A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes.

Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory loss, and right-sided hemispatial neglect. Whole-exome sequencing (WES) identified rare single heterozygous variants in ATP7B (c.3207C>A), SORL1 (c.352G>A), SETX (c.2385_2387delAAA), and FOXP1 (c.1762G>A) genes. The functional analysis revealed that the deletion in the SETX gene changed the splicing pattern, which was accompanied by lower SETX mRNA levels in the patient's fibroblasts, suggesting loss-of-function as the underlying mechanism. In addition, the patient's fibroblasts demonstrated altered mitochondrial architecture with decreased connectivity, compared to the control individuals. This is the first association of the CBS-PNFA phenotype with the most common ATP7B pathogenic variant p.H1069Q, previously linked to Wilson's disease, and early onset Parkinson's disease. This study expands the complex clinical spectrum related to variants in well-known disease genes, such as ATP7B, SORL1, SETX, and FOXP1, corroborating the hypothesis of oligogenic inheritance. To date, the FOXP1 gene has been linked exclusively to neurodevelopmental speech disorders, while our study highlights its possible relevance for adult-onset progressive apraxia of speech, which guarantees further study.

The scintigraphic diagnosis of cardiac amyloidosis. An expert opinion endorsed by the Section of Nuclear Medicine of the Polish Cardiac Society and the Polish Nuclear Medicine Society.

Amyloid transthyretin cardiomyopathy is a progressive disease that confers significant mortality. While it is relatively rare, the frequency of diagnoses has risen with the increased contribution of novel diagnostic approach over the last decade. Traditionally tissue biopsy was considered to be a gold standard for amyloidosis diagnosis. However, there are significant limitations in the wide application of this approach. A noninvasive imaging-based diagnostic algorithm has been substantially developed in recent years. Establishing radionuclide imaging standards may translate into a further enhancement of disease detection and improving prognosis in the group of patients. Therefore we present in the following document current evidence on the scintigraphic diagnosis of cardiac transthyretin amyloidosis. Moreover, we present standardized protocol for the acquisition and interpretation criteria in the scintigraphic evaluation of cardiac amyloidosis.

Two Rare Variants in PLAU and BACE1 Genes-Do They Contribute to Semantic Dementia Clinical Phenotype?

We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified: a nonsense variant c.366C>A/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C>T/p.Thr315Met in ß-site APP-cleaving enzyme 1 (BACE1)-along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced PLAU and elevated BACE1 mRNA and protein levels compared to control fibroblasts. Successful rescue of PLAU mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.

Neuroimaging in Parkinson's Disease: necessity or exaggeration?

INTRODUCTION: Neuroimaging plays an increasingly important role in the diagnosis of parkinsonian syndromes. AIM OF THE STUDY: In this paper, the authors elaborate on the necessity of using magnetic resonance imaging (MRI) in Parkinson's Disease (PD) and its potential role in differential diagnosis versus other neurodegenerative parkinsonian syndromes such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal syndrome. STATE OF THE ART: The currently known characteristic abnormalities are listed and tabulated, current recommendations are summarised and sample images are provided. As routine MRI scanning in PD remains controversial, the authors' aim is to show the pros and cons in clinical practice. Additionally, the rationale for functional imaging examination, including [123I]-FP-CIT SPECT (DaTSCAN) and [99mTc]- HMPAO-SPECT, [18F]-FDG-PET, [123I]-mIBG-SPECT is discussed. CLINICAL VIGNETTE: This paper is accompanied by two illustrative clinical cases in which neuroimaging studies played a key role in diagnosis and further management. CONCLUSIONS: Neuroimaging can be helpful in differentiating PD from both atypical and symptomatic parkinsonism. Nevertheless, extensive neurological assessment in a majority of PD cases is sufficient to make a diagnosis. A network of specialists in movement disorders should be established in order to enable better, faster and more precise diagnosis of parkinsonism.

Cognitive and behavioral profile of Perry syndrome in two families.

OBJECTIVE: Perry syndrome (PS) is a rare neurodegenerative disorder with autosomal dominant inheritance caused by point mutations in DCTN1 and characterized by parkinsonism, hypoventilation, weight loss, and psychiatric symptoms. Even though behavioral manifestation is a main feature of PS, detailed neuropsychological assessment was not performed in this cohort. In this study, the neuropsychological profile of individuals from one Polish and one Colombian family are presented. METHODS: Detailed clinical and neuropsychological data were obtained from Polish and Colombian families. Clinical and neuropsychological examinations on the proband from the Polish family were performed 6 times over 11 years. Each of 3 individuals from the Colombian family received a clinical and neuropsychological assessment. RESULTS: The neurologic examination showed severe parkinsonism, levodopa-induced motor fluctuations, and dyskinesias in all cases. Respiratory insufficiency was observed in 2 patients and weight loss in 1 individual. Neuropsychological assessment revealed predominant deterioration of working memory and learning capacity in the Polish patient. He also demonstrated compulsive behaviors, such as excessive shopping and eating, but only in the "on" phase. In the Colombian family, attentional deficits were present in 2 out of 3 cases. Out of 4 reported cases apathy and depressed mood were present in 2 individuals. Two cases demonstrated impulsivity and one had episodes of hypomania. CONCLUSIONS: Both of these families revealed relatively similar neurologic and neuropsychological profiles. The Polish patient's behavioral and neuropsychological profile was mostly compatible with a behavioral variant of frontotemporal dementia. Of note, not only depression and apathy, but also impulsivity can occur in PS.

Functional characterization of a novel progranulin mutation in a patient with progressive nonfluent aphasia.

Loss-of-function mutations in progranulin (PGRN) gene cause frontotemporal lobar degeneration. Here, we report a case of a 63-year-old woman with a 2-year history of speech impairment, diagnosed with a nonfluent variant of primary progressive aphasia, a subtype of frontotemporal lobar degeneration. In this patient, a novel heterozygous frameshift mutation, c.77delG, in exon 2 of PGRN gene, introducing premature stop codon, p.(C26SfsX28), has been identified. Cultured fibroblasts derived from the patient and her asymptomatic first-degree relative with c.77delG mutation had decreased levels of PGRN messenger RNA (mRNA) and protein. However, PGRN mRNA levels did not recover upon incubation with inhibitors of nonsense-mediated mRNA decay (cycloheximide or puromycin), suggesting involvement of other mRNA degradation pathways. In addition, we observed upregulated wingless-type mouse mammary tumor virus integration site (WNT) signaling pathway gene, WNT3A, in fibroblasts of the patient and her asymptomatic first-degree relative with c.77delG mutation. As reported previously, this is an early hallmark of PGRN deficiency.

The role of neuroimaging in the diagnosis of the atypical parkinsonian syndromes in clinical practice.

Atypical parkinsonian disorders (APD) are a heterogenous group of neurodegenerative diseases such as: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), cortico-basal degeneration (CBD) and dementia with Lewy bodies (DLB). In all of them core symptoms of parkinsonian syndrome are accompanied by many additional clinical features not typical for idiopathic Parkinson's disease (PD) like rapid progression, gaze palsy, apraxia, ataxia, early cognitive decline, dysautonomia and usually poor response to levodopa therapy. In the absence of reliably validated biomarkers the diagnosis is still challenging and mainly based on clinical criteria. However, robust data emerging from routine magnetic resonance imaging (MRI) as well as from many advanced MRI techniques such as: diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), voxel-based morphometry (VBM), susceptibility-weighted imaging (SWI) may help in differential diagnosis. The main aim of this review is to summarize briefly the most important and acknowledged radiological findings of conventional MRI due to its availability in standard clinical settings. Nevertheless, we present shortly other methods of structural (like TCS - transcranial sonography) and functional imaging (like SPECT - single photon emission computed tomography or PET - positron emission tomography) as well as some selected advanced MRI techniques and their potential future applications in supportive role in distinguishing APD.

Neuroimaging in the differential diagnosis of primary progressive aphasia - illustrative case series in the light of new diagnostic criteria.

BACKGROUND: Primary progressive aphasia (PPA) is a progressive language disorder associated with atrophy of the dominant language hemisphere, typically left. Current PPA criteria divide PPA into three variants: non-fluent (nfvPPA), semantic (svPPA) and logopenic (lvPPA). The classification of PPA into one of the three variants may be performed at 3 levels: I) clinical, II) imaging-supported, III) definite pathologic diagnosis. This paper aimed at assessing the feasibility of the imaging-supported diagnostics of PPA variants in the Polish clinical setting with access to magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) examinations. CASE REPORT: We present the clinical and neuroimaging data on 6 patients (4 women, 2 men) clinically diagnosed with PPA (3 with nfvPPA and 3 with lvPPA) in whom MRI and SPECT were performed in order to determine if imaging-supported diagnosis could be established in those cases. In 4 individuals (2 with nfvPPA and 2 with lvPPA) clinical diagnosis was supported by neuroimaging (SPECT, albeit not MRI), thus level II of PPA diagnosis could be established in those cases. MRI results were either inconsistent with the clinical diagnosis (Patients 1 and 2) or a mixed pattern of atrophy was observed (Patients 3-6). CONCLUSIONS: Imaging-supported diagnosis of PPA variant is more feasible with quantitative analysis of SPECT images than with purely qualitative visual analysis of MRI. Hypoperfusion abnormalities evidenced by SPECT are more variant-specific than patterns of atrophy.

Agraphia in patients with frontotemporal dementia and parkinsonism linked to chromosome 17 with P301L MAPT mutation: dysexecutive, aphasic, apraxic or spatial phenomenon?

OBJECTIVES: Patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) may be agraphic. The study aimed at characterizing agraphia in individuals with a P301L MAPT mutation. METHODS: Two pairs of siblings with FTDP-17 were longitudinally examined for agraphia in relation to language and cognitive deficits. RESULTS: All patients presented with dysexecutive agraphia. In addition, in the first pair of siblings one sibling demonstrated spatial agraphia with less pronounced allographic agraphia and the other sibling had aphasic agraphia. Aphasic agraphia was also present in one sibling from the second pair. CONCLUSION: Agraphia associated with FTDP-17 is very heterogeneous.

A patient with posterior cortical atrophy possesses a novel mutation in the presenilin 1 gene.

Posterior cortical atrophy is a dementia syndrome with symptoms of cortical visual dysfunction, associated with amyloid plaques and neurofibrillary tangles predominantly affecting visual association cortex. Most patients diagnosed with posterior cortical atrophy will finally develop a typical Alzheimer's disease. However, there are a variety of neuropathological processes, which could lead towards a clinical presentation of posterior cortical atrophy. Mutations in the presenilin 1 gene, affecting the function of γ-secretase, are the most common genetic cause of familial, early-onset Alzheimer's disease. Here we present a patient with a clinical diagnosis of posterior cortical atrophy who harbors a novel Presenilin 1 mutation (I211M). In silico analysis predicts that the mutation could influence the interaction between presenilin 1 and presenilin1 enhancer-2 protein, a protein partner within the γ-secretase complex. These findings along with published literature support the inclusion of posterior cortical atrophy on the Alzheimer's disease spectrum.

[Estimation of cerebral perfusion among patients with eating disorders, neurotic and depressive disorders]. / Ocena mózgowego przeplywu krwi u pacjentów z zaburzeniami odzywiania sie, nerwicowymi i depresyjnymi.

AIM: Assessment of the cerebral blood perfusion among patients with eating (ED), anxiety (AD) and depressive disorders (DD), diagnosed according to ICD-10. METHOD: 57 females and 22 males, aged 17-50 were examined using the Single Photon Emission Computer Tomography (SPECT) and the neuropsychological tests, Benton and Bender. We also used the Beck Depression Inventory, the Hospital Anxiety and Depression Scale, and the Spielberger Self-Evaluation Questionnaire. Electroencephalography was also performed. RESULT: In ED, hypoperfusion occurred in 84.21%, and impairment of the central nervous system (CNS), was found in 27.77%, abnormalities in the electroencephalography--in 33.33% of the patients. In AD, hypoperfusion occurred in 72.72%, impairment of CNS--in 40%, abnormalities in EEG--in 48% of patients. In DD, hypoperfusion occurred in 81.48%, impairment of CNS--in 34.61%, abnormalities in EEG--in 38.46% of patients. CONCLUSIONS: Hypoperfusion was observed mostly among patients with ED, mainly in the frontal, temporal areas, and in the thalamus, on the left hand side, similar to DD group. Among patients with AD, hypoperfusion at the left hand side occurred almost three times more frequently than among patients with DD (Chi2 = 6.54, p < .025) and was significant. Anxiety as a trait was the highest in ED, but not significant. Among patients with AD, anxiety as a trait and as a state were almost at the same level.

The influence of vascular risk factors and white matter hyperintensities on the degree of cognitive impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: Vascular risk factors may contribute to deterioration of cognitive functions in Alzheimer's disease and vascular (or mixed) dementia. Parkinson's disease (PD) is an age-related disorder and vascular risk factors potentially might be the main co-morbidity responsible for motor and cognitive impairment. However, only a few studies focused on this problem have been published. The aim of the study was to assess the contribution of vascular risk factors and white matter abnormalities in magnetic resonance imaging (MRI) on cognitive impairment in PD patients. MATERIAL AND METHODS: Sixty consecutive patients (M: 35, F: 25), mean age 68.36 years (SD: 7.25, range: 51-81) with diagnosis of idiopathic PD underwent a semi-structured questionnaire on demographics and vascular risks factors, neurological, neuropsychological and neuroimaging (MRI) examinations with quantitative assessment according to the scale by Wahlund et al. According to cognitive status they were divided into 3 groups: without cognitive disability (I, n=17), with mild cognitive impairment (II, n=25) and with dementia (III, n=18). RESULTS: There were no significant differences between groups in terms of the number of vascular risk factors (except for the ischaemic heart disease difference between group I and III) and severity of white matter hyperintensities in MRI studies. CONCLUSIONS: Vascular risk factors along with white matter vascular abnormalities probably do not contribute to cognitive impairment in patients with PD. This is in concordance with previously published studies.

Regional cerebral blood flow in Parkinson's disease as an indicator of cognitive impairment.

OBJECTIVE: To investigate the pattern of regional cerebral blood flow (rCBF) deficits in Parkinson's disease patients in relation to cognitive decline and to assess the clinical usefulness of single photon emission tomography (SPET) scanning in differentiation between Parkinson's disease patients with dementia and those without cognitive deficits. METHODS: We performed Tc-ECD SPET in 60 patients with idiopathic Parkinson's disease (F: 25, M: 35), with average age of 68.4 years (SD+/-7.3, range 51-81 years). All patients were examined neurologically with the assessment of stage and severity of Parkinson's disease (Hoehn-Yahr scale, UPDRS, Schwab-England scale). Detailed neuropsychological examination was performed in each Parkinson's disease patient. On the basis of DSM-IV criteria of dementia and the results obtained in psychological examination, the whole group was divided into three subgroups: I, with no cognitive changes (n = 17); II, with mild cognitive impairment (n = 25); and III, with dementia (n = 18). RESULTS: There was noticeable significant decrease of perfusion in all areas in Parkinson's disease patients when compared to the age-matched control group of healthy volunteers (n = 20). In group III, perfusion was significantly decreased (when compared to groups I and II), particularly in parietal and temporal areas with the predominance of the left side. Regression analysis revealed two independent factors related to dementia: decrease of perfusion within left temporal lobe and its increase within left thalamus. CONCLUSION: Parkinson's disease patients with dementia showed left temporo-parietal hypoperfusion as compared to a group of patients without dementia, which resembles perfusion deficits described in Alzheimer's disease. The hypoperfusion of the left temporal lobe with increase of rCBF within the left thalamus might be clinically useful in discrimination of Parkinson's disease patients with dementia against those without cognitive impairment.

Cerebral blood flow changes in patients with dementia with Lewy bodies (DLB). A study of 6 cases.

BACKGROUND: The aim of this study was to show the application of cerebral blood flow SPECT (rCBF SPECT) study in dementia with Lewy bodies (DLB). MATERIAL AND METHODS: (99m)Tc-ECD regional cerebral blood flow SPECT scanning was performed using a triple head, high resolution gamma camera on a group of six patients who ful- -filled criteria for clinical diagnosis of DLB. All patients were examined neurologically by a neurologist specialized in movement disorders. Detailed neuropsychological examination was performed on each patient with a psychological tests battery by an experienced neuropsychologist. Qualitative and quantitative analysis was performed utilizing an asymmetry index for unilateral perfusion deficits and a comparison to cerebellar perfusion to assess regional cerebral perfusion. A control group of 20 patients was studied to assess normal values, utilizing an asymmetry index for unilateral perfusion deficits, and a comparison to cerebellar perfusion was performed to assess regional cerebral perfusion. RESULTS: In four cases rCBF SPECT images showed patterns of bilateral hypoperfusion of the temporal, parietal and occipital lobes. In two other cases parietal deficits were observed. CONCLUSIONS: Functional neuroimaging with the use of CBF SPECT may contribute to clinical diagnosis of DLB.

[Headache occurrence and assessment of regional blood flow after brain concussion in children]. / Wystepowanie bólów glowy oraz zmian regionalnego przeplywu mózgowego krwi po wstrzasnieniu mózgu u dzieci.

BACKGROUND AND PURPOSE: Headaches which can last for many months and even years belong to the most frequent consequences of closed head injuries in children. The method which makes it possible to demonstrate the presence and extent of the nervous tissue damage caused by trauma is the regional cerebral blood flow (rCBF) evaluation with single photon emission computerized tomography (SPECT). In the present study the regional cerebral blood flow (rCBF) was assessed 10-15 days after trauma, 3 months and one year in cases of brain concussion. We tried to establish whether there was a correlation between changes in rCBF and the occurrence of posttraumatic headache. MATERIAL AND METHODS: SPECT was applied in 32 children, aged 6-16, 10-15 days, and then 3 and 12 months after brain concussion. In all children no changes were found in CT and MRI examinations. RESULTS: In the studied group in the early period after trauma, blood flow impairment was found in 21 children, mostly in frontal areas. One year after trauma the rCBF improved in 11 children, in 10 cases the pattern was normal. In a group of 4 children with headache one year after brain concussion, three of them still presented the impairment of blood flow. CONCLUSIONS: SPECT shows a great sensitivity and usefulness in the assessment of consequences of head trauma and it can explain some posttraumatic complaints in children.

An introduction to economic analysis in medicine--the basics of methodology and chosen terms. Examples of results of evaluation in nuclear medicine.

This article overviews the basic terms and methodology approaches in economic analysis in medicine: cost-benefit analysis, cost-effectiveness analysis, cost-utility analysis and costminimisation analysis. Particular emphasis is put on nuclear medicine economic evaluation, e.g. FDG - PET studies, sestamibi breast cancer imaging and radioiodine therapy of hyperthyroidism.