Peter Dal-Bianco

Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial

BACKGROUND Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimers disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease-modifying treatment of Alzheimers disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial. METHODS We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50-85 years with mild-to-moderate Alzheimers disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198. FINDINGS This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres. INTERPRETATION AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. FUNDING AXON Neuroscience SE.

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.

Annual conversion to Alzheimer disease among patients with memory complaints attending an outpatient memory clinic: the influence of amnestic mild cognitive impairment and the predictive value of neuropsychological testing

SummaryOBJECTIVE: The goals of this study were to determine the annual conversion rate to Alzheimer disease (AD) among patients reporting memory problems, including a subgroup with amnestic mild cognitive impairment (aMCI), and to investigate the predictive value of neurocognitive testing for future dementia. METHODS: A prospective study was carried out in an outpatient memory clinic. One hundred and seven patients underwent a clinical examination and completed a battery of standard cognitive tests at study entry and two years later. The conversion rate to clinically manifested AD two years later was investigated, and sensitivity, specificity, receiver operating characteristics (AUC), positive predictive value and negative predictive value for each neuropsychological test were determined. RESULTS: We found an annual rate of conversion to AD of 6.5% among patients reporting memory decline in the setting of our clinic. Specifically, patients with aMCI had an annual conversion rate of approximately 20%. The annual conversion rate for patients reporting memory problems but showing no memory deficit at memory testing was approximately 3%. Receiver operating characteristics (AUC) of the neuropsychological tests ranged from 0.60 to 0.94. CONCLUSIONS: Patients with aMCI have 8.6-fold higher odds of developing AD compared with patients without evident memory impairment on neuropsychological testing. Although the risk of developing AD among patients without objective memory decline is small, some patients in this group still convert to AD, and therefore, close clinical monitoring of patients is necessary.ZusammenfassungZIEL: Ziel der vorliegenden Studie war die Bestimmung der jährlichen Konversionsrate von Patienten mit subjektiver Gedächtnisbeeinträchtigung zur Alzheimerkrankheit unter Berücksichtigung der amnestischen Milden Kognitiven Störung (aMCI). Die Wertigkeit zur Vorhersage der Konversion durch einzelne neuropsychologische Testverfahren wurde ebenfalls untersucht. METHODIK: Im Rahmen einer Gedächtnisambulanz wurde eine prospektive Studie durchgeführt. 107 Patienten wurden in die Studie inkludiert. Alle Patienten durchliefen eine neurologische und eine neuropsychologische Untersuchung am Beginn der Studie und nach zwei Jahren am Ende der Studie. Einerseits wurde die Konversionsrate zur Alzheimerkrankheit untersucht, und anderseits wurden einige Kennwerte der Kriteriumsvalidität (Sensitivität, Spezifität, Receiver Operating Characteristics [AUC], Positive Predictive Value, Negative Predictive Value) einzelner neuropsychologischer Testverfahren zur Vorhersage der Alzheimerkrankheit bestimmt. RESULTAT: Wir fanden eine jährliche Konversionsrate von 6,5 % für Patienten, die eine Beeinträchtigung der Gedächtnisfunktionen berichteten. Patienten mit aMCI hatten eine jährliche Konversionsrate von ungefähr 20 %. Die jährliche Konversionsrate von Patienten mit subjektiver Gedächtnisbeeinträchtigung ohne testpsychologisch nachweisbare Gedächtnistörung lag bei ungefähr 3 %. Receiver operating characteristics (AUC) für einzelne neuropsychologische Verfahren lagen zwischen 0,60 und 0,94. KONKLUSION: Patienten mit aMCI haben, im Vergleich zu Patienten ohne neuropsychologisch fassbare Gedächtnisstörung, eine 8,6-fache Wahrscheinlichkeit, innerhalb von zwei Jahren eine klinisch manifeste Alzheimerkrankheit zu entwickeln. Obwohl die Wahrscheinlichkeit für Patienten ohne neuropsychologisch fassbare Gedächtnisstörung, innerhalb von zwei Jahren eine Alzheimerkrankheit zu entwickeln, gering ist, konvertieren einige wenige Patienten doch zur Alzheimerkrankheit. Engmaschige Kontrolluntersuchungen sind deshalb notwendig.

A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer's disease

This work describes a microdosing study with an investigational, carbon 11‐labeled antiamyloid drug, 1,1′‐methylene‐di‐(2‐naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimers disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single‐dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 ± 21 MBq [11C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9–17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3–2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid‐beta‐rich and ‐poor regions, with slow washout of radioactivity (half‐life, 82–185 minutes). In conclusion, these data provide important information on the blood‐brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target‐organ pharmacokinetics of radiolabeled drugs in humans.

ODOR IDENTIFICATION AND SELF-REPORTED OLFACTORY FUNCTIONING IN PATIENTS WITH SUBTYPES OF MILD COGNITIVE IMPAIRMENT

Olfactory dysfunction is a very early symptom of Alzheimers disease (AD), and olfactory dysfunction has also been found in mild cognitive impairment (MCI). The goal of the present study was to compare odor identification ability and self-reported olfactory functioning in patients with different types of MCI. We included 104 elderly participants classified into two groups: patients with mild cognitive impairment (MCI) and elderly controls (EC). Based on their performance in neuropsychological testing the study population was divided into four groups of participants based on cognitive features: amnestic MCI single domain (11), amnestic MCI multiple domain (19), non-amnestic MCI single domain (21) and non-amnestic MCI multiple domain (13), respectively. The MCI patients were compared to 40 elderly controls (EC) controls with no cognitive deficit. Comparison for odor identification revealed a significant difference between amnestic MCI multiple domain patients and the EC group. No other group comparison was significant. Statistical analyses for self-reported olfactory functioning revealed no significant group differences between any subgroup of MCI patients and the control group. Correlational analyses indicated that odor identification ability was related to cognition whereas no relationship was found for self-reported olfactory functioning. The present study showed that amnestic MCI patients with additional deficits in other cognitive domains have a specific odor identification impairment. Together with cognitive testing, olfactory testing may more accurately help predict whether or not a patient with MCI will convert to AD in the near future.

Awareness of memory deficits in subjective cognitive decline, mild cognitive impairment, Alzheimer's disease and Parkinson's disease

BACKGROUND Impaired awareness of memory deficits has been recognized as a common phenomenon in Alzheimers disease (AD) and research is now increasingly focusing on awareness in groups at risk for future dementia. This study aimed to determine whether levels of awareness differ among healthy elderly people and patients with subjective cognitive decline (SCD), amnestic and non-amnestic subtypes of mild cognitive impairment (aMCI, naMCI), Alzheimers disease (AD) and Parkinsons disease (PD), to explore correlates of awareness and to establish frequencies of memory over- and underestimation within each diagnostic group. METHODS 756 consecutive outpatients of a memory clinic and 211 healthy controls underwent thorough neuropsychological testing. Impairment of awareness was measured as the difference between subjective memory appraisals (16-item questionnaire on current memory-related problems in everyday life) and objective memory performance (15-item delayed recall task). Subgroups of over- and underestimators were classified using percentile ranks of controls. RESULTS At group level, awareness significantly decreased along the naMCI→aMCI→AD continuum, with naMCI patients showing a tendency towards overestimation of memory dysfunction. PD patients showed accurate self-appraisals as long as memory function was largely unaffected. However, there was a considerable between-group overlap in awareness scores. Furthermore, different correlates of awareness were observed depending on the diagnostic group. In general, unawareness seems to be associated with decreased cognitive performance in various domains (especially memory), higher age and lower levels of depression and self-reported functional impairment. CONCLUSION Impaired awareness is an important symptom in aMCI. Yet, given the considerable variability in awareness scores, longitudinal studies are required to evaluate their predictive power.

Prevalence of mild cognitive impairment subtypes in patients attending a memory outpatient clinic—comparison of two modes of mild cognitive impairment classification. Results of the Vienna Conversion to Dementia Study

Early detection of dementia is becoming more and more important owing to the advent of pharmacologic treatment.

Cognitive function in elderly marathon runners: Cross-sectional data from the marathon trial (apsoem)

ZusammenfassungHINTERGRUND: Die kognitive Beeinträchtigung von älteren Menschen trägt zur Morbidität, Verlust der Lebensqualität und Beeinträchtigung der Arbeitsfähigkeit in alternden westlichen Gesellschaften bei. Strategien zur Erhaltung der kognitiven Fähigkeiten im hohen Alter stellen daher eine große Herausforderung für die Arbeitsmedizin dar. ZIEL: Festzustellen, ob intensives Ausdauertraining mit einer verbesserten kognitiven Leistungsfähigkeit verbunden ist, und ob brain-derived neurotrophic factor (BDNF) und insulin-like growth factor (IGF) durch Ausdauertraining erhöht werden. METHODIK: Aktive ältere Marathonläufer oder Radfahrer über 60 Jahre wurden angeworben und einer inaktiven Kontrollgruppe nach Alter, Geschlecht und Bildungsjahren gegenübergestellt. Nachdem laut Studienprotokoll Personen mit verschiedenen Krankheiten ausgeschlossen wurden, konnten 56 Athleten und 58 Kontrollpersonen für Folgeuntersuchungen herangezogen werden. Der Einfluss von Ausdauertraining auf kognitive Funktionen wurde durch die Vienna Neuropsychologische Testbatterie (VNTB) und die CERAD Testbatterie (Consortium to Establish a Registry for Alzheimers Disease) gemessen. Andere relevante Ergebnisse waren die Werte der humoralen Wachstumsfaktoren (BDNF und IGF-1), Apo ε4 Carrierfrequenz und Selbsteinschätzungen. ERGEBNISSE: Die Leistung der älteren Marathongruppe war nur bei einer spezifischen kognitiven Aufgabe besser (beim Five Point Test, p = 0,04) und fast signifikant besser in einem zusätzlichen Test (NAI Stroop Test, p = 0,08). Weder BDNF noch IGF-1 hatten einen Bezug zur Dauer des täglichen Ausdauertrainings, und kein Unterschied wurde bei den Basalwerten dieser Wachstumsfaktoren in den Trainings- und Kontrollkohorten gefunden. Interessanterweise fanden wir auch signifikant reduzierte BDNF-Werte bei Personen mit Alzheimerkrankheit in der Familie trotz Beibehaltung der normalen kognitiven Leistung (p = 0,01). SCHLUSSFOLGERUNG: Diese Ergebnisse deuten darauf hin, dass umfassendes Ausdauertraining für die Erhaltung der kognitiven Funktionen von älteren Menschen nützlich sein könnte. Längsschnittdaten dieser prospektiven Kohortenstudie sind notwendig, um diese möglichen Auswirkungen auf Kognition zu bewerten. Zusätzlich zeigen unsere Daten, dass die nützlichen Auswirkungen von Ausdauertraining nicht mit der Hochregulation von Neurotrophinen wie BDNF und IGF-1 verbunden sind. Da wir reduzierte BDNF-Werte bei Personen mit einer positiven Familiengeschichte von Alzheimer fanden, vermuten wir, dass eine BDNF-Senkung einer kognitiven Beeinträchtigung vorausgehen könnte.SummaryBACKGROUND: Cognitive impairment of the elderly contributes to morbidity, loss of quality of life, and impairment of work ability in aging western societies. Thus strategies to maintain cognitive function at an advanced age imply a great challenge to Occupational Medicine. AIM: To study whether intensive endurance exercise training is associated with better cognitive performance and increases brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF). METHODS: Active elderly marathon runners or bicyclists older than 60 years were recruited and matched with an inactive control group according to age, sex, and education years. After exclusion of various diseases according to the study protocol 56 athletes and 58 controls could be selected for follow-up studies. The influence of endurance training on cognitive function was assessed by the use of the Vienna Neuropsychological Test Battery and the CERAD test battery. Other relevant outcomes were the levels of BDNF, IGF-1, Apo e4 carrier state, and self-ratings. RESULTS: The elderly marathon group performed better only in one specific cognitive task (the Five Point Test, p = 0.04) and almost significantly better in one additional test (the NAI Stroop Test, p = 0.08). Neither BDNF nor IGF-1 was related to the duration of daily exercise and no differences in the basal levels of these humoral growth factors in the exercise and the control cohort were found. Interestingly, we also found significantly decreased BDNF levels in subjects with Alzheimers disease in the family in spite of the maintained normal cognitive performance (p = 0.01). CONCLUSION: These results suggest that extensive endurance exercise training might be beneficial for maintaining cognitive function in elderly persons. Our data demonstrate that beneficial endurance training effects are not linked to the upregulation of the examined neurotrophins. Since we found reduced BDNF-levels in subjects with a positive family history of Alzheimers disease, we speculate that BDNF-reduction might precede cognitive impairment.

Health-Related Quality of Life in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment and its Relation to Activities of Daily Living.

BACKGROUND Health related quality of life (HRQOL) is an important issue in the context of dementia care. OBJECTIVES The purpose of this study was to investigate HRQOL in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) and its relation to Activity of Daily Living (ADL). METHODS In this cross sectional study, four experimental groups (each n = 98), controls, SCD, naMCI and aMCI, were compared. For data collection, neuropsychological methods (NTBV) and psychological questionnaires (SF-36 and B-ADL) were used. Multivariate analysis of variance was calculated to detect differences in HRQOL between groups. Correlations between HRQOL and ADL were explored. RESULTS The dimensions of HRQOL showed mainly consistent differences between the control and the SCD group and MCI subgroups. In almost every dimension of HRQOL, the control group scored higher than subjects with SCD, naMCI, or aMCI. The controls showed low to moderate negative correlations between HQROL and B-ADL in some dimensions of the HRQOL. In the SCD group, low negative correlations with ADL were observed in some HRQOL scales. Low to moderate correlations were found between each scale of the SF-36 and the B-ADL in both MCI subtypes. We found gender differences in HRQOL. CONCLUSION In conclusion, we could demonstrate that patients with SCD report reduced quality of life. This knowledge is important to get a better understanding of the individuals with SCD and may pave the way for the development of early intervention.

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 Alzheimers 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.