Sex and gender differences in Alzheimer's disease: current challenges and implications for clinical practice: Position paper of the Dementia and Cognitive Disorders Panel of the European Academy of Neurology.

Alzheimer's disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual's sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.

Improvement of medical judgments by numerical training in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: People with multiple sclerosis (MS) have to face important decisions with regard to their medical treatment. The aim of this study was to evaluate whether a targeted cognitive training reduces framing effects and thus improves medical judgments. METHODS: This was a randomized, double-blind, cross-over study enrolling patients with relapsing-remitting MS and healthy controls (HCs). Participants were randomly assigned to training order A (first week, numerical training; second week, control training) or B (reverse order). The primary endpoint was changed in a framing task score (framing effect). In the framing task, participants evaluated the success of fictive medications on a 7-point scale. Medications were described in either positive or negative terms. RESULTS: A total of 37 patients and 73 HCs performed either training order A (n = 56) or B (n = 54). The framing effect decreased after the numerical training regardless of training order. No such decrease was found after the control training. Mean change in framing effect was -0.3 ± 0.8 after the numerical training and 0.03 ± 0.6 after the control training. This specific effect of training type was comparable between groups. CONCLUSION: Judgments of medical information improve in both patients with relapsing-remitting MS and HCs after a targeted numerical training. Thus, a specific cognitive intervention may help patients making informed decisions.

Adapting a measure of gross motor skills for individuals with CDKL5 deficiency disorder: A psychometric study.

PURPOSE: Validated measures capable of demonstrating meaningful interventional change in the CDKL5 deficiency disorder (CDD) are lacking. The study objective was to modify the Rett Syndrome Gross Motor Scale (RSGMS) and evaluate its psychometric properties for individuals with CDD. METHODS: Item and scoring categories of the RSGMS were modified. Caregivers registered with the International CDKL5 Clinical Research Network uploaded motor videos filmed at home to a protected server and completed a feedback questionnaire (n = 70). Rasch (n = 137), known groups (n = 109), and intra- and inter-rater reliability analyses (n = 50) were conducted. RESULTS: The age of individuals with CDD ranged from 1.5 to 34.1 years. The modified scale, Gross Motor-Complex Disability (GM-CD), comprised 17 items. There were no floor or ceiling effects and inter- and intra-rater reliability were good. Rasch analysis demonstrated that the items encompassed a large range of performance difficulty, although there was some item redundancy and some disordered categories. One item, Prone Head Position, was a poor fit. Caregiver-reported acceptability was positive. Scores differed by age and functional abilities. SUMMARY: GM-CD appears to be a suitable remotely administered measure and psychometrically sound for individuals with CDD. This study provides the foundation to propose the use of GM-CD in CDD clinical trials. Longitudinal evaluation is planned.

Effects of ganaxolone on non-seizure outcomes in CDKL5 Deficiency Disorder: Double-blind placebo-controlled randomized trial.

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo.

Lesion topography of posterior cerebral artery infarcts.

This study analyzed the topography of acute ischemic stroke in the posterior cerebral artery (PCA) territory. We studied 84 patients with unilateral ischemic PCA stroke. Patients were classified according to lesion levels as cortico-subcortical (superficial), combined (cortical and mesodiencephalic) or isolated thalamic. To receive a lesion map, data from acute MR and CT imaging were normalized and labelled automatically by mapping to stereotaxic anatomical atlases. Cortical lesions accounted for 41.7%, combined for 36.9%, and isolated thalamic lesions for 21.4%. The maximum overlay of ischemia and, thus, highest occurrence of PCA ischemic stroke was found in the ventral and medial occipito-temporal cortex and adjacent white matter association tracts. Dorsal and peripheral segments of the occipito-temporo-parietal region were only rarely lesioned. This configuration was similar in both hemispheres. Consistent with this lesion pattern, visual field defects (VFD) were the most frequent signs, followed by sensorimotor signs, dizziness and sopor, cognitive and oculomotor deficits, and ataxia. The three vascular subgroups differed not only by their anatomical lesion profile and lesion load, but also by their clinical manifestation; although patients with combined and thalamic lesions were sigificantly younger, they were more disabled than participants with cortical lesions. VFD were only found in cortical and combined, and oculomotor deficits only in mesodiencephalic lesions. White matter lesions were common in the cortico-subcortical and the combined group. Basal occipito-temporal and calcarine regions, and neighbouring white matter tracts have the highest risk of ischemia in acute PCA stroke.

[Consensus statement "Dementia 2010" of the Austrian Alzheimer Society]. / Konsensusstatement "Demenz 2010" der Osterreichischen Alzheimer Gesellschaft.

The Austrian Alzheimer Society developed evidence-based guidelines based on a systematic literature search and criteria-guided assessment with subsequent transparent determination of grades of clinical recommendation. The authors evaluated currently available therapeutic approaches for the most common forms of dementia and focused on diagnosis and pharmacological intervention, taking into consideration the situation in Austria. The purpose of these guidelines is the rational and cost-effective use of diagnostic and therapeutic measures in dementing illnesses. Users are physicians and all other providers of care for patients with dementia in Austria.

Auditory hair cell-afferent fiber synapses are specialized to operate at their best frequencies.

Auditory afferent fiber activity is driven by high-fidelity information transfer from the sensory hair cell. Presynaptic specializations, posited to maintain fidelity, are investigated at synapses with characteristic frequencies of 120 Hz and 320 Hz. Morphological data indicate that high-frequency cells have more synapses and higher vesicle density near dense bodies (DBs). Tracking vesicular release via capacitance changes identified three overlapping kinetic components of release corresponding to morphologically identified vesicle pools. High-frequency cells released faster; however, when normalized to release site number, low-frequency cells released faster, likely due to a greater Ca2+ load per synapse. The Ca(2+)-dependence of release was nonsaturating and independent of frequency, suggesting that release, not refilling, was rate limiting. A model of release derived from vesicle equilibration between morphologically defined pools reproduced the capacitance data, supporting a critical role in vesicle trafficking for DBs. The model suggests that presynaptic specializations enable synapses to operate most efficiently at their characteristic frequencies.

Numerical deficits in a single case of basal ganglia dysfunction.

The present investigation assesses specific numerical difficulties in a patient (SJ) with basal ganglia (BG) dysfunction. While previous studies on number processing in BG disorders typically tested arithmetic facts by production tasks, the present study uses production, recognition (verification, multiple-choice) and indirect (number-matching) arithmetic tasks. Patient SJ was severely impaired in production and to a lesser extent in verification and multiple-choice tasks. In number-matching, an abnormal latency pattern was found. This study extends previous research by indicating that BG dysfunction may not only affect production processes and sequencing, as was found in previous investigations, but may lead to a breakdown of semantic relationships of arithmetic facts.

Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF-GluR2 interaction.

We investigated whether the interaction between the N-ethyl-maleimide-sensitive fusion protein (NSF) and the AMPA receptor (AMPAR) subunit GluR2 is involved in synaptic plasticity in the CA1 region of the hippocampus. Blockade of the NSF-GluR2 interaction by a specific peptide (pep2m) introduced into neurons prevented homosynaptic, de novo long-term depression (LTD). Moreover, saturation of LTD prevented the pep2m-induced reduction in AMPAR-mediated excitatory postsynaptic currents (EPSCs). Minimal stimulation experiments indicated that both pep2m action and LTD were due to changes in quantal size and quantal content but were not associated with changes in AMPAR single-channel conductance or EPSC kinetics. These results suggest that there is a pool of AMPARs dependent on the NSF-GluR2 interaction and that LTD expression involves the removal of these receptors from synapses.

Impact of ambiguity and risk on decision making in mild Alzheimer's disease.

Decisions under ambiguity and decisions under risk are crucial types of decision making in daily living at any age. This is the first study assessing these two types of decisions in patients with mild dementia of Alzheimer's type (DAT) by means of the Iowa Gambling Task (IGT) and a newly developed, Probability-Associated Gambling (PAG) task. While rules for gains and losses are implicit in the IGT, in the PAG task rules are explicit and winning probabilities, which change from trial to trial, can be estimated. Results of the IGT indicated that DAT patients made more disadvantageous decisions than healthy controls. Patients also shifted more frequently among decks, i.e. under ambiguity decisions were taken randomly and no advantageous strategy was established over time by DAT patients. Thus, not only actual choices but also development of advantageous strategies may be revealing about decision making in the IGT. Compared to controls, patients demonstrated less advantageous choices in the PAG task as well. They gambled more often in the low winning probabilities and less frequently in the high probabilities than healthy participants. Patients' performance on both tasks correlated with measures of executive functions. Findings of the present investigation are consistent with the early pathological cerebral changes and related (cognitive, emotional) deficits reported for DAT. As suggested by our study, decisions under ambiguity as well as decisions under risk are impaired in mild DAT. It may thus be expected that patients with mild DAT have difficulties in taking decisions in every-day life situations, both in cases of ambiguity (information on probability is missing or conflicting, and the expected utility of the different options is incalculable) and in cases of risk (outcomes can be predicted by well-defined or estimable probabilities).

The Wada test in Austrian, Dutch, German, and Swiss epilepsy centers from 2000 to 2005: a review of 1421 procedures.

Twenty-six Austrian, Dutch, German, and Swiss epilepsy centers were asked to report on use of the Wada test (intracarotid amobarbital procedure, IAP) from 2000 to 2005 and to give their opinion regarding its role in the presurgical diagnosis of epilepsy. Sixteen of the 23 centers providing information had performed 1421 Wada tests, predominantly the classic bilateral procedure (73%). A slight nonsignificant decrease over time in Wada test frequency, despite slightly increasing numbers of resective procedures, could be observed. Complication rates were relatively low (1.09%; 0.36% with permanent deficit). Test protocols were similar even though no universal standard protocol exists. Clinicians rated the Wada test as having good reliability and validity for language determination, whereas they questioned its reliability and validity for memory lateralization. Several noninvasive functional imaging techniques are already in use. However, clinicians currently do not want to rely solely on noninvasive functional imaging in all patients.

Decision-making with explicit and stable rules in mild Alzheimer's disease.

Decision-making in mild dementia of Alzheimer's type (DAT) was assessed in a gambling task with stable and explicit rules [Game of Dice Task; Brand, M., Labudda, K., Kalbe, E., Hilker, R., Emmans, D., Fuchs, G., et al. (2004). Decision-making impairments in patients with Parkinson's disease. Behavioural Neurology, 15, 77-85]. DAT patients in an early stage of the disease chose safe alternatives as frequently as healthy elderly persons and did not show risky behaviour as has been reported for other neurological patient groups. However, a more detailed analysis disclosed important differences between DAT and healthy elderly. Compared to healthy controls, DAT patients shifted more frequently between safe and risky alternatives and showed less consistent response patterns. Frequent changes between strategies indicate that decisions were taken randomly, that no advantageous strategy was established and that no consistent response pattern was developed over time. As regards performance changes over the task, healthy participants had a stronger tendency towards safe and advantageous responses than DAT patients. While healthy controls showed learning as the task proceeded, DAT patients did not adapt their strategies. The proportion of "consistently safe responders" was significantly higher in the control group than in the DAT group. Analysis of reaction times indicated that differences in response behaviour were not due to fast and impulsive decision taking in the DAT group. DAT patients' response pattern may be attributed to deficits in learning and in executive functions. The frequency of changes between safe and risky choices proved to be a fair predictor for the distinction between mild DAT and healthy aging.

Cortical motor activation patterns following hand transplantation and replantation.

We studied cortical activation patterns by functional MRI in a patient who received bilateral hand transplantation after amputation 6 years ago. In the early post-operative period, the patient who had had the hand transplantation revealed strong activation of a higher motor area, only weak activation of the primary sensorimotor motor cortex and no activation of the primary somatosensory cortex. At one-year follow-up, a small increase in primary sensorimotor motor cortex activation was observed. Activation of the primary somatosensory cortex was only seen at the 2-year follow-up. Transplantation after long-standing amputation results in cortical reorganisation occurring over a two-year period.

Knowing 7 x 8, but not the meaning of 'elephant': evidence for the dissociation between numerical and non-numerical semantic knowledge.

Patients affected by semantic dementia (SD) and other severe cognitive deficits may show preserved numerical skills, including the retrieval of multiplication facts from long-term memory. No studies so far specifically investigated the network of arithmetic facts in semantic dementia. Thus, it is unknown whether preserved multiplication in SD truly reflects intact semantic knowledge or preserved retrieval of verbal sequences (just as the recitation of rhymes or poems). In the present study a patient (SG) with SD underwent an extensive assessment of number processing and calculation abilities. In particular, multiplication knowledge was investigated through a series of computerised tasks (production task, multiple-choice task, number bisection task with multiplicative triplets, number-matching task). SG demonstrated excellent performance in all number processing and calculation tasks. In computerised tasks tapping multiplication fact knowledge, SG was as accurate and fast as healthy controls. Analyses on individual regression slopes indicated that SG's reaction time effects (problem-size effect, problem-difficulty effect, interference effects, and facilitation effect) were comparable to those found in controls in each task. These results add new evidence to the independence of numerical knowledge from other semantic information and provide further insight into the organisation of stored arithmetic knowledge.

Cortical motor activation patterns following hand transplantation and replantation.

We studied cortical activation patterns by functional MRI in a patient who received bilateral hand transplantation after amputation 6 years ago and in a patient who had received unilateral hand replantation within 2 hours after amputation. In the early postoperative period, the patient who had had the hand transplantation revealed strong activation of a higher motor area, only weak activation of the primary sensorimotor motor cortex and no activation of the primary somatosensory cortex. At 1-year follow-up, a small increase in primary sensorimotor motor cortex activation was observed. Activation of the primary somatosensory cortex was only seen at the 2 year follow-up. By contrast, after hand replantation, the activation pattern was similar to that of the uninjured hand within 6 weeks. This included activation of the primary sensorimotor motor cortex, higher motor areas and primary somatosensory cortex. Transplantation after long-standing amputation results in cortical reorganization occurring over a 2-year period. In contrast, hand replantation within a few hours preserves a normal activation pattern.

Periventricular and subcortical hyperintensities on magnetic resonance imaging. 'Rims, caps, and unidentified bright objects'.

Magnetic resonance imaging hyper-intensities were classified as periventricular rim, caps, and unidentified bright objects (UBOs). These were quantitated in 100 acute stroke and 23 hemorrhage patients and 59 control subjects selected from 590 consecutive scans. The rims, caps, and ventricular size were rated on a scale from 0 to 3 for severity, and the UBOs were counted. The results indicated that the rim is also frequent in control subjects and increases with age. Unidentified bright objects, caps, and severe rims usually signify pathology, occurring much more frequently in patients with strokes and hemorrhages than in control subjects. Hypertension is a significant risk factor in UBOs and caps, but in rims, the incidence of diabetes is higher. The clinical and pathologic significance of these hyperintensities and their relationship to Binswanger's disease, lacunar state, and "état criblé" is discussed.

Asymmetric termination of secondarily generalized tonic-clonic seizures in temporal lobe epilepsy.

In patients with secondarily generalized tonic-clonic seizures (sGTCS) an asymmetric termination of the clonic phase can be observed. The authors systematically analyzed this phenomenon in patients with temporal lobe epilepsy (TLE). Thirty-nine sGTCS from 29 patients with TLE who underwent successful epilepsy surgery were analyzed, in addition to a prospectively collected group of 28 patients with TLE who had 35 sGTCS. The clonic phase of sGTCS did not end synchronously in 65.7% of all patients and in 59.4% of all seizures. In 79.3% to 80% this was ipsilateral to the hemisphere of seizure onset, and there was excellent interobserver agreement.

Priming arithmetic facts in amnesic patients.

In this study, amnesic patients showed significant repetition priming effects in arithmetic fact retrieval tasks. The results indicate that repetition priming effects in arithmetic depend not on explicit recognition, but on the activation of specific long-term representations of arithmetic facts. Processing dissociations between easy and difficult items suggest that the priming effects results from the stage of fact retrieval and not from peripheral activation. This claim is also supported by encoding and naming tasks, which showed only slight priming effects as compared to the priming found in calculation tasks. Significant priming was found for identical (5 x 6 and 5 x 6) and complement problems (5 x 6 and 6 x 5), the latter showing a smaller magnitude of priming.

Anomia for people names in DAT--evidence for semantic and post-semantic impairments.

Proper name anomia is a frequent finding among patients in the early stages of Alzheimer's disease. The present study investigates naming of famous persons in a group of DAT patients, a group of persons with mild cognitive impairment (MCI) and healthy controls. The study is aimed at distinguishing the relative contributions of semantic and post-semantic factors to difficulties in proper name retrieval. As shown by a significantly lower score in answering semantic questions, DAT patients retrieve less biographical knowledge related to famous persons than healthy elderly subjects and persons with mild cognitive impairment. This finding is in line with the frequent observation of semantic deficits in early and moderate DAT. The high number of Tip-of-the-Tongue (TOT) answers in DAT found in relation to few spontaneously named items shows that post-semantic deficits are as important as semantic deficits in determining anomia for people names in DAT. Moreover, DAT patients were less sensitive to phonological cueing than healthy persons or persons with mild cognitive impairment. These findings suggest that proper name anomia in DAT is not only due to semantic deficits, but also to problems in accessing the phonological representation, as well as to a degradation of phonological representations. Thus, naming deficits in DAT differ not only quantitatively, but also qualitatively from the difficulties of healthy elderly persons. No significant differences were found between persons with mild cognitive impairment and healthy controls in proper name retrieval.

An investigation of the expression mechanism of LTP of AMPA receptor-mediated synaptic transmission at hippocampal CA1 synapses using failures analysis and dendritic recordings.

There is considerable controversy surrounding the mechanism of expression of long-term potentiation of AMPA receptor-mediated synaptic transmission in the CA1 region of the hippocampus, a process thought to be important for learning and memory in the mammalian CNS. We have re-examined the expression mechanism of this form of synaptic plasticity using whole-cell dendritic recordings, minimal stimulation to activate one or a few synapses, and failures analysis. Dendritic recordings provide improved resolution of small synaptic events, as compared to previous studies using somatic recordings, because there is less dendritic filtering of signals. We find that long-term potentiation (LTP) is associated with changes in the size of synaptic responses when they occur (potency) in all cells and this is accompanied by significant decreases in failure rate in approximately 60% of the experiments. This suggests that in some cells an increase in quantal amplitude is the sole expression mechanism for LTP and, in the cells where failure rate decreased, there is an additional mechanism causing a change in quantal content.