Implementation of Radscale in idiopathic normal pressure hydrocephalus

Introduction: Idiopathic normal pressure hydrocephalus (iNPH) is clinically manifested by gait disturbances, cognitive deficits and urination disorders, and can be reversed with early cerebrospinal fluid drainage (CSF) intervention. Thus, it very important to diagnose these patients early, to rule out other diseases that may cause similar symptoms and to select the patients who will respond to such an operation. Patients and Methods: The study included a total of 101 patients. Neurological history data were obtained from all patients (through which the iNPH Grading scale was also scored). The patients also went through thorough neurological examination, Magnetic Resonance Imaging (MRI) and evacuative lumbar puncture (LP) with a CSF opening pressure < 20cm H2O. Measurement and scoring of the individual imaging parameters and the overall Radscale score in brain MRI were performed for all patients as well as evaluation and recording of data from CSF flows in phase contrast sequences in a subset of them. All the patients went through Tap-test, comparing the neuropsychological and motor performance of them before the evacuative LP and at specific time-points after it. The patients were then divided into two categories according to Tap-test response with the following criteria: at least 20% motor improvement and/or at least 10% simultaneous improvement in the MiniMental State Examination and Frontal Assessment Battery neuropsychological tests. Finally, in a subset of patients, the following CSF biomarkers were measured: total tau protein (total tau), phosphorylated tau protein (phospho-tau), β-amyloid peptide with 42 amino acids (Αβ42) and β-amyloid peptide with 40 amino acids (Αβ40). Results: Female patients appear to respond more frequently to the Tap-test than men. The score of the parameter "callosal angle" significantly differs between patients with a response to Tap-test and those without a response. Radscale's overall score, scores of the rest individual imaging parameters as well as absolute stroke volume and peak flow velocity in the aqueduct of sylvius does not seem to differ between these two categories of patients. Regarding individual CSF biomarkers, high total tau and p-tau levels and low Ab42/Ab40 ratio appeared to be associated with a Tap- test non-responder status. Furthermore, patients with a biomarker profile compatible with Alzheimer's disease (AD profile) had a lower possibility of improvement compared to those who had non-AD profile. Conclusions: The evaluation of Radscale's "callosal angle" parameter as well as the analysis of the biochemical CSF profile may help in the diagnosis of iNPH and possibly in the selection of patients for placement of ventriculoperitoneal shunt.Εισαγωγή: Ο ιδιοπαθής υδροκέφαλος φυσιολογικής πίεσης εκδηλώνεται κλινικά με διαταραχές βάδισης, νοητικά ελλείμματα και διαταραχές ούρησης, και είναι δυνατόν να αναστραφεί με έγκαιρη επέμβαση παροχέτευσης εγκεφαλονωτιαίου υγρού (ΕΝΥ). Το γεγονός αυτό καθιστά πολύ σημαντική την έγκαιρη διάγνωση των ασθενών αυτών, την διαφορική διάγνωση από άλλα νοσήματα που μπορεί να προκαλούν παρόμοια συμπτώματα καθώς και την κατάλληλη επιλογή των ασθενών που θα υποβληθούν σε τέτοια επέμβαση. Ασθενείς και Μέθοδοι: Στη μελέτη συμπεριλήφθηκαν συνολικά 101 ασθενείς. Σε όλους τους ασθενείς καταγράφηκαν δεδομένα του νευρολογικού ιστορικού (μέσω των οποίων βαθμολογήθηκε και η κλίμακα κλινικής βαρύτητας iNPH Grading scale) και της αντικειμενικής νευρολογικής εξέτασης. Επίσης, όλοι οι ασθενείς υπεβλήθησαν σε Μαγνητική τομογραφία εγκεφάλου (MRI) στην οποία έγινε μέτρηση και βαθμολόγηση των επιμέρους απεικονιστικών παραμέτρων και της συνολικής βαθμολογίας της κλίμακας Radscale και σε εκκενωτική οσφυονωτιαία παρακέντηση (ΟΝΠ) με πίεση εισόδου ΕΝΥ < 20cm Η2Ο. Επιπρόσθετα, έγινε καταγραφή δεδομένων από τις ροές του ΕΝΥ σε υποσύνολο των ασθενών που υπεβλήθησαν και σε ακολουθίες αντίθεσης. Στη συνέχεια, αξιολογήθηκε η ανταπόκριση των ασθενών στη δοκιμασία Tap-test, συγκρίνοντας τις νευροψυχολογικές και κινητικές επιδόσεις των ασθενών πριν την εκκενωτική ΟΝΠ και σε συγκεκριμένες χρονικές στιγμές μετά από αυτήν. Κατόπιν οι ασθενείς χωρίσθηκαν σε δύο κατηγορίες ανάλογα με την ανταπόκριση στη δοκιμασία Tap-test με κριτήριο: την κατά 20% τουλάχιστον κινητική βελτίωση ή/και την κατά τουλάχιστον 10% ταυτόχρονη βελτίωση στις νευροψυχολογικές δοκιμασίες Mini Mental State Examination και Frontal Assessment Battery. Τέλος, σε υποσύνολο των ασθενών πραγματοποιήθηκε μέτρηση των ακόλουθων βιοδεικτών ΕΝΥ: ολική ταυ πρωτεΐνη (total tau), φωσφορυλιωμένη ταυ πρωτεΐνη (phospho-tau), β-αμυλοειδές πεπτίδιο με 42 αμινοξέα και β-αμυλοειδές πεπτίδιο με 40 αμινοξέα. Αποτελέσματα: Οι γυναίκες ασθενείς φαίνεται να ανταποκρίνονται συχνότερα στη δοκιμασία Tap-test από τους άνδρες. Η βαθμολογία της παραμέτρου «γωνία του μεσολοβίου» διαφέρει σε στατιστικά σημαντικό βαθμό μεταξύ των ασθενών με ανταπόκριση στη δοκιμασία Tap-test και εκείνων χωρίς ανταπόκριση. Η συνολική βαθμολογία της Radscale, οι βαθμολογίες των υπόλοιπων επιμέρους παραμέτρων της καθώς και ο απόλυτος όγκος παλμού και η μέγιστη ταχύτητα ροής ΕΝΥ δεν φάνηκε να διαφέρουν μεταξύ των δύο αυτών κατηγοριών ασθενών. Όσον αφορά τους βιοδείκτες ΕΝΥ, τα υψηλά επίπεδα total ή phospho- tau και ο χαμηλός λόγος Αβ42/Αβ40 φάνηκε να σχετίζονται με μη ανταπόκριση στη δοκιμασία Tap-test. Επίσης, ασθενείς με προφίλ βιοδεικτών συμβατό με νόσο Alzheimer (AD profile) είχαν μικρότερη πιθανότητα βελτίωσης σε σχέση με αυτούς που είχαν non-AD profile. Συμπεράσματα: Η αξιολόγηση της παραμέτρου «γωνία του μεσολοβίου» της Radscale καθώς και η ανάλυση του βιοχημικού προφίλ του ΕΝΥ μπορεί να βοηθήσουν στη διάγνωση του ιδιοπαθούς υδροκεφάλου φυσιολογικής πίεσης και ενδεχομένως στην επιλογή ασθενών για τοποθέτηση βαλβίδας κοιλιοπεριτοναϊκής παροχέτευσης ΕΝΥ

Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence

Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer&rsquo;s disease, Parkinson&rsquo;s disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome&ndash;lysosome pathway dysregulation, impaired ubiquitin&ndash;proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-&alpha; (TNF-&alpha;), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin&ndash;proteasome and autophagosome&ndash;lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions

Troponin elevation in subarachnoid hemorrhage

Troponin (tr) elevation in aneurysmal subarachnoid hemorrhage (SAH) patients is often difficult to be appropriately assessed by clinicians, causing even disagreements regarding its management between neurosurgeons and cardiologists. The purpose of this article was to review the literature regarding the clinical interpretation of tr elevation in SAH. We searched for articles in PubMed using the key words: “troponin elevation” and “subarachnoid hemorrhage”. All of them, as well as relative neurosurgical books, were used for this review. Some type of cardiovascular abnormality develops in most SAH patients. Neurogenic stunned myocardium is a frequent SAH complication, due to catecholamine surge which induces cardiac injury, as evidenced by increased serum tr levels, electrocardiographic (ECG) changes and cardiac wall motion abnormalities. Tr elevation, usually modest, is an early and specific marker for cardiac involvement after SAH and its levels peak about two days after SAH. Cardiac tr elevation predictors include poor clinical grade, intraventricular hemorrhage, loss of consciousness at ictus, global cerebral edema, female sex, large body surface area, lower systolic blood pressure, higher heart rate and prolonged Q-Tc interval. Elevated tr levels are associated with disability and death (especially tr >1 μg/L), worse neurological grade, systolic and diastolic cardiac dysfunction, pulmonary congestion, longer intensive care unit stay and incidence of vasospasm. Tr elevation is a common finding in SAH patients and constitutes a rightful cause of worry about the patients' cardiac function and prognosis. It should be therefore early detected, carefully monitored and appropriately managed by clinicians

Mixed Small Vessel Disease in a Patient with Dementia with Lewy Bodies

Background: Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid in small/medium size brain vessels, and may coexist with Alzheimer&rsquo;s disease or dementia with Lewy bodies (DLB). We describe a patient with a clinical diagnosis of DLB and imaging/biochemical characteristics suggestive of mixed small vessel disease (both CAA and non-amyloid microangiopathy). Methods: Clinical evaluation according to recent diagnostic criteria, magnetic resonance imaging, dopamine-transporter scan (DAT-scan) and cerebrospinal fluid (CSF) analysis for dementia biomarkers were all performed. Results: The patient is a 71-year-old male, fulfilling criteria for probable DLB, with a positive DAT-scan, but with multiple microbleeds in a cortical-subcortical location suggestive of CAA, some microbleeds in deep brain nuclei suggestive of non-amyloid microangiopathy and abnormal levels of only amyloid-beta (A&beta;42) in CSF. Conclusion: Coexistent mixed vascular and neurodegenerative disorders are frequent in older subjects with dementia and each one of the underlying pathologies may contribute to, or modify the clinical presentation

The correlation of specific medication groups and falls risk in elderly. A medication logbook survey.

Falls among elderly are a common and major public health problem. Even though most falls do not lead to injury, they threaten the independence of older people causing functional decline in activities of daily living (ADLs) with substantial socioeconomic consequences. According to current literature several risk factors have been identified. Falls rarely have a single cause and the majority of them are due to a complex interaction of the age-related changes, the underlying medical condition and the medications. Some medications due to their side effects are usually called fall-risk-increasing drugs (FRIDs). We conducted a retrospective, multicentre, observational chart review study of elderly aged over 60, which aims to reveal any correlation between specific groups of medications given for the most common diseases, and falls in elderly. The sample consists of 827 participants. The data were collected by using a medication logbook which includes information about sex, age, residency, underlying diseases and the corresponding medications, incidents of fall during the last 2 years and possible fracture as a consequence of the fall

CSF Aβ42 and Aβ42/Aβ40 Ratio in Alzheimer’s Disease and Frontotemporal Dementias

Background: Alzheimer’s disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τT and τP-181), and amyloid beta with 42 and 40 amino acids (Aβ42 and Aβ40) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ42 to Aβ42/Aβ40 ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ42/Aβ40; τT/τP-181; τT/Aβ42; τP-181/Aβ42) and composite markers (t-tau: τT/(Aβ42/Aβ40); p-tau: τP-181/(Aβ42/Aβ40) were calculated. ROC curve analysis was performed to compare AUCs of Aβ42 and Aβ42/Aβ40 ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τT, τP-181 Aβ42, and Aβ42/Aβ40 ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ42 and Aβ42/Aβ40; Results: Aβ42 did not differ from Aβ42/Aβ40 ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τT/Aβ42 ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ42/Aβ40 ratio was superior to Aβ42 in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p 42/Aβ40 ratio is superior to Aβ42 in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers

Recognizing Atypical Presentations of Alzheimer’s Disease: The Importance of CSF Biomarkers in Clinical Practice

Besides the typical amnestic presentation, neuropathological studies indicate that Alzheimer’s disease (AD) may present with atypical clinical pictures. The relative frequencies of typical and atypical or mixed presentations within the entire spectrum of AD remain unclear, while some mixed or atypical presentations may have not received adequate attention for them to be included in diagnostic criteria. We investigated the spectrum of clinical presentations in patients with the AD CSF biomarker profile (high tau and phospho-tau, low Aβ42 levels), hospitalized in a tertiary academic center. Among 98 patients with the CSF AD profile, 46% of patients had the typical presentation of “hippocampal” amnestic dementia. Additionally, 23.5% and 15.3% fulfilled the criteria of mixed or atypical presentations, respectively, as described in the IWG-2 criteria. The remaining 15.3% had unusual presentations, including non-logopenic (semantic and non-fluent agrammatic) primary progressive aphasia, corticobasal syndrome, and Richardson syndrome, or could be diagnosed with normal pressure hydrocephalus. Despite selection bias (academic center), atypical clinical presentations of AD may be more common than previously thought. CSF biomarkers seem to be a useful tool for antemortem identification of such patients, which is likely to affect therapeutic decisions. Some of the unusual presentations described above should be incorporated in diagnostic criteria

Callosal Angle Sub-Score of the Radscale in Patients with Idiopathic Normal Pressure Hydrocephalus Is Associated with Positive Tap Test Response

The aim of the present study was the implementation of the composite imaging &ldquo;Radscale&rdquo; in patients with idiopathic normal pressure hydrocephalus (iNPH) and the evaluation of its score, as well as absolute stroke volume and peak flow velocity of cerebrospinal fluid (CSF) in aqueduct as indicators of a positive response following a tap test. Forty-five patients with iNPH were included. Clinical evaluation involved the 10 m timed walk test before and every 24 h for 3 consecutive days after evacuative lumbar puncture (LP). Neuropsychological evaluation comprised a mini mental state examination (MMSE), frontal assessment battery (FAB), 5-word test (5WT) and CLOX drawing test 1 and 2, which were carried out before and 48 h after LP. The tap test&rsquo;s response was defined as a &ge;20% improvement in gait and/or a &ge;10% improvement in neuropsychological tests. All scores of neuropsychological and clinical variables, except for immediate 5WT and CLOX-1, differed significantly before and 48 h after LP. Improvement in time and steps of a 10 m timed walk test differed significantly between female and male patients. Out of 45 total patients, 19 were tap test responders and 26 non-responders. The total score of Radscale and CSF flow parameters did not differ between responders and non-responders. However, &ldquo;Callosal angle&rdquo; sub-score differed significantly between these two groups. A greater &ldquo;callosal angle&rdquo; sub-score, meaning more acute callosal angle, was associated with a positive tap test response, rendering it a useful measurement in the stratification of iNPH patients that will potentially respond to CSF shunting

Cerebrospinal Fluid Biomarker Profile in TDP-43-Related Genetic Frontotemporal Dementia

Cerebrospinal fluid (CSF) biomarkers, namely total tau, phospho-tau and amyloid beta peptides, have received much attention specifically regarding Alzheimer&rsquo;s disease (AD), since they can detect the biochemical fingerprint of AD and serve as a diagnostic tool for accurate and early diagnosis during life. In the same way, biomarkers for other neurodegenerative disease pathologies are also needed. We present a case series of six patients with genetic frontotemporal dementia (FTD), with TDP-43 underlying proteinopathy, in an attempt to assess TDP-43 as a novel biomarker alone and in combination with established AD biomarkers for this specific patient group, based on the principles of personalized and precision medicine. Our results indicate that genetic TDP-43-FTD is characterized by increased CSF TPD-43 and increased TDP-43 &times; &tau;&Tau;/&tau;P-181 combination. Hence, TDP-43 combined with tau proteins could be a useful tool for the diagnosis of genetic FTD with TDP-43 underling histopathology, supplementing clinical, neuropsychological and imaging data