Achievement of Therapeutic Goals Over 2 Years of Velaglucerase Alfa Enzyme Replacement Therapy in Patients with Type 1 Gaucher Disease (original) (raw)
American Journal of Neuroradiology, 2007
BACKGROUND AND PURPOSE: Late infantile neuronal ceroid lipofuscinosis (LINCL), a form of Batten disease, is a fatal neurodegenerative genetic disorder, diagnosed via DNA testing, that affects approximately 200 children in the United States at any one time. This study was conducted to evaluate whether quantitative data derived by diffusion-weighted MR imaging (DWI) techniques can supplement clinical disability scale information to provide a quantitative estimate of neurodegeneration, as well as disease progression and severity.
Magnetic resonance brain volumetry biomarkers of CLN2 Batten disease identified with miniswine model
Scientific Reports, 2023
Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease (Batten disease) is a rare pediatric disease, with symptom development leading to clinical diagnosis. Early diagnosis and effective tracking of disease progression are required for treatment. We hypothesize that brain volumetry is valuable in identifying CLN2 disease at an early stage and tracking disease progression in a genetically modified miniswine model. CLN2 R208X/R208X miniswine and wild type controls were evaluated at 12-and 17-months of age, correlating to early and late stages of disease progression. Magnetic resonance imaging (MRI) T1-and T2-weighted data were acquired. Total intercranial, gray matter, cerebrospinal fluid, white matter, caudate, putamen, and ventricle volumes were calculated and expressed as proportions of the intracranial volume. The brain regions were compared between timepoints and cohorts using Gardner-Altman plots, mean differences, and confidence intervals. At an early stage of disease, the total intracranial volume (− 9.06 cm 3), gray matter (− 4.37% 95 CI − 7.41; − 1.83), caudate (− 0.16%, 95 CI − 0.24; − 0.08) and putamen (− 0.11% 95 CI − 0.23; − 0.02) were all notably smaller in CLN2 R208X/R208X miniswines versus WT, while cerebrospinal fluid was larger (+ 3.42%, 95 CI 2.54; 6.18). As the disease progressed to a later stage, the difference between the gray matter (− 8.27%, 95 CI − 10.1; − 5.56) and cerebrospinal fluid (+ 6.88%, 95 CI 4.31; 8.51) continued to become more pronounced, while others remained stable. MRI brain volumetry in this miniswine model of CLN2 disease is sensitive to early disease detection and longitudinal change monitoring, providing a valuable tool for pre-clinical treatment development and evaluation. Abbreviations CLN2 Late-infantile neuronal ceroid lipofuscinosis type 2 MRI Magnetic resonance imaging GM Gray matter WM White matter CSF Cerebrospinal fluid ICV Intracranial volume WT Wild type (control) CI Confidence interval SubC Mictochondrial ATP synthase subunit c Batten disease, or neuronal ceroid lipofuscinoses, is a group of neurodegenerative diseases in which mutations in 13-14 different genes can cause issues with a lysosome's capability to recycle or process molecules. All forms of Batten disease show similar symptoms but are caused by different gene mutations 1,2. The late-infantile neuronal
American Journal of Neuroradiology, 2013
BACKGROUND AND PURPOSE: LINCL is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene that encodes for tripeptidyl peptidase 1, a lysosomal enzyme necessary for the degradation of products of cellular metabolism. With the goal of developing quantitative noninvasive imaging biomarkers sensitive to disease progression, we evaluated a 5-component MR imaging metric and tested its correlation with a clinically derived disease-severity score. MATERIALS AND METHODS: MR imaging parameters were measured across the brain, including quantitative measures of the ADC, FA, nuclear spin-spin relaxation times (T2), volume percentage of CSF (%CSF), and NAA/Cr ratios. Thirty MR imaging datasets were prospectively acquired from 23 subjects with LINCL (2.5-8.4 years of age; 8 male/15 female). Whole-brain histograms were created, and the mode and mean values of the histograms were used to characterize disease severity. RESULTS: Correlation of single MR imaging parameters against the clinical disease-severity scale yielded linear regressions with R 2 ranging from 0.25 to 0.70. Combinations of the 5 biomarkers were evaluated by using PCA. The best combination included ADC, %CSF, and NAA/Cr (R 2 ϭ 0.76, P Ͻ .001). CONCLUSIONS: The multiparametric disease-severity score obtained from the combination of ADC, %CSF, and NAA/Cr whole-brain MR imaging techniques provided a robust measure of disease severity, which may be useful in clinical therapeutic trials of LINCL in which an objective assessment of therapeutic response is desired. ABBREVIATIONS: FA ϭ fractional anisotropy; GM ϭ gray matter; LINCL ϭ late infantile neuronal ceroid lipofuscinosis; MRIDSS ϭ MR imaging disease-severity score; PCA ϭ principal component analysis
Neurodegenerative Diseases, 2012
spectroscopy (MRS) and repeating these tests using the same mice at 4, 5 and 6 months of age. Our results showed progressive cerebral atrophy, which was associated with histological loss of neuronal content and increase in astroglia. Remarkably, while the brain volumes in Ppt1 -KO mice progressively declined with advancing age, the MRS signals, which were significantly lower than those of their wild-type littermates, remained virtually unchanged from 3 to 6 months of age. In addition, our results also showed an abnormality in cerebral blood flow in these mice, which showed progression with age. Our findings provide methods to serially examine the brains of mouse models of neurodegenerative diseases (e.g. Ppt1 -KO mice) using noninvasive and nonlethal procedures such as MRI and MRS. These methods may be useful in studies to understand the progression of neuropathology in animal models of neurodegenerative diseases as they allow repeated evaluations of the same animal in which experimental therapies are tested.
Journal of medicine and life, 2012
Magnetic Resonance Spectroscopy is a non-invasive method, which can be performed following a routine Magnetic Resonance investigation within the same examination, and can provide very useful molecular information related to the metabolism and function of the normal and pathological structures of the brain. Its role is increasing in the establishment of a clear diagnosis, in both focal and diffuse central nervous system diseases, and the tendency is to replace the histopathology test, in certain cases, with similar or sometimes better diagnostic accuracy. This paper summarizes the principle, method, and main clinical applications, standing as a guide to procedure performing and results interpretation.
BMJ Open, 2020
IntroductionA number of MRI methods have been proposed to be useful, quantitative biomarkers of neurodegeneration in ageing. The Calgary Normative Study (CNS) is an ongoing single-centre, prospective, longitudinal study that seeks to develop, test and assess quantitative magnetic resonance (MR) methods as potential biomarkers of neurodegeneration. The CNS has three objectives: first and foremost, to evaluate and characterise the dependence of the selected quantitative neuroimaging biomarkers on age over the adult lifespan; second, to evaluate the precision, variability and repeatability of quantitative neuroimaging biomarkers as part of biomarker validation providing proof-of-concept and proof-of-principle; and third, provide a shared repository of normative data for comparison to various disease cohorts.Methods and analysisQuantitative MR mapping of the brain including longitudinal relaxation time (T1), transverse relaxation time (T2), T2*, magnetic susceptibility (QSM), diffusion ...
American Journal of Neuroradiology, 2007
Proton MR spectroscopy ( 1 H-MR spectroscopy) is a quantitative MR imaging technique often used to complement the sensitivity of conventional MR imaging with specific metabolic information. A key metabolite is the amino acid derivative N-acetylaspartate (NAA), which is almost exclusive to neurons and their processes and is, therefore, an accepted marker of their health and attenuation. Unfortunately, most 1 H-MR spectroscopy studies only account for small 1-to 200-cm volumes of interest (VOI), representing less than 20% of the total brain volume. These VOIs have at least 5 additional restrictions: 1) To avoid contamination from subcutaneous and bone marrow lipids, they must be placed away from the skull, thereby missing most of the cortex. 2) They must be image-guided onto MR imaging-visible pathology, subjecting them to the implicit assumption that metabolic changes occur only there. 3) They encounter misregistration errors in serial studies. 4) The time needed to accumulate sufficient signal-intensity quality is often restrictive, and 5) they incur (unknown) T1-and T2-weighting. All these issues are avoided (at the cost of specific localization) by measuring the nonlocalized average NAA concentration over the entire brain. Indeed, whole-brain NAA quantification has been applied to several diffuse neurodegenerative diseases (where specific localization is less important than the total load of the pathology), and the results are presented in this review.
Neuropathological Brain Mapping
Dementia and Geriatric Cognitive Disorders, 1997
: Subacute spongiform encephalopathy. Spongiform cerebral atrophy. Neurology, 13, 6, 455 -463. Brun A, Gottfries C G, and Roos B E (1971): Studies of the monoamine metabolism in the central nervous system in Jacob-Creutzfeldt disease. Acta Neurol. Scandinav. 47, 642 -645. Sulg I A and Brun A (1972): Spongiform encephalopathi återspeglad i EEG och patohistologi. Föredrag Medicinska Riksstämman, Hygiea. Stockholm 231. Mark J and Brun A (1973): Chromosomal deviations in Alzheimer's disease compared to those in senescence and senile dementia. Ger Clin 15, 253-258. Brun A (1973). Downs' syndrom -utvecklingsstörning och demens. Läkartidningen 80, 10, pp 936. Brun A (1974): Den presenila demensens patologi relaterad till cerebralt blodflöde. Svenska läkartidningen 71, 13, 1974: Svenska läkarsällskapets endagssymposium 73-11-07 över temat demens. Patofysiologi och klinik. 71, 1290 -1291. Brun A. and L.Gustafson (1974): Extent and severity of cerebral lesions related to clinical and regional cerebral blood flow in presenile dementia. In: PPProc of the V11th Intnl Congr of Neuropathology, Akademiai Kiado, Budapest 1974, p44. Gustafson L, D.H.Ingvar and A. Brun (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. In proc. of 2nd Intnl congr of CIANS Prague 1975. p. 371 Brun A, L Gustafson, DHI Ingvar (1974/5): Neuropathological findings related to Neuropsychiatric symptoms and regional cerebral blood flow in presenile dementia. Excerpta medica, Amsterdam, Akademiai Kiado, Budapest. Pp 101-5. Brun, A. and Gustafson, L. (1976). Distribution of cerebral degeneration in Alzheimer's disease. A clinico-pathological study. Arch Psychiatr Nervenkr, 223, 15-33. Gustafson L, Brun A and Ingvar D H (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. Activ nerv Sub (Praha) 19, 2, 351 -354. Gustafson L, A Brun, DHI Ingvar (1977): Presenile dementia: Clinical symptoms, pathoanatomical findings and cerebral blood flow. Cerebral vascular disease. A Brun, E Englund (1980): degeneration av hjärnans vita substans vid demens. Riksstämman, Hygiea. P 213 Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. + abstr Brun A and Dictor M (1981): Senile plaques and tangles in dialysis dementia. Acta Path. Microbiol Scand Sect A, 89, 193-198. Brun, A. and Englund, E. (1981). Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. Histopathology, 5, 549-564. Englund E and Brun A (1981): Senile dementia -a structural basis for etiological and therapeutic considerations. Biological Psychiatry. Eds: C Perris and B Jonsson. Elsevier/North Holland Biomed Press 951 -956. Westermark P, Shirahama T, Skinner M, Brun A, Cameron R and Cohen A (1982): Immunohistochemical evidence for the lack of amyloid component in some intracrebral amyloids. Laboratory Investigation 5, 457 -460. Shirhama T, Skinner M, Westermark P, Rubinow A, Cohen A S, Brun A and Kemper T H (1982): Senile cerebral amyloid. Prealbumin as a common constituent in the neuritic plaques, in the neurofibrillary tangle and in the microangiopathic lesion. Am J Pathol 107, 41-50. Brun A (1982): Strukturellt underlag vid organisk senil demens. Symposium Sandoz: Demenstillstånd -synpunkter på etiologi och behandling, 23 -34. Brun A (1982): Alzheimer's disease and its clinical implications. In: Geriatrics. Ed: D Platt. Springer Verlag Heidelberg, NY, 343 -390. Brun A and Englund E (1982): White matter incomplete infarction in dementia. Abstract 9th Internat. Congr. Neuropath. 201. Brun A, L Gusrafson (1983). Down's syndrom -utvecklingsstörning och demens. Läkartidningen 80, 10, pp 936. Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. pp. Brun A (1983): Hjärnskada bakom vanliga former av demens. Forskning och Praktik, 15, 7, 103-106. Brun A (1983): An overview of light and electron microscopical changes. In: Alzheimer's disease. Ed: B Reisberg. The Free Press. New York, a division of Mac Millan Inc, 3 -47. Gustafson L, Brun A, Risberg J and Johansson M (1984): Evaluation of organic dementia by regional cerebral blood flow measurements and clinical psychometric methods. Monogr Neural Sci, 11, 111 -117. Karger, Basel. . Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. p 23. Brun A (1984): The neuropathological background of clinical signs and symptoms in organic dementia. 2 nd Nordic meeting in Neuropsychology. Lund Sweden. Pp 18-19. Brun A (1985): The structural development of Alzheimer's disease. Danish Medical Bulletin, 32, 1, 25 -27. Friedland R P, A Brun, T F Budinger (1985): Pathological and positron emission tomographic correlations in Alzheimer's disease. The Lancet 8422, vol. I/85, p 228. Brun A and Englund E (1985): Regional variations of cortical degeneration in Alzheimer's disease. Journal of Clinical and Experimental Neuropsychology, 7, 2, 167 Brun A and Englund E (1985): White matter changes in Alzheimer's presenile and senile dementia. In: Normal aging, Alzheimer's disease and senile dementia. Aspects on etiology, pathogenesis, diagnosis and treatment, Ed: C G Gottfries. Editions de lUniversité de Bruxelle's, 47 -50. Gustafson L, Brun A, Holmkvist-Franck A, Risberg J 1985: Regional Cerebral blood flow in degenerative frontal lobe dementia of non-Alzheimer type. Cerebr. Blood Flow Metabol. 5: 141-142. Gustafson L, A Brun, J Risberg (1985): Organic dementia: Clinical picture related to regional cerebral blood flow and neuropathologic al findings. Psychiatry vol. 2. Pp 605-611. Brun A, E Englund (1985): Alzheimer type dementia and white matter changes. Ata neurol. Scand. Vil 71. Pp 87-88. Gustafson L, A Brun, J Risberg (1985): Rating scales for diagnosis of Alzheimer´s disease and frontal lobe dementia of non-Alzheimer type. 26 Englund E, A Brun (1985): A White matter disorder common in Dementia of Alzheimer´s type. Pp 168-169. Englund E, A Brun (1985): demyelination contributes to Alzheimer´s disease. 18. Brun A, L Gustafson, E Englund (1985): Morphology of white matter, subcortical dementia in Alzheimer´s disease. Pp 79 -83. Brun A, Englund E (1986): A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 1986;19:253-262. -Brun A and Gustafson L (1990): Clinico-pathological correlates of dementia: The pathoanatomical substrate of Alzheimer's disease. Excerpta Medica. -Gustafson L, Brun A, Cronqvist S, Dalfelt G, Risberg J, Riesenfeldt W and Rosén I (1990): Regional cerebral blod flow, MRI and BEAM in Alzheimer's disease. J Cer Blood Flow Metab, 9, 1, 543. Brun A, Gustafson L, and Risberg J (1990): A review of 20 years dementia research. Psychiatric Medicine, vol 32k 7, 781 -788. Igakushoin Tokyo Japan. Brun A (1991): Trends in neuropathological enquiry into the dementias: The late life pattern. Workshop on therapeutic and epidemiological aspects. Proc. IPA workshop, Cambridge. Brun A (1991): Dementia of frontal lobe type. Elsevier Science Publishers B V. Biological Psychiatry. Volume 2. G Racagni et al, eds. Pp 126 -127. Pinheiro T, Tapper U A S, Sturesson K, Brun A (1991): Experimental investigation into sample preparation of Alzheimer tissue specimens for nuclear microprobe analysis. Nuclear Instruments and Methods in Physics Research B 54, 186 -190. Brun A (1991): Structural and topographic aspects of degenerative dementia: aspects of degenerative dmentia. Diagnostic considerations. Internat Psychogeriatrics, vol 3, supp. Pp. 75 -83. Englund E, Brun A (1991): Neuropathology of vascular dementia. 5th Congr. Int. Psychogeriatr. Ass. (IP), Rome, Italy, August 18 -23. Brun A (1992): Alzheimer -en demenssjukdom. Vandringar med Böcker. Bibliotekstjänst, Lund. Basun H, O Almquist, K Axelman , A Brun, T A Campbell, J Collinge, C Forsell . S Froelich , L-O Wahlund, L Wetterberg, L Lannfeldt (1997). Clinical characteristics of a family with chromosome 17 -linked rapidly progressive frontotemporal dementia . Arch Neurol, 54 : 539 -544 . Liu X and A Brun (1996): Regional and laminar synaptic pathology in frontal lobe degeneration of non-Alzheimer type. Int. J. Ger. Psych.11, 47-55. Liu X, C Erikson, A Brun (1996). Cortical synaptic changes and gliosis in normal aging, Alzheimer´s disease and frontal lobe degeneration. Dementia 7, 128-134. A 136 Brun A and Passant U (1996): Frontal lobe degeneration of non-Alzheimer type. Structural changes, diagnostic criteria and relation to other fronto-temporal dementias. Acta Neurol.Scand. Suppl 168 28 -30 . A Swedish state of the art document on dementia diseases .Eds L -O Wahlund , B Winblad . Ohlsson Y. A Brun, E Englund (1996): Fundamental pathological lesions in vascular dementia . Acta Neurol Scand Suppl 168, 31-38.A Swedish state of the art document on dementia diseases. ( 1997 ): Misclassification of dementia subtype using the Hachinski ischemic score : results of a meta-analysis of patients with pathologically verified dementias . Annals New York Academy of Sciences. 490 -492....
Brain MRI and biological diagnosis in five Tunisians MLD patients
Diagnostic Pathology, 2012
Metachromatic leukodystrophy (MLD) is a recessive autosomal disease which is characterized by an accumulation of sulfatides in the central and peripheral nervous system. It is due to the enzyme deficiency of the sulfatide sulfatase i.e. arylsulfatase A (ASA). we studied 5/200 cases of MLD and clearly distinguished three clinical forms. One of them presented the juvenile form; two presented the late infantile form; and two other presented the adult form. The Magnetic Resonance Imaging (MRI) of these patients showed a diffuse, bilateral and symmetrical demyelination. The biochemical diagnosis of MLD patients evidencing the low activity of ASA and sulfatide accumulation. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1791578262610232 Patients and methods: We studied 5/200 MLD patients addressed to us for behavioral abnormalities and progressive mental deterioration. All of them were diagnosed at first by brain MRI evidencing a bilateral demyelination, then the measurement of ASA activity using P-nitrocathecol sulfate as substrate, finally the sulfatiduria was performed using thin-layer chromatography using alpha-naphtol reagent. Results: In this study, from 200 patients presenting behavioral abnormalities and a progressive mental deterioration, we reported just 2 patients were diagnosed as late-infantile form of MLD. Only1 case presented as the juvenile form; and 2 patients with the adult-type of MLD. The brain magnetic resonance imaging (MRI) of all patients showed characteristic lesions of MLD with extensive demyelination. Biochemical investigations of these patients detected a low level of ASA activity at 0°C and 37°C; the excess of sulfatide in sulfatiduria.