Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid(1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F(2, 626) = 7.0, p = 0.001) and the homozygous CDC2 Ex6 + 7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD.     

White matter lesions in dementia: an MRI study on blood-brain barrier dysfunction

White matter lesions (WMLs) and blood-brain barrier (BBB) dysfunction are common in dementia. Both conditions may be a consequence of small-vessel disease, in which case the BBB damage would be suspected to be located to the WMLs. To further evaluate the nature of WMLs in dementia we examined 10 demented patients with WMLs, including 5 cases with elevated CSF/serum albumin ratios as an indication of BBB damage. An optimised gadolinium (Gd)-enhanced MRI technique was used including a double dose of Gd, a 30-min scan time after injection and analysis of the MR signal in the WMLs as a function over time. Results showed no significant changes in MR signal in the WMLs after contrast administration. We conclude that WMLs are not connected to BBB damage to such a degree that is detectable with this method and that the elevated CSF albumin might have another origin.     

CT and MRI rating of white matter lesions

Rating scales play an important role in the evaluation of computed tomography (CT) or magnetic resonance-detected white matter lesions (WML). Unfortunately, this type of visual semiquantitative assessment is not yet an optimal tool because commonly agreed concepts regarding its use are lacking. To generate a discussion platform for further improvement of CT and MRI rating, we will provide some basic definitions, summarize the advantages and disadvantages of scoring schemes and review current efforts towards the improvement of this tool. Future research will have to concentrate on deepening our understanding of the histopathologic substrates of WML and on strategies to document their progression.     

Postmortem MRI and histopathology of white matter changes in Alzheimer brains. A quantitative,comparative study

To evaluate whether magnetic resonance imaging (MRI) of white matter changes in Alzheimer's disease either under- or overestimates the findings on neuropathology. Postmortem MRI and neuropathological examination were performed on 6 brains from elderly individuals with a postmortem diagnosis of AD. Using a specially designed brain slicer, the brains were cut corresponding to the MRI images, and stained by Luxol Fast Blue. Quantitative analysis of white matter changes on MRI and neuropathology was performed using stereological principles. Measures from MRI and pathology were highly correlated (r(2) = 0.71). However, pathology showed significantly more extensive changes than did MRI in all cases, with a mean of 54% larger areas. The lesions not identified with MRI represented, however, only minor changes with lower intensity of myelin staining and with an accentuation of the distance between fibres but with preserved axonal network and glial cell density.     

Structural correlates of mild cognitive impairment

The structural correlates of mild cognitive impairment (MCI) were examined in 105 elderly subjects whose cognitive function ranged from intact to demented, including 38 subjects with MCI. Hippocampal volumes (left and right HcV), brain volume (BV), and grey matter volume (GMV) and white matter volume (WMV) were segmented from high resolution magnetic resonance data sets and normalised to intracranial volume (ICV). Hippocampal volume reductions, but not global brain, white or grey matter atrophy, were associated with MCI. White matter lesion severity did not differ over cognitive states. In multiple logistic regression models, normalised HcV and ICV (indicating premorbid brain volume) were significant predictors of MCI versus normality. Normalised BV and ICV significantly predicted dementia versus MCI. Absolute volumetric measures of HcV and BV yielded comparable classification accuracies. Hippocampal atrophy may be the crucial step for the transition from normality to MCI. Widespread brain atrophy may be the step to determine the transition from MCI to dementia. Brain volume reserve effects appear to be involved in both of these steps.     

Quantitative electroencephalography in mild cognitive impairment: longitudinal changes and possible prediction of Alzheimer's disease

The present study evaluated the clinical course of patients with mild cognitive impairment (MCI), the pattern of electroencephalography (EEG) changes following cognitive deterioration, as well as the potential of neurophysiological measures in predicting dementia. Twenty-seven subjects with MCI were followed for a mean follow up period of 21 months. Fourteen subjects (52%) progressed (P MCI) to clinically manifest Alzheimer's disease (AD), and 13 (48%) remained stable (S MCI). The two MCI subgroups did not differ in baseline EEG measures between each other and the healthy controls (n = 16), but had significantly lower theta relative power at left temporal, temporo-occipital, centro-parietal, and right temporo-occipital derivation when compared to the reference AD group (n = 15). The P MCI baseline alpha band temporo-parietal coherence, alpha relative power values at left temporal and temporo-occipital derivations, theta relative power values at frontal derivations, and the mean frequency at centro-parietal and temporo-occipital derivations overlapped with those for AD and control groups. After the follow-up, the P MCI patients had significantly higher theta relative power and lower beta relative power and mean frequency at the temporal and temporo-occipital derivations. A logistic regression model of baseline EEG values adjusted for baseline Mini-Mental Test Examination showed that the important predictors were alpha and theta relative power and mean frequency from left temporo-occipital derivation (T5-O1), which classified 85% of MCI subjects correctly.     

Odor identification in normal aging and early Alzheimer's disease: effects of retrieval support

Odor sensitivity and identification were examined in normal aging and early Alzheimer's disease (AD). The aims were to investigate AD as associated with lower odor sensitivity, odor identification as a function of retrieval support, and the relationship between global cognitive functioning (Mini-Mental State Exam [MMSE]; M. F. Folstein, S. E. Folstein, & P. R. McHugh, 1975) and olfactory performance. Results indicated intact odor sensitivity but deficient odor identification in AD. Both groups benefited from cues in identification, and the size of the gains was equally large in AD patients and controls. The finding of no selective benefit from retrieval support in AD suggests that a degradation of olfactory knowledge contributes to the odor identification deficits in these patients. MMSE and identification were positively related, whereas MMSE and olfactory sensitivity were unrelated. These findings suggest that the AD-related olfactory impairment stems from lesions in cortical rather than peripheral structures.     

Edema treatment during cardiac allograft rejection

BACKGROUND: Interstitial edema of rejecting organs can be correlated with the accumulation of hyaluronan in the transplant; since hyaluronan has strong water-binding capacity, treatment with the hyaluronan-degrading enzyme hyaluronidase reduces not only the hyaluronan content but also the water content of the graft. The aim of the present study was to investigate whether a further reduction of the water content would be the result if hyaluronidase was used in conjunction with classic diuretic substances. METHODS: Five days after heterotopic heart transplantation (PVG to Wistar/Kyoto), recipient rats received hyaluronidase as a continuous intravenous infusion over 2 hours together with either a loop-diuretic (furosemide) or an osmotic diuretic (mannitol). RESULTS: Hyaluronidase was found to reduce the hyaluronan contents of the grafts from 586+/-52 microg/g in control animals receiving vehicle infusion to 161+/-48 microg/g (p < 0.001) and the water contents from 81.3+/-0.4 x 10(-2) U to 79.7+/-0.4 x 10(-2) U (p < 0.05). Combined treatment with furosemide or mannitol did not affect the results and neither furosemide nor mannitol had any intrinsic capacity to affect the water or hyaluronan contents of the cardiac grafts. CONCLUSION: This experiment confirms our previous findings of hyaluronidase as an effective edema-reducing drug and indicate that no additive effect is obtained by a combined therapy with diuretics and hyaluronidase.