41 research outputs found
Incremental value of biomarker combinations to predict progression of mild cognitive impairment to Alzheimer’s dementia
Background The progression of mild cognitive impairment (MCI) to Alzheimer’s
disease (AD) dementia can be predicted by cognitive, neuroimaging, and
cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary
information, a combination of biomarkers may increase the predictive power. We
investigated which combination of the Mini-Mental State Examination (MMSE),
Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall
from the Consortium to Establish a Registry of Dementia (CERAD) test battery,
hippocampal volume (HCV), amyloid-beta1–42 (Aβ42), amyloid-beta1–40 (Aβ40)
levels, the ratio of Aβ42/Aβ40, phosphorylated tau, and total tau (t-Tau)
levels in the CSF best predicted a short-term conversion from MCI to AD
dementia. Methods We used 115 complete datasets from MCI patients of the
“Dementia Competence Network”, a German multicenter cohort study with annual
follow-up up to 3 years. MCI was broadly defined to include amnestic and
nonamnestic syndromes. Variables known to predict progression in MCI patients
were selected a priori. Nine individual predictors were compared by receiver
operating characteristic (ROC) curve analysis. ROC curves of the five best
two-, three-, and four-parameter combinations were analyzed for significant
superiority by a bootstrapping wrapper around a support vector machine with
linear kernel. The incremental value of combinations was tested for
statistical significance by comparing the specificities of the different
classifiers at a given sensitivity of 85%. Results Out of 115 subjects, 28
(24.3%) with MCI progressed to AD dementia within a mean follow-up period of
25.5 months. At baseline, MCI-AD patients were no different from stable MCI in
age and gender distribution, but had lower educational attainment. All single
biomarkers were significantly different between the two groups at baseline.
ROC curves of the individual predictors gave areas under the curve (AUC)
between 0.66 and 0.77, and all single predictors were statistically superior
to Aβ40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81.
The three-parameter combinations ranged from AUC 0.80–0.83, and the four-
parameter combination from AUC 0.81–0.82. None of the predictor combinations
was significantly superior to the two best single predictors (HCV and t-Tau).
When maximizing the AUC differences by fixing sensitivity at 85%, the two- to
four-parameter combinations were superior to HCV alone. Conclusion A
combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is
not superior over the single parameters in identifying patients with MCI who
are most likely to progress to AD dementia, although there is a gradual
increase in the statistical measures across increasing biomarker combinations.
This may have implications for clinical diagnosis and for selecting subjects
for participation in clinical trials
Apolipoprotein E-dependent load of white matter hyperintensities in Alzheimer’s disease: a voxel-based lesion mapping study
Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer’s disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD. Methods: WM hyperintensity volume on fluid-attenuated inversion recovery images of 201 patients with AD (128 carriers and 73 non-carriers of the APOE ε4 risk allele) was determined globally as well as regionally with voxel-based lesion mapping. Clinical, neuropsychological and MRI data were collected from prospective multicenter trials conducted by the German Dementia Competence Network. Results: WM hyperintensity volume was significantly greater in non-carriers of the APOE ε4 allele. Lesion distribution was similar among ε4 carriers and non-carriers. Only ε4 non-carriers showed a correlation between lesion volume and cognitive performance. Conclusion: The current findings indicate an increased prevalence of WM hyperintensities in non-carriers compared with carriers of the APOE ε4 allele among patients with AD. This is consistent with a possibly more pronounced contribution of heterogeneous vascular risk factors to WM damage and cognitive impairment in patients with AD without APOE ε4-mediated risk
Incremental value of biomarker combinations to predict progression of mild cognitive impairment to Alzheimer’s dementia
Pathological changes in dendrites of substantia nigra neurons in Parkinson's disease: a Golgi study
Neurons of the substantia nigra show
severe morphological changes in Parkinson's disease.
Pathological alterations of cell bodies have been
described, whereas those of neuronal processes have
hardly been investigated. Golgi impregnation has
been the chosen method for demonstrating neuronal
processes and dendritic and somatic spines. We
therefore used the Golgi-Braitenberg method to
qualitatively and semi-quantitatively study the
substantia nigra of eight patients with Parkinson's
disease compared with eight control cases. Golgi
impregnation of substantia nigra neurons was good in al1
control cases. In full agreement with the analysis of
Braak and Braak (1986) three neuronal types within the
substantia nigra were found. In cases of Parkinson's
disease, severe pathological changes such as decrease of
dendritic length, loss of dendritic spines and severa1
types of dendritic varicosities were found only in the
melanin-containing pars compacta neurons. Pars
reticulata nerve cells were intact. These findings support
the predominant role played by the dopaminergic
efferent pathway in the degenerative process. The
afferent pathway was not affected. This suggests that the
substantia nigra lesion is primary in Parkinson's disease.
Loss of neurons found in H & E sections
corresponded to a lesser amount of impregnated pars
compacta neurons in cases with Parkinson's disease
when compared to controls. Evidences exist that the
duration of the disease may be related to the extent of
pathologically altered Golgi-impregnated pars compacta
cells. The amount of Lewy bodies in H & E sections
corresponded to the quantity of round varicosities in
impregnated pars compacta neurons. These round
dendritic varicosities were considered to be Lewy body
inclusions. They seem to have no influence on the
dendritic spine density and morphology in most cases
[Early diagnosis and therapy of Alzheimer dementia. Careful documentation prevents degeneration]
Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer\u27s Disease
Of 57 individuals diagnosed with Alzheimer\u27s disease (AD) in a phase III study, 13 (23) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology