CXCL13 as a biomarker in the diagnostics of European lyme Neuroborreliosis - A prospective multicentre study in Austria.

Background: 'Definite Neuroborreliosis (NB)' is diagnosed with the presence of NB-specific symptoms, cerebrospinal fluid (CSF) pleocytosis and an elevated Borrelia Burgdorferi antibody index. However, some diagnostic uncertainties exist. The B-cell chemokine CXCL13 represents an emerging biomarker for the diagnosis and treatment of NB because its intrathecal concentration rises prior to the Borrelia antibody index and drops rapidly after antibiotic therapy. Nevertheless, due to lacking prospective data, a definite CXCL13 cut-off for the diagnosis of NB is still pending. Objective: Definition of a CSF CXCL13 cut-off for the diagnosis of acute and untreated NB in a prospective study setting. Design and methods: This multicentre prospective study involved 6 neurological departments treating patients in the Lower Austria district (1.7 million inhabitants). The controls were patients scheduled for a spinal tap but not clinically diagnosed with NB. Demographic data, clinical characteristics and blood counts, as well as inflammatory CSF values and CSF CXCL13-concentration were analysed. Results: We recruited 440 adult patients, of whom 42 have been diagnosed as having an acute and untreated 'definite NB'. Three hundred ninety-eight patients were assigned to the control group. The median intrathecal CXCL13 concentration was 2384 pg/ml for patients with NB and 0 pg/ml for controls. The difference was highly statistically significant (P ≤ .001). A CSF CXCL13 cut-off of 271 pg/ml resulted in a sensitivity of 95.2% and a specificity of 97.2% for the confirmation or exclusion of NB. Conclusion: Based on our results, we propose a CSF CXCL13 cut-off of 271 pg/ml with Euroimmun-Elisa for the diagnosis of acute and untreated NB. Due to its high sensitivity and specificity, CXCL13 is a strong candidate biomarker for routine NB assessment, especially in clinically unclear cases.

Botulinum Toxin-A for the Treatment of Neuropathic Pain after Decompressive Craniotomy in Stroke: Two Cases.

Botulinum toxin-A (BoNT-A) is recommended as third-line off-label treatment for the management of neuropathic pain. BoNT-A has been reported as treatment for different neuropathic pain conditions; however, not for neuropathic pain after decompressive craniotomy for stroke. The aim of this retrospective case series is to provide information on safety, the effect, and the application method of BoNT-A in clinical practice for the treatment of neuropathic pain after trepanation. This case series describes 2 patients treated in 2021 at a BoNT outpatient clinic for chronic neuropathic pain at the incisional site after decompressive craniotomy for stroke who were resistant to pain medication. Cases were a 48-year-old woman and a 63-year-old man suffering from chronic neuropathic pain since 3 and 6 years, respectively. They were treated regularly with BoNT-A with a total dose of 100 mouse units of incobotulinumtoxin-A injected into peri-incisional sites of the scalp. Both patients reported subjective decrease in pain frequency (40% and 60%), in pain intensity (60% and 90%), and an increase of quality of life (80%). BoNT-A should be further investigated as treatment for neuropathic pain - especially in underreported conditions such as neuropathic pain after craniotomy in stroke.

C9orf72 repeat length might influence clinical sub-phenotypes in dementia patients.

BACKGROUND: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype. METHODS: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting. RESULTS: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01). CONCLUSIONS: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.

COVID-19-related delays of botulinum toxin injections have a negative impact on the quality of life of patients with dystonia and spasticity: a single-center ambulatory care study.

BACKGROUND: Botulinum toxin A (BoNT-A) is considered a safe and effective treatment for spasticity and dystonia. Individual interinjection intervals are critical for the maintenance of the effect. In Austria, BoNT outpatient clinics were shutdown from November to December 2020 during COVID-19 control measures, leading to rescheduling of BoNT-A injections. This survey aimed at investigating the influence of injection delays on symptoms, physical functioning, and quality of life (QoL) of the affected patients. METHODS: Between April and July 2021, 32 outpatients (21 females, mean age: 63.4 ± 12.1 years) treated ≥ 12 months at the BoNT outpatient clinic Horn-Allentsteig (Austria) and experienced ≥ 2 week injection delays, completed a structured face-to-face questionnaire. RESULTS: Indications were dystonia (34%), spasticity (63%), and hyperhidrosis (3%). Injections were delayed by 10 weeks (median, range: 2-15). Muscle cramps increased in 95% of patients with spasticity, muscle twitches in 91% of those with dystonia, and pain in 9% and 60% for dystonia and spasticity, respectively. Overall, 75% reported functional worsening, and deterioration in QoL by 62.6% ± 16.8 (mean ± SD). The impact on QoL correlated with the subjective global improvement induced by BoNT-A (Rs: 0.625; p < 0.001). For 75%, long-term assurance of BoNT-A therapy was very important, and 81% felt their patient rights not respected. CONCLUSIONS: COVID-19-related delays in BoNT-A injections illustrate the importance of this therapy for symptom relief, functional outcome, and QoL in patients suffering from involuntary muscle hyperactivity. BoNT-A therapy is essential and has to be guaranteed even in circumstances such as the COVID-19 pandemic.

[Position paper of the Austrian Alzheimer Association (Österreichische Alzheimer Gesellschaft, ÖAG) : Effects of the COVID-19 pandemic in Austria on people with dementia and their care environment-problem areas, recommendations, and strategies]. / Positionspapier der Österreichische Alzheimer Gesellschaft (ÖAG) : Auswirkungen der COVID-19-Pandemie in Österreich auf Menschen mit Demenz und deren Betreuungsumfeld ­ Problemfelder, Empfehlungen und Strategien.

Older adults are particularly affected by the current COVID-19 (SARS-CoV-2) pandemic. The risk of dying from COVID-19 increases with age and is often associated with pre-existing health conditions. Globally, more than 50 million-in Austria currently approximately 140,000 people-suffer from dementia. The co-occurrence of dementia as a "pandemic of old age" together with the COVID-19 pandemic has a double impact on persons living with dementia and their caregivers. The COVID-19 pandemic poses major challenges for individuals with dementia and their caregivers: (1) People with dementia have limited access to information on COVID-19, may have difficulties with protective measures such as wearing masks and in remembering safety regulations. (2) People with dementia live alone or with their family, or are institutionalized. To reduce the chance of infection among older people in nursing homes, Austrian local authorities have banned visitors to nursing homes and long-term care facilities and implemented strict social-distancing measures. As a result, older people lost face-to-face contact with their family members, became isolated and social activities stopped. Consequently, anxiety, stress and serious concerns about infections among staff in nursing homes increased and they developed signs of exhaustion and burnout during the full lockdown of the facilities. Thus, due to the emerging COVID-19 crisis, the Austrian Alzheimer Association (Österreichische Alzheimer Gesellschaft, ÖAG) and international societies developed recommendations to support people living with dementia and their caregivers on various issues of physical and mental health.

Management of mild cognitive impairment (MCI): The need for national and international guidelines.

Objectives: To review available evidence of pharmacological and non-pharmacological treatment for MCI and analyse information and limitations in national and international guidelines.Methods: Experts from several European countries conducted a qualitative review of the literature on MCI and treatments for MCI, as well as respective chapters in national and international guidelines on dementia/MCI. Psychotherapeutic/psychosocial treatments were excluded from the review.Results: Consensus diagnostic criteria for MCI are available, making early recognition and accurate classification of MCI subtypes possible. MCI can be identified in a primary care setting. Further corroboration and differential diagnosis should be done at specialist level. Mixed pathologies are the rule in MCI, thus a multi-target treatment approach is a rational strategy. Promising evidence has been generated for multi-domain interventions. Limited evidence is available for different pharmacological classes that have been investigated in MCI clinical trials (e.g. acetylcholinesterase inhibitors). EGb 761® improved symptoms in some clinical trials; it is the only pharmacological treatment recommended in existing guidelines for the symptomatic treatment of MCI.Conclusions: MCI is recognised as an important treatment target and some recent national guidelines have considered symptomatic treatment recommendations for MCI. However, more needs to be done, especially at an international level.

Prevention of poststroke cognitive decline: ASPIS--a multicenter, randomized, observer-blind, parallel group clinical trial to evaluate multiple lifestyle interventions--study design and baseline characteristics.

BACKGROUND: Cognitive impairment after stroke is a considerable burden to patients and their caregivers and occurs in one-third of stroke survivors. No strategy to prevent cognitive decline after stroke exists thus far. Established vascular risk factors have been associated with cognitive decline and may be a target for therapeutic interventions in stroke survivors. AIM: To test whether intensive multifactorial non-pharmacologic interventions based on lifestyle modification can reduce the risk of cognitive decline in patients who recently suffered ischemic stroke. METHODS: A randomized, controlled, multicenter, observer-blind trial was designed. The reference group obtains stroke care according to standard guidelines. The intervention group additionally receives intensive control and motivation for better compliance with prescribed evidence-based medication, regular blood pressure measurements, healthy diet, regular physical activity and cognitive training. Primary outcomes are the rate of cognitive decline at 24 months, assessed by a neuropsychological test battery and the cognitive subscale of the Alzheimer's Disease Assessment Scale. RESULTS: 202 patients (29% women), aged 62 ± 9 years, were recruited during 2010 to 2012. Stroke related impairment at inclusion was low (mean National Institutes of Health Stroke Scale: 1.9±1.8, median modified Rankin Scale: 1 (0-1)). At baseline, groups did not differ significantly in demographic, clinical or lifestyle characteristics. CONCLUSION: The recruitment was successful and the groups are balanced regarding potential confounding variables. The study will provide essential data about the feasibility and efficacy of lifestyle intervention after stroke in order to develop a new approach to prevent cognitive decline in patients with mild ischemic stroke.

Cognition, gender, and functional abilities in Alzheimer's disease: how are they related?

BACKGROUND: Few studies have investigated in detail which factors influence activities of daily (ADL) in Alzheimer's disease (AD). OBJECTIVE: To assess the influence of cognitive, gender, and other factors on ADL in patients with mild to moderate AD. METHODS: This study is part of the Prospective Registry on Dementia in Austria (PRODEM) project, a multicenter dementia research project. A cohort of 221 AD patients (130 females; means: age 76 years, disease duration 34.4 months, MMSE 22.3) was included in a cross-sectional analysis. Everyday abilities were assessed with the Disability Assessment for Dementia scale, and cognitive functions with the CERAD plus neuropsychological test battery. Two models of multiple linear regressions were performed to find factors predicting functional decline, one entering demographical and disease related factors, and a joint model combining demographical and disease variables with neuropsychological scores. RESULTS: Non-cognitive factors explained 18%, whereas the adding of neuropsychological variables explained 39% of variance. Poor figural and verbal memory, constructional abilities, old age, longer disease duration, depression, and male gender were independent risk factors for reduced ADL. Instrumental and basic ADL were predicted by similar factors, except gender (predicting only instrumental ADL) and phonological fluency (predictor of basic ADL). CONCLUSION: In addition to demographical factors, disease duration, and depression, neuropsychological variables are valuable predictors of the functional status in AD in an early disease stage.

Driving cessation and dementia: results of the prospective registry on dementia in Austria (PRODEM).

OBJECTIVE: To assess the influence of cognitive, functional and behavioral factors, co-morbidities as well as caregiver characteristics on driving cessation in dementia patients. METHODS: The study cohort consists of those 240 dementia cases of the ongoing prospective registry on dementia in Austria (PRODEM) who were former or current car-drivers (mean age 74.2 (±8.8) years, 39.6% females, 80.8% Alzheimer's disease). Reasons for driving cessation were assessed with the patients' caregivers. Standardized questionnaires were used to evaluate patient- and caregiver characteristics. Cognitive functioning was determined by Mini-Mental State Examination (MMSE), the CERAD neuropsychological test battery and Clinical Dementia Rating (CDR), activities of daily living (ADL) by the Disability Assessment for Dementia, behavior by the Neuropsychiatric Inventory (NPI) and caregiver burden by the Zarit burden scale. RESULTS: Among subjects who had ceased driving, 136 (93.8%) did so because of "Unacceptable risk" according to caregiver's judgment. Car accidents and revocation of the driving license were responsible in 8 (5.5%) and 1(0.7%) participant, respectively. Female gender (OR 5.057; 95%CI 1.803-14.180; p = 0.002), constructional abilities (OR 0.611; 95%CI 0.445-0.839; p = 0.002) and impairment in Activities of Daily Living (OR 0.941; 95%CI 0.911-0.973; p<0.001) were the only significant and independent associates of driving cessation. In multivariate analysis none of the currently proposed screening tools for assessment of fitness to drive in elderly subjects including the MMSE and CDR were significantly associated with driving cessation. CONCLUSION: The risk-estimate of caregivers, but not car accidents or revocation of the driving license determines if dementia patients cease driving. Female gender and increasing impairment in constructional abilities and ADL raise the probability for driving cessation. If any of these factors also relates to undesired traffic situations needs to be determined before recommendations for their inclusion into practice parameters for the assessment of driving abilities in the elderly can be derived from our data.

[Transdermal rivastigmine patch in outpatient services in Austria: a naturalistic study in 103 patients with Alzheimer dementia]. / Rivastigmin-Pflaster in der ambulanten Versorgung in Osterreich: eine naturalistische Studie an 103 PatientInnen mit Alzheimer Demenz.

We performed a 6-month open-label study on the use of the transdermal rivastigmine patch in clinical routine in 103 patients with Alzheimer's disease from 25 outpatient services in Austria. After baseline, safety and tolerability of the 10 cm2--rivastigmine patch was assessed at week 4, 12 and 24 in all patients. A Mini Mental State Examination was done at baseline and at week 12 and 24. Skin adherence of the patch was very good or good in 85% of study participants. Only 2.9% of patients had gastrointestinal adverse events. Local skin reactions occurred in 23% of individuals. Skin alteration were mostly mild in severity. In only 6.8% of subjects did they result in termination of treatment. At the earliest skin reactions were observed after 3 months of treatment. Cognitive functioning of patients improved comparable to the controlled trial which led to approval of the rivastigmine patch. In daily routine the safety profile of the rivastigmine patch is favourable, as is the response to treatment. Local, mostly mild skin reactions affect approximately every fifth patient, and they occur relatively late in the course of therapy. Patients and their caregivers should receive detailed information about skin reactions to omit unnecessary drop outs to treatment.

[Therapy of Alzheimer's disease: current status and future development]. / Therapie der Alzheimer Demenz: derzeitiger Stand und zukünftige Entwicklung.

Cholinesterase inhibitors and memantine can slow the course of Alzheimer's disease. In Austria the frequency of treatment is in the upper third among countries of the EU. Yet, the majority of Alzheimer patients does not receive adequate medication. Compliance to treatment is low. Studies on cholinesterase inhibitors show that only one third and one fifth of patients adhere to medication after 3 months and 12 months, respectively. Causes for low compliance are only partly patient-related, many factors are system-inherent. Knowledge of these factors is a pre-requisite for the treating physician to improve current unfavourable situation. Present treatment strategies are symptomatic, causal disease-modifying therapies are urgently needed. Research activity in the field is high and dominated by the amyloid hypothesis. We here review the basis and recent studies on secretase-inhibitors, immunization, aggregation of Abeta, statins and PPARgamma-agonists. Research towards strategies against tau-pathology is less dominant and focuses on inhibition of kinases and increase of activity of phosphatases. Causal therapies would have great effects on a population basis even if efficacy is only moderate. A disease-modifying therapy which delays the onset of Alzheimer disease by 5 years, will probably reduce the number of patients by nearly 50% during the next 50 years.

[Dementia with Lewy Bodies and its differentiation from Alzheimer's disease]. / Lewy-Körper-Demenz und ihre ifferentialdiagnostische Abgrenzung von Alzheimer'scher Erkrankung.

Dementia with Lewy Bodies (DLB) accounts for approximately 20 % of all autopsy-confirmed dementias in the elderly. Presumably, DLB is underdiagnosed in patients without or with only mild Parkinsonian symptoms in the daily routine of memory clinics. This motivated the Austrian Alzheimer Society and the Austrian Parkinson Society to inform about core features, suggestive features and supportive clinical findings of DLB and to provide information on diagnostic possibilities leading to better differential diagnosis. We also guide in the management of DLB as pharmacological treatment can pose difficult dilemmas for the treating clinician.

A novel LRRK2 mutation in an Austrian cohort of patients with Parkinson's disease.

To investigate the frequency of mutations in the Leucine-Rich Repeat Kinase 2 gene (LRRK2) in a sample of Austrian Parkinson's disease (PD) patients, we sequenced the complete coding region in 16 patients with autosomal dominant PD. Furthermore, we sequenced exons 31, 35, and 41 additionally in 146 patients with idiopathic PD and 30 patients with dementia with Lewy bodies. Furthermore, all 192 patients were screened for 21 putative LRRK2 mutations. While the most common mutation G2019S and the risk variant G2385R were not found in our samples, we detected a novel missense mutation (S973N) in a patient with familial, late-onset and dopa-responsive PD.

From counting neurons to the preclinical diagnosis of Alzheimer's disease.

This article is a review of scientific work on Alzheimer neurofibrillary degeneration and Ass-amyloidosis that was done in collaboration with Dr. Henryk Wisniewski, in part at the Institute for Basic Research in Developmental Disabilities. Our work on paired helical filaments and the tau protein spans from basic immunocytochemical analyses of brain tissue to clinical application as a biological marker used in diagnostic tests. Even though only a small part of Dr. Wisniewski's scientific oeuvre, these data illustrate how a great scientist opens the field to his student, collaborator and friend, how basic science can evolve, and how results can be applied in clinical practice to the benefit of our patients.