Tomasz Sobow

Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.

Frontotemporal lobar degeneration (FTLD) is the most common cause of early‐onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans‐activating response element (TAR) DNA binding protein (TDP‐43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD‐MND pedigree with no mutations in known dementia genes.

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review

IntroductionThere is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia.MethodsThe databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review.ResultsIn 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer’s disease and healthy controls.ConclusionIADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

Education increases reserve against Alzheimer’s disease—evidence from structural MRI analysis

IntroductionThe aim of this study was to determine whether years of schooling influences regional cortical thicknesses and volumes in Alzheimer’s disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls.MethodsUsing an automated image analysis pipeline, 33 regional cortical thickness and 15 regional volumes measures from MRI images were determined in 121 subjects with MCI, 121 patients with AD, and 113 controls from AddNeuroMed study. Correlations with years of schooling were determined and more highly and less highly educated subjects compared, controlling for intracranial volume, age, gender, country of origin, cognitive status, and multiple testing.ResultsAfter controlling for confounding factors and multiple testing, in the control group, subjects with more education had larger regional cortical thickness in transverse temporal cortex, insula, and isthmus of cingulate cortex than subjects with less education. However, in the AD group, the subjects with more education had smaller regional cortical thickness in temporal gyrus, inferior and superior parietal gyri, and lateral occipital cortex than the subjects with less education. No significant difference was found in the MCI group.ConclusionEducation may increase regional cortical thickness in healthy controls, leading to increased brain reserve, as well as helping AD patients to cope better with the effects of brain atrophy by increasing cognitive reserve.

Analysis of regional MRI volumes and thicknesses as predictors of conversion from mild cognitive impairment to Alzheimer's disease

We determined predictors of conversion to Alzheimers disease (AD) from mild cognitive impairment (MCI) with automated magnetic resonance imaging (MRI) regional cortical volume and thickness measures. One hundred amnestic MCI subjects, 118 AD patients, and 94 age-matched healthy controls were selected from AddNeuroMed study. Twenty-four regional cortical volumes and 34 cortical thicknesses were measured with automated image processing software at baseline. Twenty-one subjects converted from MCI to AD determined with the cognitive tests at baseline and 1 year later. The hippocampus, amygdala, and caudate volumes were significantly smaller in progressive MCI subjects than in controls and stable MCI subjects. The cortical volumes achieved higher predictive accuracy than did cognitive tests or cortical thickness. Combining the volumes, thicknesses, and cognitive tests did not improve the accuracy. The volume of amygdala and caudate were independent variables in predicting conversion from MCI to AD. We conclude that regional cortical volume measures are more powerful than those common cognitive tests we used in identifying AD patients at the very earliest stage of the disease.

Biochemical markers and risk factors of Alzheimer's disease.

As the spectrum of therapeutic options broadens, the possibility of an early and accurate diagnosis of Alzheimers disease (AD), or even isolation of a group at high risk of subsequent cognitive decline, is focusing widespread attention. Therefore, biological markers or risk factors of AD are highly desirable. In this work, we give an overview of the most extensively studied AD biomarkers, namely beta-amyloid, tau protein, and phosphorylated tau-protein, alone or in combination. Moreover, we describe the role of inflammatory markers (cytokines, acute phase proteins), oxidative stress markers (isoprostanes, 8-hydroxyguanine, 3-nitrotyrosine, plasma antioxidants, redox transition metals), homocysteine and related vitamins, cholesterol and 24S-hydroxycholesterol in the diagnostic process or prediction of AD. We briefly review less popular, though promising markers of AD - markers of apoptosis, neuronal thread protein, acetyl- and butyrylcholinesterase, sulfatide, kallikreins, matrix-degrading metalloproteinases, and novel isoforms of beta-amyloid and tau. Finally, we discuss the clinical applicability of AD-related biological markers.

Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland

Mutations in three causative genes have been identified in patients with an autosomal-dominant form of early-onset Alzheimers disease (EOAD). To determine the spectrum of mutations in a group consisting of 40 Polish patients with clinically diagnosed familial EOAD and 1 patient with mild cognitive impairment (MCI) and family history of AD, we performed a screening for mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) genes. Four previously recognized pathogenic mutations in PSEN1 gene (H163R, M139V) and APP gene (T714A, V715A), and three novel putative mutations in PSEN1 gene (P117R and I213F) and PSEN2 gene (Q228L) were identified. The 34 patients with no mutations detected were older than the patients with mutations. A frequency of APOE4 allele was higher in this group. Frequency of mutations is relatively low (17%), possibly due to used operational definition of a patient with familial EOAD (a patient having at least one relative with early-onset dementia). It could be concluded that screening for mutations in the three genes could be included in a diagnostic program directed at patients with a positive family history or age of onset before 55 years.

Effect of APOE ε4 allele on cortical thicknesses and volumes: the AddNeuroMed study.

The apolipoprotein E (APOE) ε4 allele is a risk factor for Alzheimers disease (AD), but its effect on brain volumes is controversial. We explored the effect of the ε4 allele on regional cortical thickness and volume measurements using an automated pipeline in 111 subjects with mild cognitive impairment (MCI), 115 AD patients, and 107 age-matched healthy controls. The clinical data were used as covariates in the thickness and volume comparisons. The ε4 carriers had significantly smaller volume than non-carriers in caudate (p=0.028) in controls; in amygdala and caudate in the MCI group (p <or= 0.049); and in hippocampus and amygdala in the AD group (p <or= 0.001). In the female subjects, the ε4 carriers had significantly thinner cortical thickness or smaller volume than non-carriers in medial orbitofrontal gyrus and caudate in controls (p <or= 0.014); in amygdala in MCI subjects (p=0.047) and in hippocampus and amygdala in AD patients (p <or= 0.024). However, in the male subjects, there were significant differences in cortical thickness and volume between ε4 carriers and non-carriers in several structures in the MCI group, but no differences in the controls and AD patients. Compared to the non-carriers, the homozygous ε4 carriers showed significant volume loss in hippocampus, deep nuclei, and caudal anterior cingulate cortex in MCI. In the AD group, the homozygous ε4 carriers had significant volume loss in hippocampus and amygdala. We conclude that the APOE ε4 allele modulates regional cortical thickness and volume in relation to diagnostic group and gender. The ε4 allele has a dose-dependent and regionally specific effect on brain structures.

Combination analysis of neuropsychological tests and structural MRI measures in differentiating AD, MCI and control groups—The AddNeuroMed study

To study the ability of neuropsychological tests, manual MRI hippocampal volume measures, regional volume and cortical thickness measures to identify subjects with Alzheimers disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls. Neuropsychological tests, manual hippocampal volume, automated regional volume and regional cortical thickness measures were performed in 120 AD patients, 120 MCI subjects, and 111 controls. The regional cortical thickness and volumes in MCI subjects were significantly decreased in limbic/paralimbic areas and temporal lobe compared to controls. Atrophy was much more extensive in the AD patients compared to MCI subjects and controls. The combination of neuropsychological tests and volumes revealed the highest accuracy (82% AD vs. MCI; 94% AD vs. control; 83% MCI vs. control). Adding regional cortical thicknesses into the discriminate analysis did not improve accuracy. We conclude that regional cortical thickness and volume measures provide a panoramic view of brain atrophy in AD and MCI subjects. A combination of neuropsychological tests and regional volumes are important when discriminating AD from healthy controls and MCI.

Ultrastructural study of florid plaques in variant Creutzfeldt-Jakob disease: a comparison with amyloid plaques in kuru, sporadic Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease.

Background: Although the histological features of the amyloid plaques in variant Creutzfeldt–Jakob disease (vCJD) are distinct from those in other forms of prion disease [kuru, sporadic Creutzfeldt–Jakob disease (sCJD) and Gerstmann–Sträussler–Scheinker disease (GSS)], their ultrastructural features have only been described in a single case report. Aims: To study vCJD plaques systematically and compare them with plaques in kuru, sCJD, GSS and Alzheimer disease (AD). Methods: Amyloid plaques were studied by transmission electron microscopy and image analysis in five cases of vCJD, three cases of GSS, two cases of sCJD, one case of kuru and five cases of AD. Immunohistochemistry was performed on paraffin sections from one case of vCJD, two cases of GSS, one case of kuru and two cases of sCJD. Results: The florid plaques in vCJD were either compact or more diffuse; in both forms, the radiating fibrils were organized into thick ‘tongues’, in contrast to kuru plaques. Dystrophic neurites (DNs) containing lysosomal electron‐dense bodies or vesicles surrounded florid plaques. Microglial cells were found within florid plaques; occasional amyloid fibrils were identified in membrane‐bound pockets of microglial cells. In vCJD, there was significant tau immunoreactivity in DNs around florid plaques while, in sCJD, GSS and kuru, minimal tau immunoreactivity was observed around plaques. Conclusions: The ultrastructure of the florid plaques and DNs in vCJD is more reminiscent of neuritic plaques in AD than kuru or multicentric plaques. These findings may reflect differences both in the strains of the transmissible agents responsible for these disorders and in host factors.

APOE ε2 Allele Is Associated with Larger Regional Cortical Thicknesses and Volumes

Background: The protective effect of the apolipoprotein E (APOE) Ε2 allele against Alzheimer’s disease (AD) is controversial. Objective: Our purpose was to clarify if the Ε2 allele affects regional cortical thicknesses and volumes. Methods: Regional cortical thicknesses and volumes were measured with an automated pipeline in 109 subjects with mild cognitive impairment, 114 AD patients and 105 age-matched healthy controls. Results: In the mild cognitive impairment group, the Ε2 carriers had thicker regional cortices at the transverse temporal cortex and parahippocampal gyrus than the subjects with Ε3/Ε3, and a larger cerebral gray matter and smaller lateral ventricles than the Ε3/Ε3 and Ε4 carriers. In the AD group, the Ε2 carriers had significantly thicker entorhinal and transverse temporal cortices, a larger whole cerebral gray matter, and smaller lateral ventricles than the subjects with the Ε3/Ε3 genotype, and a significantly thicker entorhinal cortex and larger cerebral gray matter than Ε4 carriers. No APOE2 effect was found in the control group. Conclusion: The APOE Ε2 allele is associated with larger regional cortical thicknesses and volumes in mild cognitive impairment and AD.