Biography:

Solveig Niklass has her expertise in basic research in the field of cerebral small vessel disease (CSVD) as a cause of acute strokes. She established the 2-photon-microscopy in spontaneously hypertensive stroke prone rats as a tool for intravital imaging of the cerebral vasculature. New dyes for in vivo imaging allow for the simultaneous detection of CSVD and cerebral amyloid pathology, defining the focus of her actual research. 

Abstract:

Statement of the Problem: In human autopsy studies of the non-demented elderly and Alzheimer’s disease non-amyloid cerebral small vessel pathology (CSVD) and cerebral amyloid angiopathy (CAA) are found in the same brain. We here hypothesize a causal link between the two CSVD entities that goes beyond just a simple co-occurrence. We therefore investigated if spontaneously hypertensive stroke-prone rats (SHRSP), a valid non-transgenic animal model of human non-amyloid CSVD, develop CAA as a function of different non-amyloid CSVD stages.

Methodology: Two-photon-microscopy was performed in 21 SHSRP to assess stages of CSVD in vivo. Therefore, the fluorescent dye Dextran was used to label the cerebral vasculature, and cerebral blood flow measures (CBF) were additionally conducted. Furthermore, in 13 out of those 21 SHRSP Methoxy-X04 (Congo red derivate) was used for the intravital CAA detection.

Findings: Non-amyloid CSVD progression occurs in a temporal manner, comprising the following stages: stage 0 – no CSVD pathology, stage 1A – small vessel wall damage, stage 1B – CBF reduction, stage 2 – non-occlusive/ incomplete thrombus formation and stage 3 – occlusive/ complete thrombus formation. Six out of 13 SHRSP (46%) that underwent Methoxy-X04 imaging displayed intravital β-amyloid positivity of the cerebral small vessel walls, i.e. perivascular amyloid deposits and brightly fluorescent arteriolar/small artery wall adherent plane- or circular-shaped amyloid accumulations indicative of CAA. In nearly all Methoxy positive SHRSP amyloid deposits were detected surround thrombotic arterioles characterized by (in)complete small vessel occlusions (CSVD stage 2/3).

Conclusion & Significance: Advanced non-amyloid CSVD stages display a condition prone to vascular β-amyloid accumulations, in terms of CAA. Further investigations have to shed light on the pathophysiological interactions between the two small vessel disease entities, especially whether a failure of perivascular Aβ-drainage or disturbances of endothelial Aβ-transport across the blood brain barrier drives the vascular amyloid pathology found in the SHRSP. 

Biography:

Fan Fan is an Assistant Professor at University of Mississippi Medical Center, USA. Her research focuses on the genetic basis of the impaired myogenic response and auto-regulation of cerebral and renal blood flow and end organ damage in aging, hypertension and diabetes. She has published more than 30 papers. She currently serves as a Peer Reviewer for the American Heart and Alzheimer’s Associations, and is an Editorial Board Member and reviewer for several journals. Her work is funded by the National Institutes of Health (NIH) and the American Heart Association (AHA) to study roles of Add3 (NIH/NIA, NIH/NIDDK), CYP4A1 and 20-HETE (NIH/NIGMS, AHA) on aging and hypertension-related renal and cerebral vascular and dementia.

Abstract:

Alzheimer's disease (AD) and diabetes (DM) are two of the most common diseases of aging. More than five million Americans have AD, and 29 million Americans have DM. The cumulative incidence of AD is 12.5% and DM is 26.9% among people 65 and older in the US. Evidence suggests that DM is linked with the development of AD, and these diseases are associated with cerebral vascular dysfunction. However, the mechanisms involved have not been fully elucidated. The present studies examine whether the myogenic response of middle cerebral artery (MCA) and auto-regulation of cerebral blood flow (CBF) are impaired in the T2DN rat, a type 2 diabetic (T2DM) strain, and whether these impairments contribute to the development of dementia and AD. Our data indicate that the myogenic response of MCA and auto-regulation of CBF are impaired in T2DN rats with aging. This cerebral vascular dysfunction is in association with blood-brain barrier (BBB) leakage, neurodegeneration and learning and memory dysfunction. Our results also demonstrate that the neurodegeneration in elderly T2DN rats is associated with elevated expression of beta-amyloid (Aβ) and Tau in the brain, suggesting these diabetic rats expresses the characteristic biomarkers of AD. The expression of GFAP and IL-1β is elevated in aged T2DN rats indicating that glial activation and inflammation may link aging, diabetes and cognitive deficits in this model. In summary, our studies suggest that the impaired auto-regulation of CBF plays an important role for the development of cognitive dysfunction and AD, and present information critical to the development of new treatments to prevent elder and DM- related dementia including AD.

Biography:

Dr. Ramel Carlos is a practicing neurologist in the Island of Guam for the past 15 years. He completed his residency and fellowship training in Pediatrics, Child Neurology, Epilepsy, and Clinical Neurophysiology at Wake Forest University Baptist Medical Center I n Winston Salem, N.C. He is a diplomate of American Board of Psychiatry and Neurology. He has presented his various clinical researches internationally regarding neurodegenerative diseases including Dementia and Parkinson disease and its association with various vascular diseases. His research on “Silent Strokes and Vascular Diseases in Cognitive Impairment in the island of Guam was awarded the Best Poster Research Presentation in London last March 2016 during the World Congress of Neurology and Therapeutics. He has published 3 books, entitled Essentials of Stroke and Heart Disease, Basic Brain Boosters, and 101 Inspirational Quotes on Health. He obtained his medical.                                                            

Abstract:

Emerging evidence suggested a link between Obstructive Sleep Apnea (OSA) and cognitive decline, including dementia. The severity of cognitive impairment has been reported to be directly correlated with the degree of OSA. Neurodegenerative changes and vascular diseases are significant comorbidities on these patients.  We report the occurrence of OSA in patients with dementia in the Island of Guam and to correlate the severity of OSA with the results of the neuropsychological testing and neuroimaging studies. We also report the prevalence of comorbid vascular diseases in these patients. A retrospective analysis of medical records of patients evaluated in The Neurology Clinic with the diagnosis of OSA and dementia from August 2006 to June 2016 was conducted. There were 359 patients with dementia and 17% have been diagnosed with OSA.  Among patients with OSA, 45% have moderate to severe OSA with moderate degree of cerebral atrophy on the neuroimaging studies and 17% have mild OSA with mild degree of cerebral atrophy. Seventeen percent of patients with moderate to severe OSA have moderate impairment on global cognitive scores and 17% with mild OSA have mild impairment on global cognitive scores. Twenty five percent of patients with moderate to severe OSA have stroke and 17% have Leukoaraiosis in the neuroimaging studies. The prevalence of vascular diseases on patients with moderate to severe dementia showed that  75%, 58%, 66% and 33% of patients have hypertension, diabetes mellitus, hyperlipidemia and heart diseases, respectively, Wherein patients with mild dementia,  hypertension, diabetes mellitus, hyperlipidemia and heart diseases were identified on 70%, 54%, 60% and 30% of patients, respectively. Conclusion: OSA is a common sleep disturbance in patients with dementia. The severity of OSA correlates closely with the degree of cerebral atrophy and global cognitive scores. Various comorbid vascular diseases are frequently encountered in patients with OSA and dementia. 

Biography:

Prof. Boon Chuan LOW is a Principal Investigator at the Mechanobiology Institute and Department of Biological Sciences, National University of Singapore. His group focuses on defining cellular and molecular mechanisms underlying neuronal differentiation and cancer metastasis. His discovery on the BCH domain as a versatile protein scaffold has led to our better understanding of the intricate spatiotemporal    regulation    of    GTPases,    kinases    and metabolic signaling in cell morphogenesis, cell motility, cell growth and differentiation. His work also extends to BCH and other scaffold proteins that can integrate both biochemical and mechanical signals in cell-cell and cell- matrix interaction, leading to tissue organization and organogenesis.

Abstract:

The neurotransmitter acetylcholine (ACh) is essential for neuron development, memory, learning and motor movement. It is synthesized from choline and acetyl-CoA by choline acetyltransferase (ChAT). ATP citrate lyase (ACL) is a key metabolic enzyme that produces the acetyl-CoA for this process. However, the precise spatial disposition of this cholinergic machinery for both morphogenesis and neurotransmission remain largely unknown.

Mutations in the ATCAY/Atcay gene, which encodes a BCH domain- containing BNIP-H (also known as Caytaxin), lead to ataxia and mental retardation in humans (Cayman ataxia), as well as ataxia and dystonia in several rodent models. Recently, we used molecular genetics, biochemical and imaging methods and revealed that BNIP-H recruits the cholinergic machinery to neurite terminal to regulate cholinergic signaling (Developmental Cell, 2015). BNIP-H links kinesin-1 (KLC1) motor protein to ACL and transports ACL towards neurite terminal. There, the BNIP-H/ACL complex synergistically recruits ChAT, leading to enhanced secretion of ACh. ACh then activates MAPK/ERK via muscarinic receptors to promote neuritogenesis. In mice deficient in BNIP-H, ACL fails to interact with KLC1, and formation of the ACL/ChAT complex is prevented. Significantly, Bnip-h knockdown in zebrafish causes axon defect of motor neuron through impaired cholinergic pathway, leading to motor disorder. Here, we further show that BNIP-H specifically engages Rab11 GTPases and a component of the actin-based exocyst complex to regulate its dynamic disposition and neurologic function.

In conclusion, BNIP-H promotes cholinergic signaling by trafficking ACL to neurite end, where ChAT is subsequently recruited to regulate the local production of ACh. Our results provide the first molecular evidence that precise spatial regulation of the cholinergic machinery is crucial in neuronal differentiation and neurotransmission, the significance of which will be further discussed.

Biography:

Abstract:

Testicular torsion/detorsion (T/D) can  induce depression in pre- and post-pubertal patients. This study was conducted to investigate the psychological impact of testicular torsion and mechanism underlying its depressive-like behaviour, as well as antidepressant-like activity of minocycline and possible involvement of nitric oxide (NO)/cyclic GMP pathway in this paradigm in male rats undergoing testicular T/D. Unilateral T/D was performed in 36 male adult Wistar rats, and different doses of minocycline were injected alone or combined with Nx-nitro-L-arginine methyl ester (L-NAME), non-specific NO synthase (NOS)inhibitor; aminoguanidine (AG), specific inducible NOS inhibitor;L-arginine, an NO precursor; and selective PDE5I, sildenafil. After assessment of locomotor activity in open-field test, immobility times were recorded in the forced swimming test (FST). Moreover, 30 days after testicular T/D, testicular venous testosterone and serum nitrite concentrations were measured. A correlation was observed between either a decrease in plasma testosterone or an increase in serum nitrite concentrations with prolongation in immobility time in the testicular T/D-operated rats FST. Minocycline (160 mg/kg) exerted  the highest significant antidepressant-like effect in the operated rats in the FST (p<0.001). Furthermore,   combination   of  subeffective doses of minocycline (80 mg/kg) and either L-NAME (10 mg/kg) or AG (50 mg/kg) demonstrated a significant robust antidepressant-like activity in T/D group (p<0.01). Consequently, NO/cGMP pathway was involved in testicular T/D-induced depressive-like behavior and antidepressant- like activity of minocycline in the animal model. Moreover, a contribution was observed between either decreased testosterone or elevated serum nitrite levels and depressive-like behaviour following testicular T/D.

Biography:

Abstract:

Evidence show that gamma-aminobutyric acid (GABA) receptors are involved in depression, so the aim of this study was to investigate the effect of nitrazepam as agonist of GABAA receptors on depression and curiosity in male mice and the role of potassium channel in antidepressant-like response. For this purpose, we studied the antidepressant-like properties of fluoxetine, nitrazepam, glibenclamide, and cromakalim by both forced swimming test (FST) and tail suspension test (TST). Animals were injected by various doses of nitrazepam (0.05, 0.1, and 0.5 mg/kg). Nitrazepam at dose of 0.5 mg/kg significantly  decreased the immobility time compared to control group in both FST and TST. Fluoxetine also showed such a response. Co-administration of nitrazepam (0.05 mg/kg) with glibenclamide in TST (1 mg/kg) and in FST (0.3, 1 mg/kg) also showed antidepressant- like response. Beside, cromakalim (0.1 mg/kg) could reverse the antidepressant-like effect of nitrazepam (0.5 mg/kg) in both  FST    and    TST,    while    cromakalim   and glibenclamide alone could not change the immobility time compared to control group (P40.05). The hole-board test revealed that nitrazepam at doses of 0.5 and 0.1  mg/kg could increase the activity of the animal’s head-dipping and boost the curiosity and  exploration  behavior  of mice.

The results of this study revealed that nitrazepam may possess antidepressant-like properties and this effect is dependent to potassium channels in   both FST and TST.

Biography:

Abstract:

Cirrhosis is associated with cardiac chronotropic and inotropic dysfunction which is known as cirrhotic cardiomyopathy. Cardiac responsiveness to adrenergic stimulation is impaired in cirrhosis. Moreover there is vagal nerve dysfunction which is related to neuromodulatory dysfunction of the angiotensin II in the cirrhosis. This study was aimed to explore the hypothesis that administration of Losartan-angiotensin II receptor antagonist- increases cadiac chronotropic response to isoproterenol in cirrhotic rats; and if so, whether this is associated with altered cardiac TGF-β receptor expression. Cirrhosis was induced by surgical ligation of the bile duct (BDL) in male Wister rats. Half of the BDL-group and control group were treated with losartan for four weeks. Four weeks after bile duct ligation or sham surgery the atria were isolated and spontaneously beating rate and chronotropic responsiveness to β-adrenergic stimulation was assessed using standard organ bath. Pathological assessment was done on the atria. Moreover the expression of TGF-β was assessed the atria using quantitative RT-PCR. Bile duct ligation could induce a significant hypo-responsiveness to adrenergic stimulation. In cirrhotic rats, the chronotropic responses increased after chronic treatment with losartan but it was not significant. Pathological study showed that losartan decreases fibrosis in atria in losartan treated cirrhotic group. TGF-β expression is markedly increased in cirrhotic rats which is significantly decreased in atria following administration  of  losartan.  These  results  might be considered as angiotensin II role in cirrhotic cardiomyopathy but further studies are required to elaborate the mechanism as well as possible advantage of losartan. We conclude that cirrhosis in rats is associated with altered expression of TGF-β in atrium which losartan can ameliorate it.