Association between cognitive performance and cortical glucose metabolism in patients with mild Alzheimer's disease

Background: Neuronal and synaptic function in Alzheimer's disease (AD) is measured in vivo by glucose metabolism using positron emission tomography (PET). Objective: We hypothesized that neuronal activation as measured by PET is a more sensitive index of neuronal dysfunction than activity during rest. We investigated if the correlations between dementia severity as measured with the Mini Mental State Examination (MMSE) and glucose metabolism are an artifact of brain atrophy. Method: Glucose metabolism was measured using {[}F-18]fluorodeoxyglucose PET during rest and activation due to audiovisual stimulation in 13 mild to moderate AD patients (MMSE score >= 17). PET data were corrected for brain atrophy. Results: In the rest condition, glucose metabolism was correlated with the MMSE score primarily within the posterior cingulate and parietal lobes. For the activation condition, additional correlations were within the primary and association audiovisual areas. Most local maxima remained significant after correcting for brain atrophy. Conclusion: PET activity measured during audiovisual stimulation was more sensitive to functional alterations in glucose metabolism in AD patients compared to the resting PET. The association between glucose metabolism and MMSE score was not dependent on brain atrophy. Copyright (C) 2005 S. Karger AG, Basel

Tau protein, A beta 42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies

The intra vitam diagnosis of dementia with Lewy bodies (DLB) is still based on clinical grounds. So far no technical investigations have been available to support this diagnosis. As for tau protein and beta-amyloid((1-42)) (Abeta42), promising results for the diagnosis of Alzheimer's disease ( AD) have been reported; we evaluated these markers and S-100B protein in cerebrospinal fluid (CSF), using a set of commercially available assays, of 71 patients with DLB, 67 patients with AD and 41 nondemented controls (NDC) for their differential diagnostic relevance. Patients with DLB showed significantly lower tau protein values compared to AD but with a high overlap of values. More prominent differences were observed in the comparison of DLB patients with all three clinical core features and AD patients. Abeta42 levels were decreased in the DLB and AD groups versus NDC, without significant subgroup differences. S-100B levels were not significantly different between the groups. Tau protein levels in CSF may contribute to the clinical distinction between DLB and AD, but the value of the markers is still limited especially due to mixed pathology. We conclude that more specific markers have to be established for the differentiation of these diseases. Copyright (C) 2005 S. Karger AG, Basel

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,F- 626 = 7.0, p = 0.001) and the homozygous CDC2Ex6 +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. Copyright (C) 2005 S. Karger AG, Basel

Multivariate regression methods for estimating velocity of ictal discharges from human microelectrode recordings

Objective. Epileptiform discharges, an electrophysiological hallmark of seizures, can propagate across cortical tissue in a manner similar to traveling waves. Recent work has focused attention on the origination and propagation patterns of these discharges, yielding important clues to their source location and mechanism of travel. However, systematic studies of methods for measuring propagation are lacking. Approach. We analyzed epileptiform discharges in microelectrode array recordings of human seizures. The array records multiunit activity and local field potentials at 400-micron spatial resolution, from a small cortical site free of obstructions. We evaluated several computationally efficient statistical methods for calculating traveling wave velocity, benchmarking them to analyses of associated neuronal burst firing. Main results. Over 90% of discharges met statistical criteria for propagation across the sampled cortical territory. Detection rate, direction and speed estimates derived from a multiunit estimator were compared to four field potential-based estimators: negative peak, maximum descent, high gamma power, and cross-correlation. Interestingly, the methods that were computationally simplest and most efficient (negative peak and maximal descent) offer non-inferior results in predicting neuronal traveling wave velocities compared to the other two, more complex methods. Moreover, the negative peak and maximal descent methods proved to be more robust against reduced spatial sampling challenges. Using least absolute deviation in place of least squares error minimized the impact of outliers, and reduced the discrepancies between local field potential-based and multiunit estimators. Significance. Our findings suggest that ictal epileptiform discharges typically take the form of exceptionally strong, rapidly traveling waves, with propagation detectable across millimeter distances. The sequential activation of neurons in space can be inferred from clinically-observable EEG data, with a variety of straightforward computation methods available. This opens possibilities for systematic assessments of ictal discharge propagation in clinical and research settings

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures

Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/

Neuropsychiatric symptoms in 921 elderly subjects with dementia: a comparison between vascular and neurodegenerative types.

Objective:  i) to describe the neuropsychiatric profile of elderly subjects with dementia by comparing vascular (VaD) and degenerative dementias, i.e. dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD); ii) to assess whether the severity and type of dementia are associated with clinically relevant neuropsychiatric symptoms (CR‐NPS). Method:  One hundred and thirty‐one out‐patients with VaD, 100 with DLB and 690 with AD were studied. NPS were evaluated by the neuropsychiatric inventory (NPI). Results:  Vascular dementia had lower total and domain‐specific NPI scores and a lower frequency of CR‐NPS than AD and DLB, for which frequency of CR‐NPS increased significantly with disease severity, particularly in AD. Logistic regression analysis showed that a higher CDR score and a diagnosis of degenerative dementia were independently associated with CR‐NPS. Conclusion:  Vascular dementia is associated less with CR‐NPS than AD and DLB. Frequency of CR‐NPS increases with disease severity in AD and, to a lesser extent, in DLB

Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD