To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to fronto... more To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD). It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations. Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (A beta(42)). Patients also were assessed with a brief neuropsychological battery. CSF total tau level and the ratio of CSF total tau to A beta(42) (tau/A beta(42)) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/A beta(42) ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD. The ratio of CSF tau/A beta(42) is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.
Neurobiology of Aging, Volume 25, Issue null, Pages S521-S522, July 2004, Authors:Kristel Sleeger... more Neurobiology of Aging, Volume 25, Issue null, Pages S521-S522, July 2004, Authors:Kristel Sleegers; Inge de Koning; Yurii S. Aulchenko; Esther A. Croes; John C. van Swieten; Ben A. Oostra; Cornelia M. van Duijn.
Several mutations in the amyloid precursor protein (APP) gene may lead to either Alzheimer&am... more Several mutations in the amyloid precursor protein (APP) gene may lead to either Alzheimer's disease or cerebral haemorrhage due to congophilic amyloid angiopathy (CAA). A single family is known in which both types of pathology are expressed because of a missense mutation at codon 692 of the APP gene (APP692). Here we describe the clinical and pathological expression of APP692 in eight patients with the mutation. Furthermore, 21 first-degree relatives with an a priori risk of 50% of being a carrier were tested for the APP692 mutation and studied for presymptomatic signs by neurological examination, neuropsychological testing and brain MRI. Patients with APP692 presented with haemorrhage, dementia or both. The dementia in patients with the APP692 mutation was compatible with Alzheimer's disease both clinically and neuropathologically. Of the 21 healthy relatives at 50% risk, five carried the APP692 mutation. The presymptomatic carriers showed a subtle, non-significant impairment of cognitive function compared with relatives without APP692. A significant increase in the number of periventricular and subcortical white matter lesions at young age was seen in presymptomatic carriers (mean age 26.4 years). The findings of this study suggest that a single (genetic) mechanism may underlie the pathology of Alzheimer's disease and CAA. These diseases are manifested subclinically by white matter pathology. Further insight into the relationship between CAA and Alzheimer's disease may provide clues about the aetiology of Alzheimer's disease.
To systematically review the literature for studies on cognitive functioning in patients with low... more To systematically review the literature for studies on cognitive functioning in patients with low-grade glioma to evaluate assessment methods and prevalence of cognitive dysfunction. A search was made in PubMed, Embase, and PsycINFO for articles published between January 2002 and June 2012 using cognition, memory, attention, executive functioning, and low-grade glioma as search terms. Two reviewers independently performed the study selection and data extraction. Inclusion criteria were: studies including at least 10 adult patients, with suspected or confirmed low-grade glioma and cognitive functioning as outcome measure. A standard data extraction form was used, with items regarding study quality, patient characteristics, type of measurement instruments, cognitive domain, definition of cognitive dysfunction, and reported prevalence. Of the 312 articles screened on title/abstract, 69 were screened on full-text and, finally, 17 were included. A total of 46 different measurement instru...
Cerebral small vessel disease (CSVD) is thought to contribute to cognitive dysfunction in patient... more Cerebral small vessel disease (CSVD) is thought to contribute to cognitive dysfunction in patients with mild cognitive impairment (MCI). The underlying mechanisms, and more specifically, the effects of CSVD on brain functioning in MCI are incompletely understood. The objective of the present study was to examine the effects of CSVD on brain functioning, activation and deactivation, in patients with MCI using task-related functional MRI (fMRI). We included 16 MCI patients with CSVD, 26 MCI patients without CSVD and 25 controls. All participants underwent a physical and neurological examination, neuropsychological testing, structural MRI, and fMRI during a graded working memory paradigm. MCI patients with and without CSVD had a similar neuropsychological profile and task performance during fMRI, but differed with respect to underlying (de)activation patterns. MCI patients with CSVD showed impaired deactivation in the precuneus/posterior cingulate cortex, a region known to be involved in the default mode network. In MCI patients without CSVD, brain activation depended on working memory load, as they showed relative 'hyperactivation' during vigilance, and 'hypoactivation' at a high working memory load condition in working memory related brain regions. We present evidence that the potential underlying mechanism of CSVD affecting cognition in MCI is through network interference. The observed differences in brain activation and deactivation between MCI patients with and without CSVD, who had a similar 'clinical phenotype', support the view that, in patients with MCI, different types of pathology can contribute to cognitive impairment through different pathways.
Sirs: Dysarthria can be the first sign of a neurological disease. In the ini-tial phase it can be... more Sirs: Dysarthria can be the first sign of a neurological disease. In the ini-tial phase it can be difficult to differ-entiate dysarthria from other (ac-quired) speech disturbances, espe-cially if the speech problem remains mild and isolated for a long period. We describe the course of a slowly ...
The brain areas that are responsible for cognitive functioning have the same embryonic origin as ... more The brain areas that are responsible for cognitive functioning have the same embryonic origin as the retina. The association between cognitive functioning and retinal nerve fiber layer (RNFL) thickness was assessed in a large, population-based sample. Neuropsychological and ophthalmic examinations were performed in 1485 healthy individuals (mean age, 46 years; range, 18-85) from the Erasmus Rucphen Family (ERF) study, a study in a genetic isolate from the Netherlands. Different domains of cognitive functioning were assessed with the Dutch Adult Reading Test, the Rey Auditory Verbal Memory Test, semantic fluency, the Trail-Making Test, the Stroop Color-Word Test, and Block Design. RNFL thickness was measured with scanning laser polarimetry. The association between cognitive test scores and peripapillary RNFL thickness was studied with linear regression analyses, adjusting for age, sex, level of inbreeding, and refractive error. After adjustment for confounders, a better cognitive performance was significantly associated with a thicker RNFL in all tests (P < 0.03) except for the Stroop Color-Word Test (P = 0.15). RNFL thickness explained up to 2.8% (R(2) = 0.028) of the total variance in cognitive test scores. The association diminished in age groups beyond 40 years. The present study shows that cognitive functioning is associated with RNFL thickness in healthy young individuals. The lack of association in older individuals suggests that loss of neurons in the cerebrum and retina is not concomitant and may have different origins.
To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to fronto... more To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD). It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations. Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (A beta(42)). Patients also were assessed with a brief neuropsychological battery. CSF total tau level and the ratio of CSF total tau to A beta(42) (tau/A beta(42)) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/A beta(42) ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD. The ratio of CSF tau/A beta(42) is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.
Neurobiology of Aging, Volume 25, Issue null, Pages S521-S522, July 2004, Authors:Kristel Sleeger... more Neurobiology of Aging, Volume 25, Issue null, Pages S521-S522, July 2004, Authors:Kristel Sleegers; Inge de Koning; Yurii S. Aulchenko; Esther A. Croes; John C. van Swieten; Ben A. Oostra; Cornelia M. van Duijn.
Several mutations in the amyloid precursor protein (APP) gene may lead to either Alzheimer&am... more Several mutations in the amyloid precursor protein (APP) gene may lead to either Alzheimer's disease or cerebral haemorrhage due to congophilic amyloid angiopathy (CAA). A single family is known in which both types of pathology are expressed because of a missense mutation at codon 692 of the APP gene (APP692). Here we describe the clinical and pathological expression of APP692 in eight patients with the mutation. Furthermore, 21 first-degree relatives with an a priori risk of 50% of being a carrier were tested for the APP692 mutation and studied for presymptomatic signs by neurological examination, neuropsychological testing and brain MRI. Patients with APP692 presented with haemorrhage, dementia or both. The dementia in patients with the APP692 mutation was compatible with Alzheimer's disease both clinically and neuropathologically. Of the 21 healthy relatives at 50% risk, five carried the APP692 mutation. The presymptomatic carriers showed a subtle, non-significant impairment of cognitive function compared with relatives without APP692. A significant increase in the number of periventricular and subcortical white matter lesions at young age was seen in presymptomatic carriers (mean age 26.4 years). The findings of this study suggest that a single (genetic) mechanism may underlie the pathology of Alzheimer's disease and CAA. These diseases are manifested subclinically by white matter pathology. Further insight into the relationship between CAA and Alzheimer's disease may provide clues about the aetiology of Alzheimer's disease.
To systematically review the literature for studies on cognitive functioning in patients with low... more To systematically review the literature for studies on cognitive functioning in patients with low-grade glioma to evaluate assessment methods and prevalence of cognitive dysfunction. A search was made in PubMed, Embase, and PsycINFO for articles published between January 2002 and June 2012 using cognition, memory, attention, executive functioning, and low-grade glioma as search terms. Two reviewers independently performed the study selection and data extraction. Inclusion criteria were: studies including at least 10 adult patients, with suspected or confirmed low-grade glioma and cognitive functioning as outcome measure. A standard data extraction form was used, with items regarding study quality, patient characteristics, type of measurement instruments, cognitive domain, definition of cognitive dysfunction, and reported prevalence. Of the 312 articles screened on title/abstract, 69 were screened on full-text and, finally, 17 were included. A total of 46 different measurement instru...
Cerebral small vessel disease (CSVD) is thought to contribute to cognitive dysfunction in patient... more Cerebral small vessel disease (CSVD) is thought to contribute to cognitive dysfunction in patients with mild cognitive impairment (MCI). The underlying mechanisms, and more specifically, the effects of CSVD on brain functioning in MCI are incompletely understood. The objective of the present study was to examine the effects of CSVD on brain functioning, activation and deactivation, in patients with MCI using task-related functional MRI (fMRI). We included 16 MCI patients with CSVD, 26 MCI patients without CSVD and 25 controls. All participants underwent a physical and neurological examination, neuropsychological testing, structural MRI, and fMRI during a graded working memory paradigm. MCI patients with and without CSVD had a similar neuropsychological profile and task performance during fMRI, but differed with respect to underlying (de)activation patterns. MCI patients with CSVD showed impaired deactivation in the precuneus/posterior cingulate cortex, a region known to be involved in the default mode network. In MCI patients without CSVD, brain activation depended on working memory load, as they showed relative 'hyperactivation' during vigilance, and 'hypoactivation' at a high working memory load condition in working memory related brain regions. We present evidence that the potential underlying mechanism of CSVD affecting cognition in MCI is through network interference. The observed differences in brain activation and deactivation between MCI patients with and without CSVD, who had a similar 'clinical phenotype', support the view that, in patients with MCI, different types of pathology can contribute to cognitive impairment through different pathways.
Sirs: Dysarthria can be the first sign of a neurological disease. In the ini-tial phase it can be... more Sirs: Dysarthria can be the first sign of a neurological disease. In the ini-tial phase it can be difficult to differ-entiate dysarthria from other (ac-quired) speech disturbances, espe-cially if the speech problem remains mild and isolated for a long period. We describe the course of a slowly ...
The brain areas that are responsible for cognitive functioning have the same embryonic origin as ... more The brain areas that are responsible for cognitive functioning have the same embryonic origin as the retina. The association between cognitive functioning and retinal nerve fiber layer (RNFL) thickness was assessed in a large, population-based sample. Neuropsychological and ophthalmic examinations were performed in 1485 healthy individuals (mean age, 46 years; range, 18-85) from the Erasmus Rucphen Family (ERF) study, a study in a genetic isolate from the Netherlands. Different domains of cognitive functioning were assessed with the Dutch Adult Reading Test, the Rey Auditory Verbal Memory Test, semantic fluency, the Trail-Making Test, the Stroop Color-Word Test, and Block Design. RNFL thickness was measured with scanning laser polarimetry. The association between cognitive test scores and peripapillary RNFL thickness was studied with linear regression analyses, adjusting for age, sex, level of inbreeding, and refractive error. After adjustment for confounders, a better cognitive performance was significantly associated with a thicker RNFL in all tests (P < 0.03) except for the Stroop Color-Word Test (P = 0.15). RNFL thickness explained up to 2.8% (R(2) = 0.028) of the total variance in cognitive test scores. The association diminished in age groups beyond 40 years. The present study shows that cognitive functioning is associated with RNFL thickness in healthy young individuals. The lack of association in older individuals suggests that loss of neurons in the cerebrum and retina is not concomitant and may have different origins.
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