MRI temporal lobe hyperintensities: A new imaging finding in Fabry disease?

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Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320

Demonstration of F-18 FDG PET protocol for imaging neuronal activation: Human motor cortex activation using F-18 FDG PET

Diffusion tensor imaging demonstrates fiber impairment in Susac's syndrome

S. Kima, K.W. Parkb, S.P. Pyunc, Y.M. Hwangd, K. Namd, J.S. Yeoe, J.G. Choea Department of Nuclear Medicine, Korea University Hospital, Seoul, South Korea b Department of Neurology, Korea University Hospital, Seoul, South Korea c Department of Physical Medicine and Rehabilitation, Korea University Hospital, Seoul, South Korea d Department of Psychology, Korea University College of Liberal Arts, Seoul, South Korea e Department of Nuclear Medicine, Doung University Hospital, Goyang-Si, Gyeonggi-do, South Korea

I. Kleffnera, M. Deppea, S. Mohammadia, H. Schiffbauerb, N. Stuppc, H. Lohmanna, P. Younga, E.B. Ringelsteina a Department of Neurology, University of Muenster, Germany, Muenster, Germany b Department of Clinical Radiology, University of Muenster, Muenster, Germany c Department of Ophthalmology, University of Muenster, Muenster, Germany

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Aims: This study was to demonstrate the human motor cortex activation using F-18 FDG PET (FDG-PET) and to develop the FDG-PET protocol for imaging neuronal activation. Methods: A volunteer performed a rest and activation FDG-PET for 20 min). The motor task (grasp and release right hand) during 20 min. The subtraction of resting from activation PET image performed using a SISCOM method. Result: The subtracted image demonstrated the activation of the contralateral (left) motor cortex. Conclusion: We successfully demonstrated increased human motor cortex activity in a subject performing a motor task using the FDG-PET. doi:10.1016/j.jns.2009.02.060

Improving validity of TCD autoregulation assessment in vascular dementia by constant infusion of levovist N. Thoelena, N.R. Loesela, C. Lienerthb, M. Gonzaleza, M. Humpicha, W. Rolza, F. Dvoraka, M. Sitzera, M.W. Lorenza a Department of Neurology, Johann Wolfgang Goethe-University, Frankfurt, Main, Germany b Brain Imaging Center, Johann Wolfgang Goethe-University, Frankfurt, Main, Germany Background and aims: Cerebral autoregulation is an important concept in the pathophysiology of vascular dementia. It can be assessed quickly and non-invasively using Transcranial Doppler Sonography (TCD). The investigation of patients with vascular dementia is limited by the quality of the transtemporal bone window, which is often compromised in the elderly. A poor insonation window decreases the number of examinable patients, and can cause considerable systematic bias in autoregulation parameters. The ultrasound contrast agent galactose (Levovist®) can improve the insonation quality in transcranial ultrasound. Aim of this study was to investigate whether a constant infusion of galactose counteracts the detrimental effects of a poor bone window in the assessment of cerebral autoregulation. Methods: We examined 45 neurological patients with good insonation quality. To imitate a poor bone window we utilized a model to artificially worsen the insonation quality, by inserting a thin aluminum foil between the TCD probe and the patient's skin. We determined two parameters of cerebral autoregulation (Phase Difference [PD] and Cross Correlation Coefficient [Mx]) measured natively, with aluminum foil and with aluminum foil and a constant galactose infusion at 300 mg/min. Results: The aluminum foil model realistically simulated poor insonation conditions producing a decrease in the mean spectrum energy from 33.9 ± 2.7 dB to 26.3 ± 2.4 dB (p < 0.001). This produced a significant bias to all autoregulation parameters (PD from 38.2 ± 10.0° to 27.9 ± 12.5°, p < 0.001, Mx from 0.308 ± 0.170 to 0.254 ± 0.162, p < 0.01). A constant infusion of galactose largely compensated these effects (mean spectrum energy from 26.3±2.4 dB to 33.0±4.2 dB, p<0.001, PD from 27.9±12.5 to 37.2±12.3, p<0.001, Mx from 0.254±0.162 to 0.323±0.163, p<0.01). Conclusions: In the assessment of cerebral autoregulation, a constant infusion of galactose (Levovist®) can counteract the systematic bias created by poor insonation conditions. Using an ultrasound contrast agent improves the credibility of TCD autoregulation assessment in vascular dementia and in elderly patients in general. doi:10.1016/j.jns.2009.02.061

Background: Susac's syndrome is characterized by the triad of hearing loss, branch retinal artery occlusions, and encephalopathy with predominantly cognitive and psychiatric symptoms. Focal ischemic lesions in the corpus callosum detectable by conventional magnetic resonance imaging (MRI) are a characteristic feature of Susac's syndrome. They do not, however, explain the type and severity of the neuropsychological deficits. Objective: In this study, we tested the hypothesis that widespread tissue damage of the otherwise normal-appearing white matter (NAWM) can be detected in Susac's syndrome when using diffusion tensor imaging (DTI). Methods: Three-dimensional fractional anisotropy (FA) maps were calculated from DTI data of four patients with Susac's syndrome and a group of 63 matched healthy controls. Results: Voxel-based statistics of spatially normalized FA maps revealed highly significant widespread impairment of fiber integrity in all patients. Lesions were particularly located in the genu of the corpus callosum and in the frontotemporal connecting fascicles. Patients showed specifically reduced mean FA values in a region of interest containing the genu. This was true even if the genu appeared normally on conventional MRI. Conclusion: We conclude that DTI is much more sensitive than conventional MRI in demonstrating white matter abnormalities in Susac's syndrome. FA reductions in NAWM of the genu of the corpus callosum seem to be disease-specific. Psychiatric symptoms and cognitive deficits of these patients are most likely caused by the impairment of anatomical connectivity of the frontal lobes. doi:10.1016/j.jns.2009.02.062

MRI temporal lobe hyperintensities: A new imaging finding in Fabry disease? M. Mendioroza, I. Gastonb, I. Mendezc, I. Jericob, F. Garcia-Bragadod, I. Fernandez-Cadenasa, J. Montanera a Neurovascular Research Laboratory, Hospital Vall D'Hebron, Barcelona, Spain b Neurology Department, Hospital Virgen Del Camino, Pamplona, Spain c Internal Medicine Department, Hospital De Navarra, Pamplona, Spain d Pathological Anatomy Department, Hospital Virgen Del Camino, Pamplona, Spain Background and Aims: Fabry disease (FD) is an X-linked recessive lysosomal storage disorder resulting from the deficiency of alpha-galactosidase, which causes a systemic small vessel disease. Our aim is to report a case of FD with hyperintensities in both temporal lobe poles, which has not been previously described in this disease. Patients and methods: A 47-year-old man presented with recurrent transient neurological deficits secondary to multifocal small vessel disease. He had none of the classical vascular risk factors, except for a hypertrophic myocardiopathy. Moreover, he related a 36-year-history of neuropathic pain crisis and chronic acroparesthesias in all four limbs. On physical examination, neither skin lesions nor corneal lesions were identified. Surprisingly, cranial MRI revealed bilateral temporal lobe poles hyperintensities as well as deep white matter hyperintensities, resembling those usually found in CADASIL. Nevertheless, there were neither clinical nor familiar data suggestive of CADASIL, excluding early stroke. Ten months later, after developing severe kidney failure he underwent a renal biopsy which suggested FD. Finally, a decreased activity of plasma alpha-galactosidase A enzyme confirmed that diagnosis. Results: Up to now, recognized brain MRI abnormalities in FD include those related to infarction and hemorrhage, non-specific white and grey matter lesions, basilar dolicho-ectasia, and a characteristic appearance of hyperintensities in the lateral pulvinar on T1-weighted images. On the other hand, MRI temporal pole involvement has been previously described as a useful marker in CADASIL diagnosis and it has been demonstrated to have 89% sensitivity and 86%

Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320

specificity for that diagnosis. In addition, this kind of lesions can be found in other disorders, such as myotonic dystrophy. Conclusion: For the first time, we describe these lesions in FD, and propose considering FD in the differential diagnosis of MRI temporal pole hyperintensities, especially when hereditary neurological vascular diseases are suspected.

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Conclusion: The PON1 −107 TT genotype, associated with AD, determines a reduced concentration of serum PON1 enzyme, thus resulting in a decreased protective anti-oxidant activity towards circulating LDL and increased small-dense and oxidized LDL cholesterol. doi:10.1016/j.jns.2009.02.065

doi:10.1016/j.jns.2009.02.063 Vascular endothelial growth factor gene variability is associated with increased risk for AD Vascular risk factors in Alzheimer's disease: The lesson learned A.D. Korczyn Sieratzki Professor of Neurology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel Epidemiological data have demonstrated that risk factors for vascular disease in general, and for stroke in particular, are largely identical to those of Alzheimer's disease (AD). Thus, smoking, obesity, hypertension, diabetes mellitus and elevated serum levels of cholesterol and homocysteine contribute to the occurrence of both diseases. The brain of elderly people accumulates amyloid, neurofibrillary tangles, as well as vascular lesions, large and small, cortical and deep. Blood vessels may manifest lipohyalinosis which result in leucoaraiosis. Cognitive decline in old age results from this cumulative burden. The clinical distinction between vascular dementia and AD is clinically impossible in most cases, is confusing and counterproductive. Most elderly patients with dementia do not have a monolithic pathologic disorder (e.g. AD or vascular dementia) but rather a combination of both. This overlap is supported by imaging evidence as well as by neurochemical markers. Unfortunately, mixed dementia, the most common cause of dementia, is not yet defined clinically or pathologically. Public health measures should be taken to lower the impact of the risk factors responsible for these diseases. Attention to these risk factors by drugs and lifestyle is important in reducing the incidence and prevalence of dementia. doi:10.1016/j.jns.2009.02.064

Genetic association of paraoxonase 1 polymorphisms with Alzheimer's disease A. Cagnina, A. Zambonb, V. Lunardellia, G. Zarantonelloa, A. Leonc, L. Battistina,d Department of Neurological Sciences , University of Padova, Padova, Italy b Internal Medicine, University of Padova, Padova, Italy c Research and Innovation, Padova, Italy d I.R.C.S.S. Ospedale San Camillo, Venice, Italy

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Background: Paraoxonase 1 (PON1) is an esterase residing on the surface of circulating high density lipoproteins and exerts antioxidant effects on low density lipoproteins (LDL). Common PON1 polymorphisms have been recently found associated with Alzheimer's disease (AD). Objective: (a) To study the association between PON1 polymorphisms and AD, (b) to investigate the effect of these polymorphisms on the serum lipid profile, and (c) to explore the possible interaction between PON1 polymorphisms and APOE genotype. Methods: We studied 96 AD patients without concomitant cerebrovascular lesions and 78 healthy controls without both dementia and cerebrovascular disease. Each subject was evaluated with neurological and neuropsychological examinations, biochemical screening and brain CT/MRI scans. The Wahlund's Age-Related White Matter Changes scale applied to the individual's CT/MRI brain scan was used to confirm that vascular lesion load was minimal or absent. Serum concentrations of lipoproteins were measured by using a density-gradient ultracentrifugation method. PON1 polymorphisms (−107C/T and 192Q/R) and APOE ?4 genotypes were analyzed. Results: The TT genotype at position −107 in the promoter region of PON1 was significantly associated with AD (p = 0.03). AD patients carrying the −107 TT genotype have increased levels of serum small-dense LDL with respect to those carrying the CT or CC genotypes (p = 0.01). The distribution of APOE epsilon 4 genotypes was significantly different among AD patients and controls (p < 0.001) but logistic regression model showed that APOE genotype and serum level of small-dense LDL were independent variable associated with AD.

R. Del Bo, S. Ghezzi, E. Scarpini, N. Bresolin, G.P. Comi Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, Milan, Italy Genetically, Alzheimer's disease (AD) is a heterogeneous disorder with both familial and sporadic forms. Mutations in APP, PS1 and PS2 genes account for relatively rare early-onset autosomal dominant forms of AD; by contrast, the genetics of the common late-onset sporadic form is far more complex and several determinants have been proposed as playing a causative role. Converging evidence points to a pivotal role for Vascular Endothelial Growth Factor (VEGF) in neuronal protection and a lack of its activity in neurodegenerative disorders. VEGF is a cytokine involved in neuronal survival, neuroprotection, regeneration, growth, differentiation and axonal outgrowth. An impaired regulation of VEGF expression has been reported in AD pathogenesis. The human VEGF gene is highly polymorphic, with at least 25 different polymorphisms organized into haplotypes. Promoter variations in the VEGF gene are of particular interest: VEGF variability has been associated with increased risk of developing a wide variety of disorders from diabetes to neurodegenerative diseases suggesting functions not confined to its vascular effects, originally described. VEGF gene variability has been inserted among the genetic factors influencing the lifespan. We demonstrated that VEGF-2578AA genotype was associated with an increased risk for the disease in 249 Italian subjects with sporadic AD; the risk was significantly increased with respect to various VEGF genotype/ haplotype combinations. Conversely, two independent investigations failed to find a positive association between VEGF variability and greater risk for AD. Recently, the VEGF-2578AA genotype was associated with an accelerated cognitive decline in APOEe4 positive Italian AD patients; the same genotype was a risk factor for mild cognitive impairment (MCI) and for MCI conversion to AD in APOEe4+ patients. Overall, polymorphisms within VEGF gene promoter might confer greater risk for AD at least in Italian population; these findings add a new risk factor to the multifactorial genetic contribution of AD pathogenesis. doi:10.1016/j.jns.2009.02.066

Cholesterol and statins in dementia: To be or not to be relevant? P. Riederer, S. Hoyer Department of Neurochemistry, Clinic and Policlinic of Psychiatry and Psychotherapy, Wuerzburg, Bavaria, Germany Cerebral cholesterol (CH) is based almost exclusively by in situ biosynthesis in an energy dependent process. Its metabolite 24S-Hydroxycholesterin can be detected in the CSF. CH is found mainly in the caveolae of membranes, which also contain insulin receptors, insulin receptorsubstrate-1 and protein kinases, all being necessary requisites for signal transduction. CH is important for the stability and fluidity of membranes but also in the build up of synapses. Age-dependent loss of acetyl-CoA leads to reduced synthesis of intracellular CH, which is further enhanced by increased membranal CH-turnover. Reduced CSF-CH and increase in CSF-24-S-hydroxy-CH reflects this fact. This process is even pronounced in Alzheimer's disease (AD). Lipophile lovastatin and simvastatin pass the blood-brain barrier and reduce free CH. This effect is directly correlated to facilitation of ĩau-hyperphosphorylation. In addition βA4 is able to destroy cell membranal fluidity. And APO-E4 facilitates CH in the exofacial membrane. Therefore, there is an age-dependent and AD pronounced change in the ratio of cytofacial and exofacial CH in favor of the latter.