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Neurodegeneration with brain iron accumulation (NBIA) encompasses a number of heritable disorders affecting children and adults characterized by diverse clinical manifestations and brain iron deposition detected on magnetic resonance imaging (MRI). The most frequent NBIA subtypes are pantothenate kinase-associated neurodegeneration, phospholipase A2-associated neurodegeneration, fatty acid-2 hydroxylase- associated neurodegeneration and mitochondrial- membrane proteinassociated neurodegeneration (MPAN). Here, we report a male patient presenting with optic atrophy, progressive cognitive and movement impairment, bilateral hypointensity of the basal ganglia on T2-weighted MRI and proven mutation for MPAN. The NBIA disorders can remain undiagnosed for 3 to 30 years. In children developing optic atrophy, NBIA should be taken into consideration.

Introduction: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are characterized by different phases of cognitive decline. In AD, there is a progressive impairment of acquired cognitive abilities while subjects with MCI show less severe cognitive disturbances. Cognitive dysfunction develops as a result of the complex interactions between multiple genetic, epigenetic, developmental, and environmental factors. Among many genes involved in cognition is the gene coding for catechol- O-methyltransferase (COMT), the enzyme responsible for the degradation of dopamine, resulting in the modulation of dopaminergic function. Therefore, COMT genetic variants were studied in various dementias characterized by cognitive loss. The aim of the study was to evaluate the possible association between COMT rs6269 and COMT rs4680 polymorphisms and cognitive decline in subjects with AD and MCI. Methods: Cognitive deterioration was assessed with the Mini-Mental State Examination (MMSE) and the Clock Drawing test (CDT) scores in 193 patients with AD and 269 subjects with MCI. COMT rs6269 and COMT rs4680 (Val158Met) were genotyped using the real-time PCR. Multiple linear regressions and Kruskal Wallis ANOVA were used to detect the association of the COMT rs6269 or COMT rs4680 genotypes with cognitive decline. Results: Multiple linear regression showed that COMT rs6269 was significantly associated with MMSE and CDT scores and these effects were affected by diagnosis and COMT rs6269 genotypes and age. In contrast, multiple linear regression revealed that COMT rs4680 was not significantly associated with MMSE or CDT scores, and the only significant effects were found for age and diagnosis. To further evaluate the effect of COMT polymorphisms on cognition, all subjects were subdivided into AA, GA, or GG genotype carriers of the COMT rs6269 or COMT rs4680, respectively, and according to MMSE or CDT scores. Carriers of the GG genotype of the COMT rs6269 had significantly (p=0.007) lower CDT scores than AA carriers, while other genotype groups did not differ significantly according to the CDT or MMSE scores. Conclusion: Although COMT rs4680 (Val158Met) was reported to be related to cognitive loss in various neuropsychiatric disorders, present results revealed a significant association between the other COMT polymorphism, rs6269, with cognitive deterioration in dementia.

In addition to amyloid β and tau protein pathology, Alzheimer's disease (AD) is characterized by dysregulation of the inflammatory response. The main objective of this study was to find out how the concentrations of immune mediators (cytokines and chemokines) differ between AD, patients with mild cognitive impairment (MCI), and healthy controls (HC) in two different types of samples, cerebrospinal fluid (CSF) and plasma. We also wanted to determine the cytokine profile for each group. Using the Bio-Plex Pro Human Cytokine 48-Plex Screening Panel, we determined the levels of 35 cytokines in CSF and 47 in plasma samples. Twenty-nine AD, 35 MCI, and 40 HC CSF and 102 AD, 37 MCI, and 10 HC plasma samples were analyzed. In the plasma samples, only 4 cytokines differed significantly between the groups (CTACK, IL-12 (p40), IL-4, IL1Rα), whereas analysis of the CSF samples revealed significantly different levels of 15 immune mediators (IL-1β, IL-1α, IL-3, IL-4, IL-7, IL-16, IL-17A, IL-18, IFN-γ, GRO-α, MIP-1β, CTACK, TNF-α, IL-2Rα, IP-10). Most of the mediators whose levels differed significantly were increased in the AD group ; only IP-10 had the highest levels in the MCI group. CSF analysis showed that the AD group was characterized by a pro-inflammatory profile and a higher rate of an adaptive immune response. Higher levels of predominantly pro-inflammatory cytokines (IL-1β, IL-18, MIG, EOTAXIN, MIP-1α, MIP-1β, TNF-β) were associated with higher levels of cognitive deficits. This study has shown that measurement of immune mediators in CSF, but not in plasma, may be a good strategy to track the immune response during disease progression and could be a promising tool for evaluating potential future immune and anti-inflammatory interventions.

The CACNA1A gene encodes the voltage-gated P/Q- type calcium channel that mediates neurotransmitter release by promoting the flow of calcium ions to stimulate the presynaptic membrane. Progressive myoclonic epilepsy (PME) represents distinct clinical entities characterized by substantial clinical and genetic variability. We report a 32-year-old patient with the myoclonic epilepsy, mild cognitive deterioration, nystagmus, intention and postural tremor, and gait disturbance. Due to neurological findings, we evaluated the patient as possible PME. During controls at our Referral Centre for Epilepsy, patient didn’t show progression in neurological decline as would be expected in patients with PME, so we performed targeted next generation sequencing of 142 epilepsy genes. Sequencing revealed novel missense CACNA1A variant. Several neurological disorders are caused by pathogenic variants in CACNA1A including the familial hemiplegic migraine, spinocerebellar ataxia type 6, and episodic ataxia type 2. Patients with epilepsy due to pathogenic variants in CACNA1A have been previously described in literature. Epilepsy types were referred as generalized seizure (absence), while in some cases they were described as generalized, but it was not clearly defined whether they were myoclonic seizures. We believe that the clinical presentation of our patient may be related to the known clinical presentation of CACNA1A pathogenic variants, but at this point we cannot fully implement the patient`s symptoms into one of the three most reported CACNA1A related disorders or consider him as PME.

Uvod. Autoinflamatorne bolesti klinički su poremećaji kojima je u podlozi poremećena regulacija prirođene imunosti, a obilježene su kontinuiranom ili ponavljajućom upalom. U svjetlu novih spoznaja govori se o poremećajima imunosne regulacije koji uključuju autoimunosne, autoinflamatorne bolesti i primarne imunodeficijencije jer se u većine bolesti iz ovog spektra u različitom stupnju preklapaju fenotipske značajke navedena tri procesa. Do danas je poznato preko 40 različitih monogenskih autoinflamatornih bolesti te je otkriveno preko 800 genskih varijanti povezanih s autoinflamatornim bolestima. U dijagnostici ovih bolesti posebno mjesto ima genska dijagnostika koja je, osim za potvrdu ili isključivanje dijagnoze, bitna zbog odabira ciljane terapije koja djeluje na signalni put zahvaćen u pojedinoj bolesti. Ispitanici i metode. Temeljem pregleda literature, istraživanja i usporedbom kliničke prakse iz različitih centara izvrsnosti konstruirali smo imunogenski panel koji sadrži 400 gena povezanih s 8 skupina bolesti iz spektra poremećaja imunosne regulacije. Rezultati. Skupine bolesti obuhvaćene imunogenskim panelom uključuju monogenske autoinflamatorne bolesti, poremećaje imunosne regulacije i srodne bolesti s elementima autoinflamacije (85 gena), primarne imunodeficijencije (129 gena), monogenske oblike sistemskog eritemskog lupusa i bolesti nalik lupusu (90 gena), nedostatak komponenti komplementa i regulatornih proteina (23 gena), hemofagocitnu limfohistiocitozu/sindrom aktivacije makrofaga (9 gena), monogenske vaskulitise i vaskulopatije (8 gena) i ostale bolesti(leukemije, intestinalne inflamacije, autoimune enteropatije) zastupljene s 88 gena. Glavna je indikacija za testiranje prisutnost simptoma koji su kompatibilni za jednu ili više bolesti iz skupine bolesti obuhvaćenih imunogenskim panelom. Varijante utvrđene sekvenciranjem imunogenskog panela mogu se podijeliti na patogene, vjerojatno patogene, varijante nejasnog kliničkog značaja, vjerojatno benigne i benigne. Samo patogene i vjerojatno patogene varijante imaju dijagnostičko i terapijsko značenje. Zaključak. Genski testovi dio su standardne obrade bolesnika sa sumnjom na autoinflamatornu bolest, a genski paneli i sekvenciranje egzoma najprikladniji su za kliničku primjenu. Imunogenski panel omogućuje genski probir koji će poboljšati dijagnostiku, liječenje i prognozu ove skupine bolesnika.

Neurodevelopmental disorders (NDDs) are an umbrella term describing various central nervous system development conditions. Here we present 26- year-old male and 51-year-old female patients demonstrating typical features of NDDs, including undeveloped speech, intellectual disability, epilepsy, and behavioral disorder associated with distinct facial characteristics. Custom chromosomal microarray in both cases detected a copy number loss in chromosome 15q13.2 encompassing the ARHGAP11B gene. ARHGAP11B gene belongs to a group of genes that evolved specifically in the human lineage, and recent findings suggest it has a crucial function in the evolutionary expansion of the neocortex. To elucidate the ARHGAP11B prenatal spatiotemporal expression pattern and its potential role in neurogenetic events during human corticogenesis, we performed immunofluorescence (IF) of diverse neuronal markers on the midfetal postmortem human brain tissue. Our results showed ARHGAP11B immunoreactive neurons in the marginal zone, cortical plate, and the subplate of the midfetal cortex, as well as its colocalization with markers of projecting neurons placed in the deep cortical layers. Our findings support a need for the ARHGAP11B gene to be investigated as a substantial risk gene underlying NDDs.

Many recent studies confrmed importance of the NLRP3 and NLRP1 inflammasome activation in the pathogenesis of Alzheimer’s disease (AD). Apoptosis-associated speck-like protein (ASC) has a key role in assembling inflammasome complex as it couples danger signal sensors and procaspase-1. We aimed to compare CSF and plasma concentrations of ASC protein in AD, mild cognitive impairment (MCI), and cognitively normal controls, and to correlate them with subjects’ age, Mini Mental State Examination (MMSE) score, and core CSF biomarkers of AD (levels of Aβ1-42, total tau [t-tau], and tau phosphorylated at epitope 181 [p−tau181]). Concentrations of ASC were measured in 127 AD, 78 MCI, and 39 control CSF samples and 82 AD, 33 MCI, and 9 control plasma samples using ELISA. Compared to controls, the ASC levels in CSF were significantly higher in the AD and MCI group, whereas differences in plasma levels did not reach significance. CSF levels of ASC protein also positively correlated with the age of the subjects and the concentrations of t-tau and p-tau181. Therefore, we concluded that the ASC level in CSF, but not in plasma, could be a useful biomarker of both tau pathology and inflammasome activation in AD.

The homeostasis of metals is altered in the brain of Alzheimer’s disease (AD) patients. It was proposed that changes in metal homeostasis are related to AD pathology. Additionally, metals that are not present in the brain under normal circumstances (such as mercury, lead and cadmium) were associated with AD pathogenesis. The aim of this study was to test if macro and microelements (Li, B, Na, Mg, Al, S, K, Ca, Cr, Fe, Co, Mn, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Ba, Tl, Pb, and Hg) measured in cerebrospinal fluid (CSF) and plasma of patients with dementia are associated with CSF biomarkers of AD. CSF AD biomarkers reflect pathological changes in AD brain, while the involvement of different metals in AD pathogenesis is still the matter of debate. Macro and microelements were determined by inductively coupled plasma mass spectroscopy (ICP-MS), while CSF biomarkers were measured by enzyme-linked immunosorbent assays (ELISA). Macro and microelements were measured in CSF of 194 subjects and in plasma of 144 subjects (study included overall 125 AD patients, 50 patients with mild cognitive disorder and 19 healthy controls). We used three different statistical methods to test the association of macro and microelements with CSF biomarkers of AD. All three methods (simple correlation and two machine learning algorithms ; redescription mining and principal component analysis [PCA]) demonstrated the association of macro and microelements with CSF biomarkers of AD. Possible explanations for association of macro and microelements with CSF biomarkers of AD await elucidation of their environmental sources or detection of their release from brain tissue due to cell death. Also, these results should be further validated on larger cohorts.

Introduction The most common dementia type is Alzheimer's disease (AD), characterized by progressive cognitive decline and neuronal death, which is often attributed to the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in neurogenesis and neuroplasticity. Therefore, our aim was to investigate the BDNF alternations in AD, at the genetic, epigenetic, and expression levels. Materials and methods The study included 254 patients with AD and mild cognitive impairment (MCI), as a comparative group. Plasma BDNF and cerebrospinal fluid (CSF) Aβ1–42 protein levels were measured with enzyme-linked immunosorbent assay. Quantitative PCR was used to determine the five BDNF gene polymorphisms and BDNF mRNA expression in peripheral white blood cells. The next-generation sequencing was used to determine the methylation status of nine amplicons covering 169 CpG sites in the BDNF gene region. The data were analyzed using GraphPad Prism v4.00 software. Results The results demonstrated increased BDNF plasma concentration in AD patients compared to MCI group, and its positive correlation with Aβ1–42 CSF levels. Tested BDNF polymorphisms were not associated with AD ; however, lower methylation levels, especially in BDNF3 and BDNF9 amplicon region and lower expression of the BDNF gene in peripheral blood were detected in AD patients, compared to MCI subjects. Conclusions These findings could help to elucidate the complex role of BDNF in AD, as well as its potential as an easily accessible peripheral biomarker and novel therapeutic strategy for AD.

Serotonergic receptors are affected in Alzheimer's disease (AD). The overall decrease in the serotonergic transmission is also observed in AD. Previous studies showed the association of polymorphisms in genes for serotonin (5HT) receptors with behavioral and psychological symptoms of dementia (BPSD). In this study, we aimed to test if individuals carrying different genotypes in 5HTR2A rs 6313 (T102C), 5HTR1B rs13212041, 5HTR6 rs1805054 (C267T), and 5HTR2C rs 3813929 (-795C/T) polymorphisms have a higher risk for development of AD. Cerebrospinal fluid (CSF) AD biomarkers, neuropsychological tests, and apolipoprotein E (APOE) haplotype were determined in 115 AD patients and 53 mildly cognitively impaired patients, while 2701 cognitively healthy individuals with determined APOE haplotype were also included. We observed that all four analyzed polymorphisms in genes for 5HT receptors showed an association with either CSF, neuropsychological or genetic biomarkers of AD. Thus, the potential of these polymorphisms as early genetic biomarkers of AD should be further investigated.

Decrease in serotonergic transmission throughout the brain is among the earliest pathological changes in Alzheimer’s disease (AD). Serotonergic receptors are also affected in AD. Polymorphisms in genes for serotonin (5HT) receptors were mostly associated with behavioral and psychological symptoms of dementia (BPSD). In this study we aimed to test if individuals carrying different genotypes in 5HTR1B rs13212041, 5HTR2A rs6313 (T102C), 5HTR2C rs3813929 (-795C/T) and 5HTR6 rs1805054 (C267T) polymorphisms have higher risk for development of AD. Study included 115 AD patients and 53 mild cognitive impairment patients with determined cerebrospinal fluid (CSF) AD biomarkers, neuropsychological tests, and apolipoprotein E (APOE) haplotype and 2701 cognitively healthy individuals with determined APOE haplotype. All four analysed polymorphisms of serotonin receptor genes showed the association with either genetic, CSF or neuropsychological biomarkers of AD. Thus, these polymorphisms deserve further investigation as potential genetic biomarkers and therapeutic targets for AD.