB than in PDD (P = 0.009), with significantly higher CAA scores in the parietal lobe (P = 0.043), and the occipital lobe (P = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. CONCLUSIONS: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

Review: Clinical, neuropathological and genetic features of Lewy body dementias.

Lewy body dementias are the second most common neurodegenerative dementias after Alzheimer's disease and include dementia with Lewy bodies and Parkinson's disease dementia. They share similar clinical and neuropathological features but differ in the time of dementia and parkinsonism onset. Although Lewy bodies are their main pathological hallmark, several studies have shown the emerging importance of Alzheimer's disease pathology. Clinical amyloid-ß imaging using Pittsburgh Compound B (PiB) supports neuropathological studies which found that amyloid-ß pathology is more common in dementia with Lewy bodies than in Parkinson's disease dementia. Nevertheless, other co-occurring pathologies, such as cerebral amyloid angiopathy, TDP-43 pathology and synaptic pathology may also influence the development of neurodegeneration and dementia. Recent genetic studies demonstrated an important role of APOE genotype and other genes such as GBA and SNCA which seem to be involved in the pathophysiology of Lewy body dementias. The aim of this article is to review the main clinical, neuropathological and genetic aspects of dementia with Lewy bodies and Parkinson's disease dementia. This is particularly relevant as future management for these two conditions may differ.

Pharmacological assessment of ibuprofen arginate on platelet aggregation and colon cancer cell killing.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are amongst the most commonly used medications and produce their anti-inflammatory and analgesic benefits by blocking cyclooxygenase (COX)-2. These drugs also have the potential to prevent and treat cancer and some members of the class including ibuprofen can produce anti-platelet effects. Despite their utility, all NSAIDs are associated with increased risk of cardiovascular side effects which our recent work suggests could be mediated by increased levels of the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) leading to reduced endothelial NOS activity and associated endothelial cell dysfunction. ADMA is a cardiotoxic hormone and biomarker of cardiovascular risk whose effects can be prevented by l-arginine. The ibuprofen salt, ibuprofen arginate (Spididol®) was created to increase drug solubility but we have previously established that it not only effectively blocks COX-2 but also provides an arginine source able to reverse the effects of ADMA in vitro and in vivo. Here we have gone on to explore whether the formulation of ibuprofen with arginine influences the potency and efficacy of the parent molecule using a range of simple in vitro assays designed to test the effects of NSAIDs on (i) platelet aggregation and (iii) colon cancer cell killing. Our findings demonstrate that ibuprofen arginate retains these key functional effects of NSAIDs with similar or increased potency compared to ibuprofen sodium, further illustrating the potential of ibuprofen arginate as an efficacious drug with the possibility of improved cardiovascular safety.

Inhibition of platelet aggregation ex vivo is repressed in apolipoprotein E deficient mice.

In the present study, we assessed whether the endogenous platelet inhibitory mechanisms are altered in the early to moderate stages of the atherosclerotic process. Apolipoprotein E deficient mice (ApoE-/-), a mouse model of atherosclerosis, and their wild-type (WT) counterparts were used to assess agonist-stimulated synthesis of prostacyclin (PGI2), inhibition of platelet aggregation ex vivo, and intra-platelet cAMP levels. Basal U46619 and ADP -induced platelet aggregation in vitro were increased in ApoE-/- mice at 18-20 weeks in comparison with 8-10 weeks of age. Systemically administered endothelin-1 (ET-1) or bradykinin (BK) inhibited platelet aggregation in a similar fashion in 8- to 10-week-old ApoE-/- and WT mice, but not in the ApoE-/- mice at 18-20 weeks of age, although both peptides maintained their capacity to increase plasma levels of the PGI2. Intravenous infusion of PGI2 also failed to inhibit platelet aggregation ex vivo in 18- to 20-week-old ApoE-/- mice. Interestingly, both BK and PGI2 retained their ability to increase intraplatelet cAMP in WT and ApoE-/- mice. Our results suggest that a loss of activity of endogenous inhibitorymechanisms could contribute to the increased platelet reactivity in ApoE-/- mice, and that this phenomenon occurs early in the intermediate stage of the atherosclerotic process.

Review: Induced pluripotent stem cell models of frontotemporal dementia.

The increasing prevalence of dementia in the ageing population combined with the lack of treatments and the burden on national health care systems globally make dementia a public health priority. Despite the plethora of important research findings published over the past two decades, the mechanisms underlying dementia are still poorly understood and the progress in pharmacological interventions is limited. Recent advances in cellular reprogramming and genome engineering technologies offer an unprecedented new paradigm in disease modeling. Induced pluripotent stem cells (iPSCs) have enabled the study of patient-derived neurons in vitro, a significant progress in the field of dementia research. The first studies using iPSCs to model dementia have recently emerged, holding promise for elucidating disease pathogenic mechanisms and accelerating drug discovery. In this review, we summarize the major findings of iPSC-based studies in frontotemporal dementia (FTD) and FTD overlapping with amyotrophic lateral sclerosis (FTD/ALS). We also discuss some of the main challenges in the use of iPSCs to model complex, late-onset neurodegenerative diseases such as dementias.

A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes.

BACKGROUND: Patients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). OBJECTIVE: To use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia. METHODS: A prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total τ (t-τ), phosphorylated τ (p-τ), ß-amyloid 1-42 (Aß42), neurofilament light chain (NFL), α-synuclein (α-syn), amyloid precursor protein soluble metabolites α and ß (soluble amyloid precursor protein (sAPP)α, sAPPß) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used. RESULTS: CSF NFL (p<0.001), sAPPα (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls. CONCLUSIONS: A panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies.

Evaluation of cerebrospinal fluid alpha-synuclein seed amplification assay in PSP and CBS.

Background: Seed amplification assay (SAA) testing has become an important biomarker in the diagnosis of alpha-synuclein related neurodegenerative disorders. Objectives: To assess the rate of alpha-synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), and analyse the clinical and pathological features of SAA positive and negative cases. Methods: 106 CSF samples from clinically diagnosed PSP (n=59), CBS (n=37) and indeterminate parkinsonism cases (n=10) were analysed using alpha-synuclein SAA. Results: Three cases (1 PSP, 2 CBS) were Multiple System Atrophy (MSA)-type SAA positive. 5/59 (8.5%) PSP cases were Parkinson's disease (PD)-type SAA positive, and these cases were older and had a shorter disease duration compared with SAA negative cases. In contrast, 9/35 (25.7%) CBS cases were PD-type SAA positive. Conclusions: Our results suggest that PD-type seeds can be detected in PSP and CBS using a CSF alpha-synuclein SAA, and in PSP this may impact on clinical course.

High level of ATP citrate lyase expression in human and rat pancreatic islets.

A comparison of an enzyme's level in pancreatic islets with its level in other body tissues can give clues about the importance of a metabolic pathway in the islets. ATP citrate lyase plays a key role in the pyruvate citrate shuttle, as well as for the synthesis of short chain acyl-CoAs and lipid, and its level in human and rat pancreatic islets relative to other tissues has not been previously reported. We compared the level of ATP citrate lyase mRNA and enzyme activity in pancreatic islets of humans and rats and the INS-1 832/13 cell line to levels in liver, a lipid synthesizing organ, and also kidney. The mRNA level was much higher in human islets and rat islets than in liver and kidney of the same genus and the enzyme activity was 8-fold and 12-fold higher in islets of humans and rats, respectively, compared to liver of the same genus. These data support other evidence that indicates ATP citrate lyase is important for the pyruvate citrate shuttle and lipid synthesis in insulin secretion.

Gamma delta T cell-induced nitric oxide production enhances resistance to mucosal candidiasis.

Despite the prevalence of gamma delta T cells in mucosae that are typically colonized by Candida albicans, little is known of the possible role of these cells in resistance to candidiasis. A sharp increase in the number of gamma delta T cells and macrophages following intraperitoneal inoculation of mice with C. albicans led us to examine the role of these cells in the immune response to C. albicans. We show that the gamma delta T cells enhance macrophage nitric oxide (NO) production and anti-candida activity, in vitro. We also propose that the gamma delta T cells regulate macrophage function during candidiasis in vivo as well, because depletion of these cells abrogated inducible NO synthase expression in mucosae and enhanced murine susceptibility to candidiasis.

Targeted gene disruption reveals an adhesin indispensable for pathogenicity of Blastomyces dermatitidis.

Systemic fungal infections are becoming more common and difficult to treat, yet the pathogenesis of these infectious diseases remains poorly understood. In many cases, pathogenicity can be attributed to the ability of the fungi to adhere to target tissues, but the lack of tractable genetic systems has limited progress in understanding and interfering with the offending fungal products. In Blastomyces dermatitidis, the agent of blastomycosis, a respiratory and disseminated mycosis of people and animals worldwide, expression of the putative adhesin encoded by the WI-1 gene was investigated as a possible virulence factor. DNA-mediated gene transfer was used to disrupt the WI-1 locus by allelic replacement, resulting in impaired binding and entry of yeasts into macrophages, loss of adherence to lung tissue, and abolishment of virulence in mice; each of these properties was fully restored after reconstitution of WI-1 by means of gene transfer. These findings establish the pivotal role of WI-1 in adherence and virulence of B. dermatitidis yeasts. To our knowledge, they offer the first example of a genetically proven virulence determinant among systemic dimorphic fungi, and underscore the value of reverse genetics for studies of pathogenesis in these organisms.

The role of torsinA in dystonia.

DYT1 dystonia is an autosomal-dominant movement disorder, characterised by early onset of involuntary sustained muscle contractions. It is caused by a 3-bp deletion in the DYT1 gene, which results in the deletion of a single glutamate residue in the C-terminus of the protein torsinA. TorsinA is a member of the AAA-ATPase family of; chaperones with multiple functions in the cell. There is no evidence of neurodegeneration in DYT1 dystonia, which suggests that mutant torsinA leads to functional neuronal abnormalities leading to dystonic movements. In the recent years, different functional roles have been attributed to torsinA, including being a component of the cytoskeleton and the nuclear envelope, and involvement in the secretory pathway and synaptic vesicle machinery. The aim of this review is to summarise these findings and the different models proposed, which have contributed to our current understanding of the function of torsinA.

Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra-familial variability in age of onset and complex phenotype.

Mutation of the atlastin gene (SPG3A) is responsible for approximately 10% of autosomal dominant hereditary spastic paraplegia (AD-HSP) cases. The goal of this study was to identify novel disease causing atlastin mutations. Atlastin nucleotide variations were detected by direct sequencing of all 14 exons in 70 autosomal dominant (AD), 16 single sibship and 14 sporadic spastic paraplegia patients. Six mis-sense mutations (four of which were novel) were identified in six unrelated AD-HSP kindreds in exons 4, 7 and 8 of the atlastin gene. One kindred with a novel mutation showed variability in clinical phenotype and age of onset. Mutations are predicted to decrease GTPase activity, cause morphological abnormalities of the endoplasmic reticulum and prevent maturation of the Golgi complex resulting in impaired vesicle trafficking. Our study significantly adds to the spectrum of mutations and clinical phenotype of SPG3A. We advocate that all spastin mutation negative AD-HSP kindreds should be screened for pathogenic atlastin mutations regardless of age of onset or phenotypic complexity.

Fluoride in seawater: measurement with lanthanum fluoride electrode.

Fluoride ion concentrations are quickly and easily determined in seawater by means of a fluoride-selective electrode. Samples require little pretreatment; a determination takes 15 minutes; error limits are 5 percent; equipment required is rugged, inexpensive, and motion-insensitive; and minimum demands are made on the operator.

Insulin secretion from pancreatic B cells caused by L-arginine-derived nitrogen oxides.

L-arginine causes insulin release from pancreatic B cells. Data from three model systems support the hypothesis that L-arginine-derived nitrogen oxides (NOs) mediate insulin release stimulated by L-arginine in the presence of D-glucose and by the hypoglycemic drug tolbutamide. The formation of NO in pancreatic B cells was detected both chemically and by the NO-induced accumulation of guanosine 3',5'-monophosphate. NG-substituted L-arginine analogs inhibited the release of both insulin and NO. Protein immunoblot and histochemical analysis with antiserum to type I NO synthase suggest that the formation of NO in pancreatic B cells is catalyzed by an NADPH- (reduced form of nicotinamide adenine dinucleotide phosphate), Ca2+/calmodulin-dependent type I NO synthase of about 150 kilodaltons.

Prevalence of nocturia and fecal and urinary incontinence and the association to childhood obesity: a study of 6803 Danish school children.

INTRODUCTION: Fecal and urinary incontinence are common disorders in children. Obesity and its associated comorbidities have become increasingly common, and a relation between obesity, nocturia, incontinence, and nocturnal enuresis has been suggested. OBJECTIVE: This large scale population study aims to determine the prevalence of fecal incontinence (FI), daytime urinary incontinence (DUI), nocturnal enuresis (NE), and nocturia in children at school entry and in adolescence and to clarify whether obesity is associated to any of the aforementioned symptoms. STUDY DESIGN: First-grade children and their parents and adolescents in the seventh to ninth grades were interviewed in relation to school nurse visits. The interview included questions on whether incontinence or nocturia were experienced at least once per month. The participants' age was recorded, and weight and height were measured. Body mass index (BMI) was calculated and age standardized by the use of BMI-standard deviation score (SDS), with reference to World Health Organization normative BMI data. Obesity was defined as BMI-SDS >2. Associations between obesity and incontinence and nocturia were quantified by odds ratio (OR). RESULTS: Completed interview questionnaires and measurements were obtained from 4002 children (95.1%) in the child population and 2801 adolescents (84.4%) in the adolescent population. The mean age of children was 6.45 ± 0.39 years, and 4.4% were obese. Overall 11.2% reported FI, 21.8% DUI, 16.8% NE, and 31.4% experienced nocturia. Obesity was associated with FI in first-grade boys (OR 1.86 compared with normal weight). Mean age of adolescents was 13.9 ± 0.85 years, and 7.6% of adolescent boys and 5.5% of the girls were obese. Fecal incontinence was reported by 2.1% of the adolescents, 4.5% had DUI, 1.0% stated to have NE, and 32.3% reported nocturia. Obesity was significantly associated with nocturia in adolescents (OR 1.74-2.01). DISCUSSION: The prevalence of nocturia seems constant throughout childhood and adolescent life; this has not previously been documented. Incontinence is very common at school entry, with DUI reported more frequently than enuresis by both children and adolescents. Obesity is associated with nocturia in adolescents and FI in first-grade boys, but no significant association between obesity and NE or DUI is found. Strength of this study is the very high participation rates, but the study does not reveal information on previous treatment, subtype, or severity of symptoms. CONCLUSIONS: Incontinence is very common in children. One-third of both children and adolescents experience nocturia. Obesity is associated with FI in first-grade boys and nocturia in adolescents.

Platelet responses to pharmacological and physiological interventions in middle-aged men with different habitual physical activity levels.

The current guidelines following an acute coronary syndrome recommend dual-antiplatelet therapy (DAPT) (aspirin plus a P2Y12 antagonist) alongside lifestyle modifications, including more regular physical activity. It is currently unknown whether regular exercise affects the pharmacology of DAPT. AIM: To explore how exercise-induced improvements in vascular and platelet function affect the efficacy of DAPT, in a cross-sectional study of men with different physical activity levels (training status). METHODS: A total of 42 healthy, normal-weight, middle-aged men were divided into 3 groups: untrained, moderately trained and well-trained. Their platelet reactivity (agonist-induced % aggregation) was investigated in platelet-rich plasma at rest and after inhibition with aspirin and ticagrelor and/or prostacyclin and nitric oxide added to the blood in vitro, and after physiological tests of vascular function; passive movement of the leg, flow-mediated dilation and one-leg knee-extensor exercise. Vascular function of the femoral artery (changes in arterial blood flow) was assessed by ultrasound Doppler. RESULTS: Platelets from the well-trained subjects had lower basal reactivity, a higher sensitivity to the anti-aggregatory effects of prostacyclin and were more potently inhibited by DAPT compared to the untrained subjects. The moderately trained and well-trained subjects had a superior vascular function compared to untrained subjects, and their platelets were more inhibited by the passive movement, flow-mediated dilation and one-leg knee-extensor exercise. DISCUSSION: A habitually active lifestyle leads to an increased platelet sensitivity to pharmacological and physiological platelet inhibitors. We suggest that physical activity habits (training status) should be considered when personalizing and optimizing antithrombotic treatment strategies.

Catecholaminergic neurons in medullary nuclei are among the post-synaptic targets of descending projections from infralimbic area 25 of the rat medial prefrontal cortex.

The infralimbic (IL) 'visceromotor' area of the rat medial prefrontal cortex projects to strategic subcortical nuclei involved in autonomic functions. Central among these targets are the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (rVLM). By combining tract-tracing using the anterograde tracer biotinylated dextran amine (BDA) with immunolabeling for tyrosine hydroxylase (TH; an enzyme marker of catecholaminergic neurons), a limited proportion of BDA-labeled IL axonal boutons in the NTS and rVLM was found to be closely associated with TH immunopositive (+) target structures. Such structural appositions were mainly located proximally over the labeled dendritic arbors of identified TH+ neurons. Quantitative ultrastructural examination revealed that in NTS, TH+ dendritic shafts comprised 7.0% of the overall post-synaptic target population innervated by BDA-labeled IL boutons, whereas TH+ dendritic spines represented 1.25% of targets. In rVLM, TH+ shafts represented 9.0% and TH+ spines 2.5% of IL targets. Labeled IL boutons established exclusively asymmetric Gray Type 1 (presumed excitatory) synaptic junctions. The results indicate that subpopulations of catecholaminergic neurons in the NTS and rVLM are among the spectrum of post-synaptic neurons monosynaptically innervated by descending 'excitatory' input from IL cortex. Such connectivity, albeit restricted, identifies the potential direct influence of IL cortex on the processing and distribution of cardiovascular, respiratory and related autonomic information by catecholaminergic neurons in the NTS and VLM of the rat.

18F-labeled resin microspheres as surrogates for 90Y resin microspheres used in the treatment of hepatic tumors: a radiolabeling and PET validation study.

(90)Y-labeled resin microspheres (SIR-Spheres) are currently used to treat patients with primary and metastatic solid liver tumors. This treatment is typically palliative since patients have exhausted all other standard treatment options. Improving the quality of life and extending patient survival are typical benchmarks for tracking patient response. However, the current method for predicting microsphere biodistributions with (99m)Tc-labeled macroaggregated albumin (MAA) does not correlate well with patient response. This work presents the development of a new (18)F-labeled resin microsphere to serve as a surrogate for the treatment microsphere and to employ the superior resolution and sensitivity of positron emission tomography (PET). The (18)F microsphere biodistributions were determined in a rabbit using PET imaging and histological review. The PET-based uptake ratio was shown to agree with the histological findings to better than 3%. In addition, the radiolabeling process was shown to be rapid, efficient and relatively stable in vivo.

Why Neighborhoods (and How We Study Them) Matter for Adolescent Development.

Adolescence is a sensitive developmental period marked by significant changes that unfold across multiple contexts. As a central context of development, neighborhoods capture-in both physical and social space-the stratification of life chances and differential distribution of resources and risks. For some youth, neighborhoods are springboards to opportunities; for others, they are snares that constrain progress and limit the ability to avoid risks. Despite abundant research on "neighborhood effects," scant attention has been paid to how neighborhoods are a product of social stratification forces that operate simultaneously to affect human development. Neighborhoods in the United States are the manifestation of three intersecting social structural cleavages: race/ethnicity, socioeconomic class, and geography. Many opportunities are allocated or denied along these three cleavages. To capture these joint processes, we advocate a "neighborhood-centered" approach to study the effects of neighborhoods on adolescent development. Using nationally representative data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we demonstrate the complex ways that these three cleavages shape specific neighborhood contexts and can result in stark differences in well-being. A neighborhood-centered approach demands more rigorous and sensitive theories of place, as well as multidimensional classification and measures. We discuss an agenda to advance the state of theories and research, drawing explicit attention to the stratifying forces that bring about distinct neighborhood types that shape developmental trajectories during adolescence and beyond.