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CSF biomarkers, impairment of cerebral hemodynamics and degree of cognitive decline: An overview in different dementia subtypes
Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320
pressure, hormone secretion and behavioral and cognitive responses. Beyond the central actions of peripheric RAS components, an independent RAS exists in the brain. We have previously shown that RAS components such as angiotensin II, angiotensin-converting enzyme (ACE) and AT1 receptor are present in several brain regions in humans. Angiotensin II was found in the striatum, cortex and hippocampus in cellular localizations indicating a role as a regulatory peptide. It was increased in Alzheimer's disease (AD) patients. ACE and AT1 expression in cells were found to be also increased in AD brain. In addition, in aged controls, AD patients and in patients with vascular dementia, there was a prominent perivascular ACE and angiotensin II staining, probably pointing to an underlying microvascular pathology. ACE, angiotensin II and AT1 were also localized in human ocular tissues in various cells pointing to different function of RAS components on neuronal cells, vessels and vitreous humor homeostasis. Taken together, there is growing evidence that the central RAS is involved in the disease process of neurodegenerative disorders at many levels. doi:10.1016/j.jns.2009.02.109
CSF biomarkers, impairment of cerebral hemodynamics and degree of cognitive decline: An overview in different dementia subtypes A. Stefania,b, M. Diomedia, A. Orlacchiob, S. Galatia, A. Martoranab, S. Bernardinic a Dept Neuroscience, Univ Tor Vergata, Policlinico Tor Vergata, Rome, Italy b IRCCS Fondazione S.Lucia, Rome, Italy c Dept Internal Medicine, Univ Tor Vergata, Policlinico Tor Vergata, Rome, Italy Background and aims: CSF biomarkers, in the diagnostic procedure for cognitively impaired patients, appear to represent a valid and specific tool, in combination with neuro-psychology evaluation and neuroimaging. The determination of beta-amyloid, total tau and phospho-tau concentrations favors brilliant differential diagnosis when on demand is the conversion of MCI to early Alzheimer's disease (AD) (Parnetti et al., 2006; Borroni et al., 2007), or the unequivocal distinction between AD vs. pseudo-dementia (Stefani et al., 2006). Less clear is the role played by conventional CSF biomarkers in “mixed” forms of dementia, as far as the vascular burden—and the hemodynamic deficits—complicates the clinical history. Methods: We studied the cerebral hemodynamic impairment in the following cohort of patients (with characterized CSF profile): AD, mixed dementia (AD plus different degree of cerebro-vascular damage, CVD) and control. Mean flow velocity (MFV), pulsatility index (PI) and cerebrovascular reactivity (BHI) were evaluated by means of bilateral TCD monitoring of middle cerebral arteries. Hemodynamic variables were correlated with severity of cognitive deficit measured with MMSE. Results: In our experience, MFV and BHI were significantly lower and PI was significantly higher in AD patients with respect to control subjects. Noticeably, MMSE score was correlated to BHI reduction (p = 0.005). The presence of small occasional WMC did not influence any of the hemodynamic variables. Our results were critically compared with previous available literature. Conclusions: This study provides the evidence for a significant impairment of cerebral autoregulatory mechanisms in AD patients, correlated to cognitive deficit and unrelated to MRI sub-cortical lesions. The results support the hypothesis of a significant pathogenetic role of vascular damage in AD. The follow-up of hemodynamic reactivity, if coupled with the collection of CSF biomarkers, promises to gather precious insights on the progression of the cognitive decline and the efficacy of ongoing therapy.
267
c
Department of Radiology, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil d Servico de verificacao de obitos da capital, University of Sao Paulo , Sao Paulo, SP, Brazil e Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, Munich, Germany f Department of Radiology, Ludwig-Maximilian University Munich, Germany g Morphological Brain Research Unit, University Wu¨rzburg, Germany h Brazilian Aging Brain Study Group, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil Background: Microvascular lesions contribute to cognitive decline, however they can be prevented. Advanced neuroimaging methods to assess the subcortical white matter may be a powerful tool for evaluating these changes; however, a number of commonly used seemingly diagnostic terms in neuroimaging are based on assumptions. We developed a state-of-the-art protocol for solving fundamental questions regarding the neuroimaging– neuropathological uncertainties. Methods: Correlations between signal changes in post-mortem DTI/ MRI in-situ, clinics, and high-resolution neurohistology/immunohistochemistry to determine to what extent the amplitude of signal changes is related to vascular lesions (Fig. 1). Computer 3D reconstructions of the neuroanatomical data and shrinkage correction allow the reference of each cyto/myeloarchitectonical maps to its corresponding in-situ scan (Fig. 2). Results: The first reconstructions have brought considerable progress supporting this platform as reliable and feasible tool using a low budget. Even minimal changes can be unequivocally located and be subjected to a detailed neuropathological diagnosis (Fig. 3). We are presently optimizing the warping procedure to correlate even minimally visible hyperintensities. Conclusions: The use of post-mortem in-situ MRI permits to correct the histological data for non-linear deformations due to fixation resulting in unbiased estimates of the vascular and white matter changes and may enhance the understanding of the signal changes due to brain vascular pathology and open up avenues for diagnosis and treatment response.
doi:10.1016/j.jns.2009.02.110
Improved detection of incipient vascular changes by a biotechnological platform combining post-mortem in-situ MRI with neuropathology L.T. Grinberga,b, E. Amaro Jr.c, D.D. Santosa, R.E. Ferrettia, R.P. Leitea, C.G. Pasqualuccia,d, W.H. Flatze, S. Teipelf, H. Heinseng B Brazilian Aging Brain Study Grouph a Aging Brain Project , Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil b INCE, Instituto Israelita de Ensino e Pesquisa Albert Einstein
Fig. 1.
pressure, hormone secretion and behavioral and cognitive responses. Beyond the central actions of peripheric RAS components, an independent RAS exists in the brain. We have previously shown that RAS components such as angiotensin II, angiotensin-converting enzyme (ACE) and AT1 receptor are present in several brain regions in humans. Angiotensin II was found in the striatum, cortex and hippocampus in cellular localizations indicating a role as a regulatory peptide. It was increased in Alzheimer's disease (AD) patients. ACE and AT1 expression in cells were found to be also increased in AD brain. In addition, in aged controls, AD patients and in patients with vascular dementia, there was a prominent perivascular ACE and angiotensin II staining, probably pointing to an underlying microvascular pathology. ACE, angiotensin II and AT1 were also localized in human ocular tissues in various cells pointing to different function of RAS components on neuronal cells, vessels and vitreous humor homeostasis. Taken together, there is growing evidence that the central RAS is involved in the disease process of neurodegenerative disorders at many levels. doi:10.1016/j.jns.2009.02.109
CSF biomarkers, impairment of cerebral hemodynamics and degree of cognitive decline: An overview in different dementia subtypes A. Stefania,b, M. Diomedia, A. Orlacchiob, S. Galatia, A. Martoranab, S. Bernardinic a Dept Neuroscience, Univ Tor Vergata, Policlinico Tor Vergata, Rome, Italy b IRCCS Fondazione S.Lucia, Rome, Italy c Dept Internal Medicine, Univ Tor Vergata, Policlinico Tor Vergata, Rome, Italy Background and aims: CSF biomarkers, in the diagnostic procedure for cognitively impaired patients, appear to represent a valid and specific tool, in combination with neuro-psychology evaluation and neuroimaging. The determination of beta-amyloid, total tau and phospho-tau concentrations favors brilliant differential diagnosis when on demand is the conversion of MCI to early Alzheimer's disease (AD) (Parnetti et al., 2006; Borroni et al., 2007), or the unequivocal distinction between AD vs. pseudo-dementia (Stefani et al., 2006). Less clear is the role played by conventional CSF biomarkers in “mixed” forms of dementia, as far as the vascular burden—and the hemodynamic deficits—complicates the clinical history. Methods: We studied the cerebral hemodynamic impairment in the following cohort of patients (with characterized CSF profile): AD, mixed dementia (AD plus different degree of cerebro-vascular damage, CVD) and control. Mean flow velocity (MFV), pulsatility index (PI) and cerebrovascular reactivity (BHI) were evaluated by means of bilateral TCD monitoring of middle cerebral arteries. Hemodynamic variables were correlated with severity of cognitive deficit measured with MMSE. Results: In our experience, MFV and BHI were significantly lower and PI was significantly higher in AD patients with respect to control subjects. Noticeably, MMSE score was correlated to BHI reduction (p = 0.005). The presence of small occasional WMC did not influence any of the hemodynamic variables. Our results were critically compared with previous available literature. Conclusions: This study provides the evidence for a significant impairment of cerebral autoregulatory mechanisms in AD patients, correlated to cognitive deficit and unrelated to MRI sub-cortical lesions. The results support the hypothesis of a significant pathogenetic role of vascular damage in AD. The follow-up of hemodynamic reactivity, if coupled with the collection of CSF biomarkers, promises to gather precious insights on the progression of the cognitive decline and the efficacy of ongoing therapy.
267
c
Department of Radiology, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil d Servico de verificacao de obitos da capital, University of Sao Paulo , Sao Paulo, SP, Brazil e Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, Munich, Germany f Department of Radiology, Ludwig-Maximilian University Munich, Germany g Morphological Brain Research Unit, University Wu¨rzburg, Germany h Brazilian Aging Brain Study Group, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil Background: Microvascular lesions contribute to cognitive decline, however they can be prevented. Advanced neuroimaging methods to assess the subcortical white matter may be a powerful tool for evaluating these changes; however, a number of commonly used seemingly diagnostic terms in neuroimaging are based on assumptions. We developed a state-of-the-art protocol for solving fundamental questions regarding the neuroimaging– neuropathological uncertainties. Methods: Correlations between signal changes in post-mortem DTI/ MRI in-situ, clinics, and high-resolution neurohistology/immunohistochemistry to determine to what extent the amplitude of signal changes is related to vascular lesions (Fig. 1). Computer 3D reconstructions of the neuroanatomical data and shrinkage correction allow the reference of each cyto/myeloarchitectonical maps to its corresponding in-situ scan (Fig. 2). Results: The first reconstructions have brought considerable progress supporting this platform as reliable and feasible tool using a low budget. Even minimal changes can be unequivocally located and be subjected to a detailed neuropathological diagnosis (Fig. 3). We are presently optimizing the warping procedure to correlate even minimally visible hyperintensities. Conclusions: The use of post-mortem in-situ MRI permits to correct the histological data for non-linear deformations due to fixation resulting in unbiased estimates of the vascular and white matter changes and may enhance the understanding of the signal changes due to brain vascular pathology and open up avenues for diagnosis and treatment response.
doi:10.1016/j.jns.2009.02.110
Improved detection of incipient vascular changes by a biotechnological platform combining post-mortem in-situ MRI with neuropathology L.T. Grinberga,b, E. Amaro Jr.c, D.D. Santosa, R.E. Ferrettia, R.P. Leitea, C.G. Pasqualuccia,d, W.H. Flatze, S. Teipelf, H. Heinseng B Brazilian Aging Brain Study Grouph a Aging Brain Project , Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil b INCE, Instituto Israelita de Ensino e Pesquisa Albert Einstein
Fig. 1.