OBJECTIVE: To compare cognitive phenotypes of participants with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI), estimate progression to MCI/dementia by phenotype and assess classification error with machine learning. METHOD: Dataset consisted of 163 participants with SCD and 282 participants with aMCI from the Czech Brain Aging Study. Cognitive assessment included the Uniform Data Set battery and additional tests to ascertain executive function, language, immediate and delayed memory, visuospatial skills, and processing speed. Latent profile analyses were used to develop cognitive profiles, and Cox proportional hazards models were used to estimate risk of progression. Random forest machine learning algorithms reported cognitive phenotype classification error. RESULTS: Latent profile analysis identified three phenotypes for SCD, with one phenotype performing worse across all domains but not progressing more quickly to MCI/dementia after controlling for age, sex, and education. Three aMCI phenotypes were characterized by mild deficits, memory and language impairment (dysnomic aMCI), and severe multi-domain aMCI (i.e., deficits across all domains). A dose-response relationship between baseline level of impairment and subsequent risk of progression to dementia was evident for aMCI profiles after controlling for age, sex, and education. Machine learning more easily classified participants with aMCI in comparison to SCD (8% vs. 21% misclassified). CONCLUSIONS: Cognitive performance follows distinct patterns, especially within aMCI. The patterns map onto risk of progression to dementia.

• Klíčová slova
• Machine learning, Mild cognitive impairment, Neuropsychological performance, Prospective cohort study, Subjective cognitive complaints, Transition to dementia,
• MeSH
• fenotyp MeSH
• kognice MeSH
• kognitivní dysfunkce * komplikace   MeSH
• lidé MeSH
• mozek MeSH
• neuropsychologické testy MeSH
• senioři MeSH
• stárnutí MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Bardet-Biedl syndrome (BBS) is a recessive genetic disease causing multiple organ anomalies. Most patients carry mutations in genes encoding for the subunits of the BBSome, an octameric ciliary transport complex, or accessory proteins involved in the BBSome assembly or function. BBS proteins have been extensively studied using in vitro, cellular, and animal models. However, the molecular functions of particular BBS proteins and the etiology of the BBS symptoms are still largely elusive. In this study, we applied a meta-analysis approach to study the genotype-phenotype association in humans using our database of all reported BBS patients. The analysis revealed that the identity of the causative gene and the character of the mutation partially predict the clinical outcome of the disease. Besides their potential use for clinical prognosis, our analysis revealed functional differences of particular BBS genes in humans. Core BBSome subunits BBS2, BBS7, and BBS9 manifest as more critical for the function and development of kidneys than peripheral subunits BBS1, BBS4, and BBS8/TTC8, suggesting that incomplete BBSome retains residual function at least in the kidney.

• Klíčová slova
• BBS, BBSome, Bardet-Biedl syndrome, ciliopathy, genotype-phenotype, kidney disease, meta-analysis, rare disease,
• MeSH
• ADP-ribosylační faktory genetika   MeSH
• Bardetův-Biedlův syndrom diagnóza   genetika   MeSH
• fenotyp * MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie * metody   MeSH
• genotyp * MeSH
• kognitivní dysfunkce genetika   MeSH
• ledviny abnormality   MeSH
• lidé MeSH
• mutace MeSH
• nemoci ledvin vrozené   genetika   MeSH
• penetrance MeSH
• proteiny genetika   MeSH
• vrozené vady genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ADP-ribosylační faktory MeSH
• ARL6 protein, human MeSH Prohlížeč
• Bbs2 protein, human MeSH Prohlížeč
• proteiny MeSH

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

• Klíčová slova
• behavioral phenotype, cognitive impairment, iNTD, intelligence, neurotransmitter deficiencies, quality of life,
• MeSH
• chování MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp * MeSH
• inteligence MeSH
• internacionalita MeSH
• kognitivní dysfunkce etiologie   MeSH
• kojenec MeSH
• kvalita života * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neurotransmiterové látky nedostatek   MeSH
• předškolní dítě MeSH
• registrace MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• neurotransmiterové látky MeSH

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease that seriously affects the brain. Severity of neurocognitive symptoms in attenuated MPS subtype (MPS IA) broadly varies partially, due to restricted permeability of blood-brain barrier (BBB) which limits treatment effects of intravenously applied α-L-iduronidase (rhIDU) enzyme. Intrathecal (IT) rhIDU application as a possible solution to circumvent BBB improved brain outcomes in canine models; therefore, our study quantifies effects of IT rhIDU on brain structure and function in an MPS IA patient with previous progressive cognitive decline. Neuropsychological testing and MRIs were performed twice prior (baseline, at 1 year) and twice after initiating IT rhIDU (at 2nd and 3rd years). The difference between pre- and post-treatment means was evaluated as a percentage of the change. Neurocognitive performance improved particularly in memory tests and resulted in improved school performance after IT rhIDU treatment. White matter (WM) integrity improved together with an increase of WM and corpus callosum volumes. Hippocampal and gray matter volume decreased which may either parallel reduction of glycosaminoglycan storage or reflect typical longitudinal brain changes in early adulthood. In conclusion, our outcomes suggest neurological benefits of IT rhIDU compared to the intravenous administration on brain structure and function in a single MPS IA patient.© 2017 Wiley Periodicals, Inc.

• Klíčová slova
• blood-brain barrier, brain, diffusion tensor imaging, enzyme replacement therapy, intrathecal administration, magnetic resonance imaging, mucopolysaccharidosis, neuropsychology,
• MeSH
• bílá hmota účinky léků   patologie   MeSH
• enzymová substituční terapie * škodlivé účinky   metody   MeSH
• fenotyp MeSH
• iduronidasa aplikace a dávkování   škodlivé účinky   MeSH
• kognitivní dysfunkce farmakoterapie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mladý dospělý MeSH
• mukopolysacharidóza I diagnóza   farmakoterapie   psychologie   MeSH
• neuropsychologické testy MeSH
• spinální injekce MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• iduronidasa MeSH

OBJECTIVE: In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype. METHODS: We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid1-42 and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+. RESULTS: A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in APOE ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype. CONCLUSIONS: Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.

• MeSH
• amyloidní beta-protein mozkomíšní mok   metabolismus   MeSH
• apolipoprotein E4 genetika   MeSH
• biologické markery metabolismus   MeSH
• demence s Lewyho tělísky klasifikace   komplikace   metabolismus   patofyziologie   MeSH
• fenotyp MeSH
• kognitivní dysfunkce etiologie   patofyziologie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidové fragmenty mozkomíšní mok   MeSH
• pozitronová emisní tomografie MeSH
• proteiny tau mozkomíšní mok   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• amyloid beta-protein (1-42) MeSH Prohlížeč
• amyloidní beta-protein MeSH
• apolipoprotein E4 MeSH
• biologické markery MeSH
• peptidové fragmenty MeSH
• proteiny tau MeSH

A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson's disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions.

• MeSH
• fenotyp MeSH
• kognice fyziologie   MeSH
• lidé MeSH
• nervový přenos fyziologie   MeSH
• odměna * MeSH
• poruchy příjmu potravy patofyziologie   MeSH
• prefrontální mozková kůra patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Mucopolysaccharidosis type II (Hunter syndrome, MPS II, OMIM 309900) is an X-linked lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS). We analyzed clinical and laboratory data from 44 Slavic patients with this disease. In total, 21 Czech, 7 Slovak, 9 Croatian and 7 Serbian patients (43 M/1 F) were included in the study (median age 11.0 years, range 1.2-43 years). Birth prevalence ranged from 1:69,223 (Serbia) to 1:192,626 (Czech Rep.). In the majority of patients (71%), the disease manifested in infancy. Cognitive functions were normal in 10 patients. Four, six and 24 patients had mild, moderate, and severe developmental delay, respectively, typically subsequent to developmental regression (59%). Residual enzyme activity showed no predictive value, and estimation of glycosaminoglycans (GAGs) had only limited importance for prognosis. Mutation analysis performed in 36 families led to the identification of 12 novel mutations, eight of which were small deletions/insertions. Large deletions/rearrangements and all but one small deletion/insertion led to a severe phenotype. This genotype-phenotype correlation was also identified in six cases with recurrent missense mutations. Based on patient genotype, the severity of the disease may be predicted with high probability in approximately half of MPS II patients.

• Klíčová slova
• Hunter syndrome, MPS II, Slavic origin, genotype-phenotype correlation, mucopolysaccharidosis type II,
• MeSH
• dítě MeSH
• dospělí MeSH
• genetické asociační studie MeSH
• glykoproteiny genetika   MeSH
• glykosaminoglykany moč   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mukopolysacharidóza II etiologie   genetika   MeSH
• mutace * MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Chorvatsko MeSH
• Slovenská republika MeSH
• Srbsko MeSH
• Názvy látek
• glykoproteiny MeSH
• glykosaminoglykany MeSH
• IDS protein, human MeSH Prohlížeč

Huntington's disease (HD) is an inherited devastating neurodegenerative disease with no known cure to date. Several therapeutic treatments for HD are in development, but their safety, tolerability and efficacy need to be tested before translation to bedside. The monogenetic nature of this disorder has enabled the generation of transgenic animal models carrying a mutant huntingtin (mHTT) gene causing HD. A large animal model reflecting disease progression in humans would be beneficial for testing the potential therapeutic approaches. Progression of the motor, cognitive and behavioral phenotype was monitored in transgenic Huntington's disease minipigs (TgHD) expressing the N-terminal part of human mHTT. New tests were established to investigate physical activity by telemetry, and to explore the stress-induced behavioral and cognitive changes in minipigs. The longitudinal study revealed significant differences between 6- to 8-year-old TgHD animals and their wild-type (WT) controls in a majority of the tests. The telemetric study showed increased physical activity of 4.6- to 6.5-year-old TgHD boars compared to their WT counterparts during the lunch period as well as in the afternoon. Our phenotypic study indicates progression in adult TgHD minipigs and therefore this model could be suitable for longstanding preclinical studies of HD.This article has an associated First Person interview with the first author of the paper.

• Klíčová slova
• Cognitive and behavioral studies, Huntington's disease, Large animal model, Motor, Phenotyping,
• MeSH
• chování zvířat fyziologie   MeSH
• geneticky modifikovaná zvířata MeSH
• Huntingtonova nemoc komplikace   patofyziologie   MeSH
• jazyk MeSH
• kognice fyziologie   MeSH
• kondiční příprava zvířat MeSH
• longitudinální studie MeSH
• miniaturní prasata MeSH
• modely nemocí na zvířatech MeSH
• pohybová aktivita * MeSH
• prasata MeSH
• psychický stres komplikace   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Neurodegenerative diseases of childhood present with progressive decline in cognitive, social, and motor function and are frequently associated with seizures in different stages of the disease. Here we report a patient with severe progressive neurodegeneration with drug-resistant epilepsy of unknown etiology from the age of 2 years. METHODS AND RESULTS: Using whole exome sequencing, we found heterozygous missense de novo variant c.628G > A (p.Glu210Lys) in the UBTF gene. This variant was recently described as de novo in 11 patients with similar neurodegeneration characterized by developmental decline initially confined to motor development followed by language regression, appearance of an extrapyramidal movement disorder, and leading to severe intellectual disability. In 3 of the 11 patients described so far, seizures were also present. CONCLUSIONS: Our report expands the complex phenotype of neurodegeneration associated with the c.628G > A variant in the UBTF gene and helps to clarify the relation between this one single recurrent pathogenic variant described in this gene to date and its phenotype. The UBTF gene should be considered a novel candidate gene in neurodegeneration with or without epilepsy.

• MeSH
• fenotyp * MeSH
• lidé MeSH
• mladiství MeSH
• mutace genetika   MeSH
• neurodegenerativní nemoci komplikace   diagnostické zobrazování   genetika   MeSH
• refrakterní epilepsie komplikace   diagnostické zobrazování   genetika   MeSH
• transkripční iniciační komplex Pol1 - proteiny genetika   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• transcription factor UBF MeSH Prohlížeč
• transkripční iniciační komplex Pol1 - proteiny MeSH

BACKGROUND: While several novel therapeutic approaches for HD are in development, resources to conduct clinical trials are limited. Large animal models have been proposed to improve assessment of safety, tolerability and especially to increase translational reliability of efficacy signals obtained in preclinical studies. They may thus help to select candidates for translation to human studies. We here introduce a battery of novel tests designed to assess the motor, cognitive and behavioral phenotype of a transgenic (tg) HD minipig model. NEW METHODS: A group of tgHD and wildtype (wt) Libechov minipigs (n=36) was available for assessment with (1) a gait test using the GAITRite(®) automated acquisition system, (2) a hurdle-test, (3) a tongue coordination test, (4) a color discrimination test, (5) a startbox back and forth test and (6) a dominance test. Performance of all tests and definition of measures obtained is presented. RESULTS: Minipigs were able to learn performance of all tests. All tests were safe, well tolerated and feasible. Exploratory between group comparisons showed no differences between groups of tgHD and wt minipigs assessed, but low variability within and between groups. COMPARISON WITH EXISTING METHOD(S): So far there are no established or validated assessments to test minipigs in the domains described. CONCLUSIONS: The data shows that the tests presented are safe, well tolerated and all measures defined can be assessed. Prospective longitudinal application of these tests is warranted to determine their test-retest reliability, sensitivity and validity in assessing motor, cognitive and behavioral features of tg and wt minipigs.

• Klíčová slova
• Animal models, Behavioral, Cognitive, Minipig, Motor, Phenotyping, Preclinical research,
• MeSH
• chování zvířat * MeSH
• chůze (způsob) fyziologie   MeSH
• design vybavení MeSH
• diskriminace (psychologie) fyziologie   MeSH
• fenotyp MeSH
• geneticky modifikovaná zvířata * MeSH
• Huntingtonova nemoc genetika   MeSH
• jazyk patofyziologie   MeSH
• lidé MeSH
• miniaturní prasata genetika   fyziologie   psychologie   MeSH
• modely nemocí na zvířatech * MeSH
• neuropsychologické testy MeSH
• pohybová aktivita fyziologie   MeSH
• prasata MeSH
• protein huntingtin genetika   metabolismus   MeSH
• studie proveditelnosti MeSH
• učení fyziologie   MeSH
• vidění barevné fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• HTT protein, human MeSH Prohlížeč
• protein huntingtin MeSH