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Clinical Neuroscience

MARCH 30, 2016

Cerebral amyloid angiopathy related inflammation: is susceptibility weighted imaging the clue for diagnosis?

CSÉCSEI Péter, KOMOLY Sámuel, SZAPÁRY László, BARSI Péter

Background - Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by various neurological symptoms such as gradually developing confusion, progressive cognitive decline, seizure or headaches; T2 hyperintensities on magnetic resonance imaging (MRI); and neuropathological evidence of cerebral amyloid angiopathy (CAA) and associated vascular or perivascular inflammation. Although histological confirmation is necessary for accurate diagnosis, in case of typical clinical features and neuroimaging, the diagnosis can be established without biopsy. Case summary - We present the case of a 57-year-old man with a history of hypertension who presented to the emer¬gency department 3-week history of progressive headache and a gradually developing altered mental status. On examination, he was found to have left sided weakness and decreased pscyhomotility. Routine clinical work-up (lab investigations, CT, cerebrospinal fluid analysis) did not show obvious diagnosis, so we performed an MRI. It raised the suspicion of CAA-ri which diagnosis was verified by neuroradiological evaluation. High dose steroid treatment was initiated. The patient rapidly responded to treatment, his focal neurological signs resolved. Control MRI after 1.5 months showed multiple haemorrhagic laesions in the field of previous inflammation which posteriorly supported the previous supposed work-diagnosis. Conclusions - Although histopathology is the gold standard for the diagnosis of cerebral amyloid angiopathy, the typical clinical presentation, good response to steroids and accurate neuroradiological criteria make biopsy unnecessary to diagnose CAA-ri.

Clinical Neuroscience

JULY 30, 2016

[Transthyretin familial amyloid polyneuropathy - three Hungarian cases with rare mutations (His88Arg and Phe33Leu)]

CSILLIK Anita, POZSONYI Zoltán, SOÓS Krisztina, BALOGH István, BODÓ Imre, ARÁNYI Zsuzsanna

[Introduction - Transthyretin familial amyloid polyneuropathy is a rare autosomal dominant progressive systemic disesase of adults caused by endoneural amyloid deposition due to point mutations of the transthyretin gene. It is the most severe form among hereditary polyneuropathies, being fatal within 10 years if left untreated. The disease is underdiagnosed, the late onset forms (above the age of 50) being probably more widespread than previously thought. Early diagnosis is essential as the early introduction of causal therapy (tafamidis) slows progression and prolongs survival. Patients - We report here three non-related Hungarian cases of transthyretin familial amyloid polyneuropathy with non- Val30Met mutations (His88Arg in two cases, Phe33Leu in one case). They were all characterized by late-onset, progressive, length-dependent, axonal, sensorimotor polyneuropathy and the simultaneous presentation of severe restrictive cardiomyopathy. In all three cases, clinical and electrophysiological signs of myopathy were also present, suggesting the involvement of skeletal muscles as well. In two cases, high resolution ultrasound of the peripheral nerves was also performed, which showed segmental structural alterations (change or loss of fascicular structure) and some increase of echogenicity of the interfascicular epineurium, without substantial enlargement of the nerves. Conclusion - In Hungary, mainly the rare, non-Val30Met mutation forms of transthyretin familial amyloid polyneuropathy are encountered, as in our cases. As opposed to the Val30Met forms, these mutations are characterized by late onset and simultaneous presentation of severe cardiomyopathy. Our report highlights the importance of considering transthyretin familial amyloid polyneuropathy in the differential diagnosis of late-onset, progressive, axonal polyneuropathies of unknown etiology, particularly if associated with cardiac disease.]

Clinical Neuroscience

JULY 30, 2015

[The role of β-amyloid and mitochondrial dysfunction in the pathogenesis of Alzheimer’s disease]

SZARKA András

[Alzheimer’s disease is the most common form of dementia in mid- and late life. The 7-10% of the population over 65 and the 50-60% of the population over 85 are affected by this disease. On the contrary of its prevalence the pathogenesis of the disease is not well defined and there is no effective neuroprotective therapeutic agent. Three predominant neuropathological features of the Alzheimer’s disease brain are intracellular neurofibrillary tangles consisting mainly of the hyperphosphorylated protein t; the extracellular amyloid deposits (neuritic plaques) consisting of amyloid b peptide; and the extensive neuronal cell loss in the hippocampus and in portions of the cerebral cortex. The possible reason of the extensive neuronal cell loss can be the mitochondrial dysfunction observed in Alzheimer’s disease. Beyond the unclarified pathogenesis the causality of these characteristic neuropathologic phenomena are still unknown. In this study we would like to deal with two actual hypotheses, with the amyloid cascade and with the mitochondrial cascade hypotheses. We try to give an overview of these two hypotheses and to depict their interrelationship.]

Clinical Neuroscience

NOVEMBER 20, 2012

[The role of immobilization stress and sertindole on the expression of APP, MAPK-1 and β-actin genes in rat brain]

KÁLMÁN János, PÁKÁSKI Magdolna, SZŰCS Szabina, KÁLMÁN Sára, FAZEKAS Örsike, SÁNTHA Petra, SZABÓ Gyula, JANKA Zoltán

[Stress, depending on its level and quality, may cause adaptive and maladaptive alterations in brain functioning. As one of its multiple effects, elevated blood cortisol levels decrease the synthesis of the neuroprotective BDNF, thus leading to hippocampal atrophy and synapse loss, and rendering it a possible cause for the Alzheimer’s disease (AD) related neuropathological and cognitive changes. As a result of the stress response, intraneuronal alterations - also affecting the metabolism of β-actin - can develop. These have a role in the regulation of memory formation (LTP), but in pathological conditions (AD) they could lead to the accumulation of Hirano bodies (actin-cofilin rods). According to the dementia treatment guidelines, the behavioural and psychological symptoms of AD can be treated with certain antipsychotics. Therefore, the aim of our study was to examine the effects of sertindole (currently not used in the standard management of AD) on the transcription of some AD associated genes (amyloid precursor protein [APP], mitogen activated protein kinase-1 [MAPK-1], β-actin) in the brain of rats exposed to chronic immobilization stress (CIS). Male Wistar rats were exposed to CIS for three weeks. The four groups were: control (n=16), CIS (n=10), 10 mg/kg sertindole (n=5) and 10 mg/kg sertindole + CIS (n=4). Following transcardial perfusion, the relative levels of hippocampal and cortical mRNA of the previously mentioned genes were measured with real-time PCR. CIS induced hippocampal β-actin (p<0.01), MAPK-1 and APP (p<0.05) mRNA overexpression. The simultaneous administration of sertindole suppressed this increase in β-actin, MAPK-1 and APP expression (p<0.05). Ours is the first report about CIS induced β-actin gene overexpression. This finding, in accordance with the similar results in APP and MAPK-1 expression, underlines the significance of cytoskeletal alterations in AD pathogenesis. The gene expression reducing effect of sertindole suggests that antipsychotic drugs may have a neuroprotective effect.]

Clinical Neuroscience

MAY 30, 2012

[Acute and chronic stress induced changes in gene transcriptions related to Alzheimer’s disease]

SÁNTHA Petra, PÁKÁSKI Magdolna, FAZEKAS Örsike, SZŰCS Szabina, FODOR Eszter Klára, KÁLMÁN János ifj., KÁLMÁN Sára, SZABÓ Gyula, JANKA Zoltán, KÁLMÁN János

[Preclinical and clinical studies demonstrate that stress may be implicated in the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Our study aimed to investigate the effects of acute and chronic immobilization stress (IS) on the gene transcriptions of β-actin, amyloid precursor protein (APP) and mitogen activated protein kinase-1 (MAPK-1), proteins related to synaptic plasticity and neuronal degeneration. Male Wistar rats were exposed to IS for five hours daily for 3 days (acute stress) or through 7-14-21 days (chronic stress). At the end of exposure periods, total RNA was purified from the cortex and hippocampus. The amounts of β-actin, APP and MAPK-1 mRNA were determined with real time PCR method. Our results indicate that the mRNA expression of β-actin and APP followed a U-shaped time-response curve. Both acute and chronic IS caused a significant increase in β-actin and MAPK-1 mRNA expression. Significant APP mRNA elevation was observed only by the 3rd week after RS. Our findings demonstrate that both acute and chronic IS lead to gene transcriptional changes of β-actin, APP and MAPK-1. These proteins maintain the normal function of the cytoskeleton and the synaptic plasticity. The above changes may lead to cognitive deterioration, and the development of AD.]

Clinical Neuroscience

OCTOBER 20, 2009

[The transcription of the amyloid precursor protein and tryptophan 2,3-dioxygenase genes are increased by aging in the rat brain]

KÁLMÁN Sára, PÁKÁSKI Magdolna, SZŰCS Szabina, GARAB Dénes, DOMOKOS Ágnes, ZVARA Ágnes, PUSKÁS László, BAGDY György, ZELENA Dóra, KÁLMÁN János

[Aging itself is considered as a major risk factor of dementia. The prevalence of the Alzheimer’s disease (AD) is increasing exponentially after the age of 65 and doubles every 5 years. The major aim of our present research was to examine the effect of aging on the transcription of certain genes associated with neurodegenerative disorders in the rat brain. The influence of the vasopressin (VP) hormone was also examined in the same experimental paradigm. Age dependent transcriptional changes of the following four genes were examined in the cerebral cortex: the first was the gene of the amyloid precursor protein (APP) which is abnormally cleaved to toxic beta-amyloid fragments. These aggregated peptides are the major components of the senile plaques in the AD brain. The second one was the mitogen-activated protein kinase (MAPK1) gene. The MAPK is involved in the abnormal hyperphosphorylation of the tau-protein which results in aggregated neurofibrillary tangles. The beta-actin gene was the third one. The protein product of this gene is considered to be involved in synaptogenesis, neuronal plasticity and clinical conditions like depression and AD. The last one was the gene of the tryptophan 2,3-dioxygenase (TDO2) enzyme. The activity of this enzyme is considered as a rate limiting factor in the metabolism of the neuro-immune modulator quinolinic acid (QUIN). The transciptional activity of young (2.5 months) and aged (13 months) Brattleboro rats with or without VP expression were compared by means of real time PCR technique. The cortical transciptional activity of the APP and TDO2 genes were increased in the aged animals as compared with the activity of the young ones, and this effect was independent on the presence of the VP. Our results indicate the importance of certain age dependent transcriptional changes might influence the mechanism of AD and other neurodegenerative disorders.]

Lege Artis Medicinae

MAY 21, 2006

[BETA-CELL DYSFUNCTION AND PROTECTION IN TYPE 2 DIABETES]

VÁNDORFI Győző, URICH Elemér

[Type 2 diabetes is caused by increased insulin resistance coupled with the disturbance of the secretion function of beta-cells. While the importance of insulin resistance has been emphasized in the last two decades, the pathogenetic role of beta-cell dysfunction has received less attention. Regarding this latter, several underlying mechanisms have been implicated, including increased secretory demand due to insulin resistance, glucose toxicity, lipotoxicity, islet cell amyloid deposition, and insulin resistance of the beta-cells themselves. In the milestone UKPDS (United Kingdom Prospective Diabetes Study) trial the metabolic status of the patients gradually deteriorated after 1 to 2 year of temporary improvement despite of an intensive sulfonylurea, insulin or metformin treatment. Progression of the disease could be slowed down but not stopped, which was attributed to progressive beta-cell failure. In this regard the insulinsensitizer thiazolidinediones, having recently joined the therapeutic palette, are promising because they protect and spare beta-cells through several ways. However, as the disease carrier progresses, it can reach a point when without using insulin the treatment cannot be successful anymore. Early use of thiazolidinediones may result in a marked delay of this point. This concept is supported by studies completed so far, and further clinical trials are ongoing so as to strengthen the evidence.]

Clinical Neuroscience

NOVEMBER 30, 2007

[THE ROLE OF CHRONIC BRAIN HYPOPERFUSION IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE - FACTS AND HYPOTHES]

ZÁDORI Dénes, DATKI Zsolt, PENKE Botond

[In Alzheimer’s disease, which belongs to the neurodegenerative disorders, the ethiopathogenetic role of several risk factors has been proved. A considerable number of them are mainly known as cardiovascular risk factors and can precipitate chronic brain hypoperfusion. Using functional imaging techniques, this hypoperfusion and the resulting hypometabolism become detectable in the watershed areas of the brain as early as in the stage of mild cognitive impairment. Hypoperfusion leads to the degeneration of capillaries in this area causing the deterioration of diffusion. The further reduction of nutrient and oxygen support of neurons is capable to initiate a neurodegenerative process which spreads along the glutamaterg system arising from the neurons of the association cortices. The neuropathological lesions of this neuronal system, such as the neurofibrillary tangles and the β-amyloid plaques, are known to be the characteristic markers of Alzheimer's disease. In our review we present the development of hypoperfusion and its consequences in the watershed areas of the brain and describe the neurodegenerative process of the neuronal system arising from the neurons of the association cortices in the early stage of Alzheimer's disease. Considering the previous hypotheses and the neuropathological lesions of Alzheimer's disease we give a new consensus model to characterize the pathomechanism of the disorder.]

Clinical Neuroscience

MAY 30, 2006

[NEUROPATHOLOGICAL EXAMINATIONS IN AUTOPSIES WITH SPECIAL FOCUS ON FINDINGS IN ALZHEIMER’S DISEASE]

LEEL-ŐSSY Lóránt, KINDLER Miklós, SZŰCS Iván, SCHWARCZ Tibor

[Out of an average total of 1400 autopsies per year, neuropathological examinations were performed in 477 cases between 1997 and 1999 to investigate the incidence of dementias. The majority of the studied subjects were over 50 years old. Bielschowsky's and/or Gallyas's silver methods and, in some cases, protein tau (MAP) immuncytochemistry and amyloid staining were performed beside routine examination. Pathological changes were found in 212 of the 364 cases studied by the above methods but histological changes associated with dementia were only detected in 167 cases. The various forms of Alzheimer's dementia were also classified by age. The "incipient" form of Alzheimer's disease was verified in 23 cases. Old infarcts of various extensions were found in 42 percent of Alzheimer's dementias. Very mild or age-related degenerative changes were observed in 82 cases among subjects over 50 years old. Of these, eight patients died in their 90s. In some cases (n=38) the number of neuritic plaques dominated over the number of neurofibrillary tangles but a reverse finding also occurred (n=13). Neuronal degeneration was variable and was not always proportional to the number of neurofibrillary tangles. "Simple type of senile atrophy" was defined by the presence of minor or age-related Alzheimer changes and was considered a separate entity. The "incipient" form of Alzheimer's dementia was diagnosed in relatively young individuals where mild Alzheimer changes were found at the neuropathological examination. "Preclinical" Alzheimer's dementia could only be suspected by clinical data and could very rarely be supported by the neuropathological finding of "incipient" form. The ratio of pure Alzheimer’s to vascular dementias cases proved to be 54:41 in this study. The results suggest that dementias are considerably underdiagnosed both in the clinical and pathological practice and that the recently defined "preclinical" and "incipient" forms are very hard to recognize both clinically and pathologically. The neuropathological study of the degenerative, mainly Alzheimer's type, findings in the randomly selected autopsies revealed great variations which raises many questions concerning the normal and pathologic aging of the brain as well as the "incipient" and senile forms of Alzheimer's dementia.]

Lege Artis Medicinae

DECEMBER 20, 2003

[CEREBRAL AMYLOID ANGIOPATHY - A FATAL CASE OF RECURRENT MULTIFOCAL CEREBRAL HEMORRHAGE]

POGÁNY Péter, HERMANN Zsuzsa

[Atherosclerosis and hypertension are the leading etiological factors in the pathogenesis of cerebral hemorrhage. With old age though, several other factors may appear of which cerebral amyloid angiopathy (CAA) is of major importance. This condition is characterized by the deposition of β-amyloid in the leptomeningeal vessels as well as in the small and medium sized arteries of the cerebral cortex and it is not associated with systemic amyloidosis. This pathological protein is also seen in the brains of otherwise healthy older individuals and may also appear in other diseases such as Alzheimer disease, Down-syndrome, vascular malformations, spongiform encephalopathy and dementia pugilistica. The condition may be asymptomatic but it may also cause cerebral hemorrhage, dementia or various transient neurological symptoms. Most cases are sporadic, but familial subtypes have also been described.]