Goran Simic

University of Zagreb Medical School and Croatian Institute for Brain Research

Introduction Genetic studies have shown that variants in the microtubule-associated protein tau ( MAPT ) gene, which encodes tau protein, can increase the risk for Alzheimer’s disease (AD). Additionally, two haplotypes of the MAPT gene (H1 and H2) are associated with various neurodegenerative disorders, including AD. This study aimed to test the as...

Aim To examine whether changes in biomarker concentrations in patients with idiopathic normal-pressure hydrocephalus (iNPH) during 72 h of external lumbar drainage (ELD) can differentiate between responders and non-responders. Methods Twenty patients with clinical and neuroradiological signs of iNPH underwent ELD over a period of 72 h. During this...

Cellular‐level anatomical data from early fetal brain are sparse yet critical to the understanding of neurodevelopmental disorders. We characterize the organization of the human cerebral cortex between 13 and 15 gestational weeks using high‐resolution whole‐brain histological data sets complimented with multimodal imaging. We observed the heretofor...

Schizophrenia is a complex mental condition, with key symptoms marked for diagnosis including delusions, hallucinations, disorganized thinking, reduced emotional expression, and social dysfunction. In the context of major developmental hypotheses of schizophrenia, notably those concerning maternal immune activation and neuroinflammation, we studied...

The intricate development of the human amygdala involves a complex interplay of diverse processes, varying in speed and duration. In humans, transient cytoarchitectural structures deliquesce, leading to the formation of functionally distinct nuclei as a result of multiple interdependent developmental events. This study compares the amygdala's cytoa...

Spinal muscular atrophy (SMA) is a progressive degenerative illness that affects 1 in every 6 to 11,000 live births. This autosomal recessive disorder is caused by homozygous deletion or mutation of the SMN1 gene (survival motor neuron). As a backup, the SMN1 gene has the SMN2 gene, which produces only 10% of the functional SMN protein. Nusinersen...

Background: Individuals with specific TREM2 gene variants that encode for a Triggering Receptor Expressed on Myeloid cells 2 have a higher prevalence of Alzheimer's disease (AD). By interacting with amyloid and apolipoproteins, the TREM2 receptor regulates the number of myeloid cells, phagocytosis, and the inflammatory response. Higher TREM2 expre...

Background The primary histological characteristic of Alzheimer's disease is the presence of neurofibrillary tangles, which are large aggregates of tau protein. Aging is the primary risk factor for the development of Alzheimer's disease, however, the underlying causes of tau protein aggregation and toxicity are unclear. Aims Here we investigated t...

People with specific TREM2 gene variants are more prone to develop Alzheimer's disease (AD). The TREM2 receptor regulates the number of myeloid cells, phagocytosis, and the inflammatory response via interacting with apolipoproteins and amyloid. Higher TREM2 expression has been found to protect against AD. When TREM2 activity increases, the activity...

The role of metals in the pathogenesis of Alzheimer’s disease (AD) is still debated. Although previous research has linked changes in essential metal homeostasis and exposure to environmental heavy metals to the pathogenesis of AD, more research is needed to determine the relationship between metals and AD. In this review, we included human studies...

The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some a...

Various metals have been associated with the pathogenesis of Alzheimer’s disease (AD), principally heavy metals that are environmental pollutants (such as As, Cd, Hg, and Pb) and essential metals whose homeostasis is disturbed in AD (such as Cu, Fe, and Zn). Although there is evidence of the involvement of these metals in AD, further research is ne...

Aims Considering the substantial variability in treatment response across patients with spinal muscular atrophy (SMA), reliable markers for monitoring response to therapy and predicting treatment responders need to be identified. The study aimed to determine if measured concentrations of disease biomarkers (total tau protein, neurofilament light ch...

A 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 of serotonin (5HT) receptors have been mostly associated with behavioral and psychological symptoms of dementia (BPSD). In this study, we examined...

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate th...

Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression...

Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high‐order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human br...

A population of more than six million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invas...

Background The dopaminergic system is functionally compromised in Alzheimer’s dis-ease (AD). The activity of monoamine oxidase B (MAOB), the enzyme involved in the degradation of dopamine, is increased during AD. Also, increased expression of MAOB occurs in the post-mortem hippocampus and neocortex of patients with AD. The MAOB rs1799836 polymorphi...

Sporadični oblik Alzheimerove bolesti (AD) s kasnim početkom je najčešći uzrok demencije. Mnogobrojni rizični čimbenici za AD su starija dob, različiti čimbenici iz okoline i genetski čimbenici. Ti su rizični čimbenici odgovorni za raniji početak bolesti, bržu progresiju, jaču težinu simptoma. Uz mnoštvo rizičnih gena, gen za moždani neurotrofni či...

Emotions arise from activations of specialized neuronal populations in several parts of the cerebral cortex, notably the anterior cingulate, insula, ventromedial prefrontal, and subcortical structures, such as the amygdala, ventral striatum, putamen, caudate nucleus, and ventral tegmental area. Feelings are conscious, emotional experiences of these...

Alzheimer’s disease (AD) is a progressive, complex, and multifactorial neurodegenerative disorder, still without effective and stable therapeutic strategies. Currently, available medications for AD are based on symptomatic therapy, which include acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist. Additionally...

Increasing evidence suggests that the autism spectrum disorder (ASD) may be associated with inborn errors of metabolism, such as disorders of amino acid metabolism and transport [phenylketonuria, homocystinuria, S-adenosylhomocysteine hydrolase deficiency, branched-chain α-keto acid dehydrogenase kinase deficiency, urea cycle disorders (UCD), Hartn...

Background: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer's disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron,...

The pathogenesis of Alzheimer's disease (AD) is not fully understood. Here we summarize current knowledge on the involvement of the serotonergic, noradrenergic, dopaminergic, cholinergic, and opioid systems in AD, emphasizing the importance of interactions between the serotonergic and the other subcortical modulatory systems during the progression...

The neural crest hypothesis states that the phenotypic features of the domestication syndrome are due to a reduced number or disruption of neural crest cells (NCCs) migration, as these cells differentiate at their final destinations and proliferate into different tissues whose activity is reduced by domestication. Comparing the phenotypic character...

Background Sporadic Alzheimer’s Disease (AD) is assumed to be associated with different biological/genetic vulnerability, as well as with neuroinflammation, mediated by cytokines. The present study evaluated the role of cytokines in AD. Objective Aim was to determine the possible association of TNF-α (rs1800629), IL1-α (rs1800587) and IL-10 (rs180...

Introduction Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue o...

Uvod: Alzheimerova bolest (AB) s kasnim početkom je najčešći uzrok demencije. Blagi kognitivni poremećaj (MCI) je poremećaj kognicije koji često prethodi AB. Uz različite neurobiološke hipoteze o nastanku AB ističe se neuroupalna hipoteza koja smatra da ključnu ulogu u nastanku AB-a imaju i neuroupalni procesi i promijenjeno oslobađanje citokina. M...

All tauopathies, including Alzheimer’s disease (AD), are characterized by the intracellular accumulation of abnormal forms of tau protein in neurons and glial cells, which negatively affect microtubule stability. Under physiological conditions, tubulin-associated unit (Tau) protein is intrinsically disordered, almost without secondary structure, an...

INTRODUCTION: Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue...

INTRODUCTION: Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue...

Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when present in excess by promoting production of reactive oxygen species (ROS). The aim of the present study was to investigate potential benefits of flavonoid quercetin against copper-induced toxicity. Results obtained with MTT assay indicate that the effects...

Background: Neuroinflammation plays an important role in Alzheimer's disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor α (TNFα) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostas...

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampl...

Background: Neuroinflammation is enhanced in Alzheimer’s disease (AD) brain. Its association with both amyloid and tau pathology is well documented. Activated microglia in the AD brain release pro-inflammatory cytokines that can damage neurons, while anti-inflammatory cytokines are also released to oppose this process. Association of IL-1β -1473C/G...

The noradrenergic and dopaminergic systems are affected in Alzheimer's disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltran...

Background Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α (TNFα) that participate in neuron damage. However, anti-inflammatory cytokines (such as IL-10), which maintain homeostasis...

Razvili smo novi uređaj koji pomaže u ranoj dijagnozi blagog kognitivnog oštećenja (mild cognitive impairment – MCI, odnosno blagog neurokognitivnog poremećaja prema DSM-5) i demencije (velikog neurokognitivnog poremećaja prema DSM-5, najčešće uzrokovanog Alzheimerovom bolešću - AB). Sustav se temelji na određivanju pozicije cilja koji nakon kratko...

Uncontrolled immune response in the brain contributes to the progression of all neurodegenerative disease, including Alzheimer’s disease (AD). Recent investigations have documented the prion-like features of tau protein and the involvement of microglial changes with tau pathology. While it is still unclear what sequence of events is causal, it is l...

Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier dis...

Tau, a microtubule-associated protein with multiple phosphorylation sites, regulates microtubule assembly and dynamics. The presence of neurofibrillary tangles (NFT), consisting of intracellular aggregates of hyperphosphorylated tau protein, is one of the defining clinico-pathological hallmarks of Alzheimer’s disease (AD). Enhanced expression of tr...

The pathogenesis of Alzheimer's disease (AD) is only partly understood. This is the probable reason why significant efforts to treat or prevent AD have been unsuccessful. In fact, as of April 2019, there have been 2094 studies registered for AD on the clinicaltrials.gov U.S. National Library of Science web page, of which only a few are still ongoin...

Cell‐adhesion glycoprotein neuroplastin (Np) is involved in the regulation of synaptic plasticity and balancing hippocampal excitatory/inhibitory inputs which aids in the process of associative memory formation and learning. Our recent findings show that neuroplastin expression in the adult human hippocampus is specifically associated with major hi...

Introduction Alzheimer's disease (AD) is the world leading cause of dementia. Early detection of AD is essential for faster and more efficacious usage of therapeutics and preventive measures. Even though it is well known that one ε4 allele of apolipoprotein E gene increases the risk for sporadic AD five times, and that two ε4 alleles increase the r...

Hrvatska udruga za Alzheimerovu bolest (HUAB) osnovana je 1999. godine u Zagrebu, danas je dobro etablirana i respektabilna, te slovi kao jedna od Udruga koju se pita i za koju se zna. Od svog osnutka HUAB ima svoju misiju i od nje ne odustaje, a to je borba tj. lobiranje za osobe s demencijom, kroz edukaciju opće i ciljne populacije, kroz destigma...

Background: Since pathological process in Alzheimer's disease (AD) brain begins 20-30 years earlier than the emergence of first symptoms, early and differential diagnosis of AD should be improved. Event-related potentials (ERP) measured by electroencephalography showed diagnostic potential in AD. Objective: We compared the efficiency of P300 and...

Background: Early stages of Alzheimer's disease (AD) are characterized by high phosphorylation of microtubule-associated protein tau, which may result from the downregulation of protein phosphatases. New method: In order to model phosphatase downregulation and analyze its effect on tau aggregation in vitro, we treated neuroblastoma SH-SY5Y cells...

Alzheimer's disease (AD), the most common progressive neurodegenerative disorder, is characterized by severe cognitive decline and personality changes as a result of synaptic and neuronal loss. The defining clinicopathological hallmarks of the disease are deposits of amyloid precursor protein (APP)-derived amyloid-β peptides (Aβ) in the brain paren...

Recent data suggest that early stages of Alzheimer's disease (AD) are characterized by an abnormally high phosphorylation of microtubule-associated protein tau and truncation of its C-terminus. Tau hyperphosphorylation may result from the downregulation of phosphatases, especially protein phosphatase 2A. In an attempt to model and analyze these mol...

Background: The diagnosis of either Alzheimer's disease (AD) or vascular dementia (VaD) is still largely based on clinical guidelines and exclusion of other diseases that may lead to dementia. Aims: In this study, we assessed whether the use of sensitive and specific biomarkers such as phosphorylated tau proteins could contribute to an earlier a...

Based on a set of subjects and a collection of attributes obtained from the Alzheimer’s Disease Neuroimaging Initiative database, we used redescription mining to find interpretable rules revealing associations between those determinants that provide insights about the Alzheimer’s disease (AD). We extended the CLUS-RM redescription mining algorithm...

Dataset D2 attribute structure. (TXT)

Redescriptions obtained on D2 with support in [5, 10] interval. (TXT)

Redescriptions obtained on D3 with support in [5, 10] interval. (TXT)

Redescriptions obtained on D3 with support in [11, 39] interval. (TXT)

Pseudocode of the CLUS-RM algorithm that can use conjunction, negation and disjunction logical operator in redescription query construction and explanation of introduced constraint-based redescription mining extensions. (PDF)

Redescriptions obtained on D1 with support in [5, 10] interval. (TXT)

Redescriptions obtained on D2 with support in [11, 39] interval. (TXT)

Motivation and explanation of statistical tests used in this work. (PDF)

Dataset D1 attribute structure. (TXT)

Dataset D3 attribute structure. (TXT)

Redescriptions obtained on D1 with support in [11, 39] interval. (TXT)

Redescriptions obtained on D1 with support in [40, 99] interval. (TXT)

Redescriptions obtained on D2 with support in [100, 470] interval. (TXT)

Redescriptions obtained on D3 with support in [100, 420] interval. (TXT)

Redescriptions obtained on D1 with support in [100, 820] interval. (TXT)

Redescriptions obtained on D2 with support in [40, 99] interval. (TXT)

Redescriptions obtained on D3 with support in [40, 99] interval. (TXT)

Redescriptions obtained on D3 by using constraint-based redescription mining with support larger than 100 subjects. (TXT)