Remigiusz Switalski

Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment

OBJECTIVES To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from mild cognitive impairment (MCI) to Alzheimers disease (AD). METHODS A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau(231)), amyloid beta (Abeta) Abeta(42)/Abeta(40) ratio, isoprostane (IP) as well as P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios. RESULTS At baseline and at follow-up MCI-AD showed higher levels P-tau(231), T-tau, IP, P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios and lower Abeta(42)/Abeta(40) than MCI-MCI or NL-NL. Baseline P-tau(231) best predicted MCI-AD (80%, p<0.001) followed in accuracy by P-tau(231)/Abeta(42/40) and T-tau/Abeta(42/40) ratios (both 75%, ps<0.001), T-tau (74%, p<0.001), Abeta(42)/Abeta(40) (69%, p<0.01), and IP (68%, p<0.01). Only IP showed longitudinal effects (p<0.05). CONCLUSIONS P-tau(231) is the strongest predictor of the decline from MCI to AD. IP levels uniquely show longitudinal progression effects. These results suggest the use of CSF biomarkers in secondary prevention trials.

Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease

Background: At cross-section, cognitively normal individuals (NL) with a maternal history of late-onset Alzheimer disease (AD) have reduced glucose metabolism (CMRglc) on FDG-PET in the same brain regions as patients with clinical AD as compared to those with a paternal and a negative family history (FH) of AD. This longitudinal FDG-PET study examines whether CMRglc reductions in NL subjects with a maternal history of AD are progressive. Methods: Seventy-five 50- to 82-year-old NL received 2-year follow-up clinical, neuropsychological, and FDG-PET examinations. These included 37 subjects with negative family history of AD (FH−), 9 with paternal (FHp), and 20 with maternal AD (FHm). Two subjects had parents with postmortem confirmed AD. Statistical parametric mapping was used to compare CMRglc across FH groups at baseline, follow-up, and longitudinally. Results: At both time points, the FH groups were comparable for demographic and neuropsychological characteristics. At baseline and at follow-up, FHm subjects showed CMRglc reductions in the parieto-temporal, posterior cingulate, and medial temporal cortices as compared to FH− and FHp (p < 0.001). Longitudinally, FHm had significant CMRglc declines in these regions, which were significantly greater than those in FH− and FHp (p < 0.05). Conclusions: A maternal history of Alzheimer disease (AD) predisposes normal individuals to progressive CMRglc reductions in AD-vulnerable brain regions, which may be related to a higher risk for developing AD.

Longitudinal CSF isoprostane and MRI atrophy in the progression to AD

Very little data exist to evaluate the value of longitudinal CSF biological markers for Alzheimers disease (AD).Most studies indicate that tau and amyloid beta markers do not reflect disease progression. We now report on a longitudinal, three-time point, CSF Isoprostane (IsoP) and quantitative MRI study that examined 11 normal elderly (NL) volunteers and 6 Mild Cognitive Impairment (MCI) patients. After 4 years, all 6 MCI patients declined to AD and 2 of the NL subjects declined to MCI. At baseline and longitudinally, the MCI patients showed reduced delayed memory, increased IsoP levels, and reduced medial temporal lobe gray matter concentrations as compared to NL. A group comprised of all decliners to AD or to MCI (n = 8) was distinguished at baseline from the stable NL controls (n = 9) by IsoP with 100% accuracy.Moreover, both at baseline and longitudinally, the IsoP measures significantly improved the diagnostic and predictive outcomes of conventional memory testing and quantitative MRI measurements. These data indicate that IsoP is potentially useful for both the early detection of AD-related pathology and for monitoring the course of AD.

The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease.

While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimers disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60+/-10 years, range 36-86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Abeta42/Abeta40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by epsilon4 genotype interactions were found for P-tau231 (beta=1.82; p<0.05) and IP (beta=1.6; p<0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in epsilon4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Abeta changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study.

Magnetic Resonance Imaging Improves Cerebrospinal Fluid Biomarkers in the Early Detection of Alzheimer's Disease

Little is known of combined utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers for prediction of Alzheimers disease (AD) and longitudinal data is scarce. We examined these biomarkers at baseline and longitudinally in incipient AD. Forty-five subjects [21 controls (NL-NL), 16 stable MCI (MCI-MCI), 8 MCI who declined to AD (MCI-AD)] received MRI and lumbar puncture at baseline and after 2 years. CSF measures included total and phosphorylated tau (T-tau, P-tau(231)), amyloid-beta (Abeta(42)/Abeta(40)) and isoprostane. Voxel-based morphometry identified gray matter concentration (GMC) differences best distinguishing study groups and individual GMC values were calculated. Rate of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC-MTL, and for CSF higher CSF T-tau, P-tau(231), IP and lower Abeta(42)/Abeta(40) as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of isoprostane in MCI-AD as compared with NL-NL. Combining baseline CSF-P-tau(231) and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (p(step)<0.05). These results provide support for including multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia.

Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia

Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimers disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL = 18, 69.9 ± 6.7 years) and subjects with mild cognitive impairment (MCI = 15, 74.9 ± 8.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL = 17, MCI = 7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (ρ = −0.41, P = 0.049) and global cortical (ρ = −0.46, P = 0.02) vasoreactivity to hypercapnia (VRh). The FCRP–VRh relationships were most pronounced in the MCI group: hippocampus (ρ = 0.77, P = 0.04); global cortex (ρ = 0.83, P = 0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VRh was lower in MCI than in NL subjects (Z = −2.0, P = 0.047). This difference persisted after age and FCRP correction (F[3,20] = 4.6, P = 0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VRh is more sensitive to vascular burden than either resting CBF or brain volume.

Hippocampal blood flow in normal aging measured with arterial spin labeling at 3T

Due to methodological difficulties related to the small size, variable distribution of hippocampal arteries, and the location of the hippocampus in the proximity of middle cranial fossa, little is known about hippocampal blood flow (HBF). We have tested the utility of a pulsed arterial spin labeling sequence based on multi‐shot true fast imaging in steady precession to measure HBF in 34 normal volunteers (17 women, 17 men, 26–92 years old). Flow sensitivity to a mild hypercapnic challenge was also examined. Coregistered 3D MPRAGE sequence was used to eliminate from hippocampal and cortical regions of interest all voxel with <75% of gray matter. Large blood vessels were also excluded. HBF in normal volunteers averaged 61.2 ± 9.0 mL/(100 g min). There was no statistically significant age or gender effect. Under a mild hypercapnia challenge (end tidal CO2 pressure increase of 6.8 ± 1.9 mmHg over the baseline), HBF response was 14.1 ± 10.8 mL/(100 g min), whereas cortical gray matter flow increased by 18.0 ± 12.2 mL/(100 g min). Flow response among women was significantly larger than in the men. The average absolute difference between two successive HBF measures was 3.6 mL/(100 g min) or 5.4%. The 3T true fast imaging in steady precession arterial spin labeling method offers a HBF measurement strategy that combines good spatial resolution, sensitivity, and minimal image distortions. Magn Reson Med, 2010.

An Entorhinal Cortex Sulcal Pattern is Associated with Alzheimer's Disease

Magnetic resonance (MRI) studies rely on sulcal boundaries to delineate the human entorhinal cortex (EC) and typically show that EC size is reduced in Alzheimers disease (AD) and a predictor of future dementia. However, it is unknown if variations in the EC sulcal patterns are associated with AD. We classified the lateral EC sulcal boundary as either a rhinal or collateral pattern and tested the hypotheses that the rhinal pattern was (1) more common in AD and (2) associated with a smaller EC size.

Effects of memantine on cerebrospinal fluid biomarkers of neurofibrillary pathology.

Previous studies showed that memantine inhibits tau hyperphosphorylation in vitro. In this study, phosphorylated tau (P-tau) and total tau (T-tau) were measured before and after 6 month treatment with memantine in 12 subjects ranging from normal cognition with subjective memory complaints, through mild cognitive impairment to mild Alzheimers disease. Thirteen non-treated individuals served as controls. Treatment was associated with a reduction of P-tau in subjects with normal cognition. No treatment effects were seen among impaired individuals, suggesting that longer treatment time may be necessary to achieve biomarker effect in this group.