Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1.

BACKGROUND: In rare cases, patients with Alzheimer disease (AD) present at an early age and with a family history suggestive of an autosomal dominant mode of inheritance. Mutations of the presenilin-1 (PSEN1) gene are the most common causes of dementia in these patients. Early-onset and particularly familial AD patients frequently present with variable non-amnestic cognitive symptoms such as visual, language or behavioural changes as well as non-cognitive, e.g. motor, symptoms. OBJECTIVE: To investigate the phenotypic variability in carriers of the PSEN1 S170F mutation. METHODS: We report a family with 4 patients carrying the S170F mutation of whom 2 underwent detailed clinical examinations. We discuss our current findings in the context of previously reported S170F cases. RESULTS: The clinical phenotype was consistent regarding initial memory impairment and early onset in the late twenties found in all S170F patients. There were frequent non-amnestic cognitive changes and, at early stages of the disease, indications of a more pronounced disturbance of visuospatial abilities as compared to face and object recognition. Non-cognitive symptoms most often included myoclonus and cerebellar ataxia. A review of the available case reports indicates some phenotypic variability associated with the S170F mutation including different constellations of symptoms such as parkinsonism and delusions. CONCLUSION: The variable clinical findings associated with the S170F mutation highlight the relevance of atypical phenotypes in the context of research and under a clinical perspective. CSF sampling and detection of Aß species may be essential to indicate AD pathology in unclear cases presenting with cognitive and motor symptoms at a younger age.

The face-responsive M170 is modulated by sensor selection: An example of circularity in the analysis of MEG-data.

BACKGROUND: Magnetoencephalography (MEG) experiments create large data sets obtained from many sensors at different locations. Therefore, a process of sensor-selection prior to hypothesis-driven data analysis is common, e.g., when studying the face-selective M170 component occurring at temporal sites around 170ms post-stimulus. However, the strategies to identify sensors of interest vary across investigations, and frequently the contrast used for sensor-selection is not independent from the contrast between experimental conditions. NEW METHOD: We re-analyzed data from a previously published MEG-experiment where participants viewed faces of either a loved person or two friends. We included different strategies for identifying face-responsive sensors based on all or each one of the face-categories before comparing M170 amplitudes across conditions. RESULTS: When sensor-selection was based on signal strength elicited by one experimental condition alone, a comparison across face-categories revealed significantly increased M170 amplitudes for the respective face category. Conducting the same analysis following sensor-selection based on averaged activity across all face-categories did not yield different M170 amplitudes. COMPARISON WITH EXISTING METHOD: Whereas this pitfall of selective analysis has been studied and discussed in detail for fMRI methods there is no comparable re-analysis of real EEG/MEG-data. CONCLUSIONS: Our results demonstrate that selection-bias is as relevant for EEG/MEG analysis as for fMRI methods. Sensor-selection must be independent from the contrast analyzed with statistical comparisons, because otherwise a distorted or 'circular' analysis might result.

The 170ms Response to Faces as Measured by MEG (M170) Is Consistently Altered in Congenital Prosopagnosia.

Modularity of face processing is still a controversial issue. Congenital prosopagnosia (cPA), a selective and lifelong impairment in familiar face recognition without evidence of an acquired cerebral lesion, offers a unique opportunity to support this fundamental hypothesis. However, in spite of the pronounced behavioural impairment, identification of a functionally relevant neural alteration in congenital prosopagnosia by electrophysiogical methods has not been achieved so far. Here we show that persons with congenital prosopagnosia can be distinguished as a group from unimpaired persons using magnetoencephalography. Early face-selective MEG-responses in the range of 140 to 200ms (the M170) showed prolonged latency and decreased amplitude whereas responses to another category (houses) were indistinguishable between subjects with congenital prosopagnosia and unimpaired controls. Latency and amplitude of face-selective EEG responses (the N170) which were simultaneously recorded were statistically indistinguishable between subjects with cPA and healthy controls which resolves heterogeneous and partly conflicting results from existing studies. The complementary analysis of categorical differences (evoked activity to faces minus evoked activity to houses) revealed that the early part of the 170ms response to faces is altered in subjects with cPA. This finding can be adequately explained in a common framework of holistic and part-based face processing. Whereas a significant brain-behaviour correlation of face recognition performance and the size of the M170 amplitude is found in controls a corresponding correlation is not seen in subjects with cPA. This indicates functional relevance of the alteration found for the 170ms response to faces in cPA and pinpoints the impairment of face processing to early perceptual stages.

Dysfunctional action control as a specific feature of Parkinson's disease.

Parkinson's disease (PD) is characterised by motor deficits as well as cognitive alterations, particularly concerning frontal lobe control. Here, we were interested in whether executive function is abnormal already early in PD, as well as whether this dysfunction worsens as a part of the dementia in PD. The following groups engaged in tasks addressing action control: PD patients with mild and advanced motor symptoms (aPD) without dementia, PD patients with dementia (PDD), patients with Alzheimer's disease (AD) and healthy subjects (CON). Subjects either had to perform or inhibit button presses upon go and no-go cues, respectively. These cues were preceded by pre-cues, either randomly instructive of right or left hand preparation (switch condition), or repetitively instructive for one side only (non-switch condition). PDD and aPD omitted more go responses than CON. Furthermore, PDD disproportionally committed failures upon no-go cues compared to CON. In the non-switch condition, PDD performed worse than AD, whose deficits increased to the level of PDD in the switch condition. Over all PD patients, task performance correlated with disease severity. Under the switch condition, task performance was low in both PDD and AD. In the non-switch condition, this also held true for advanced PD patients (with and without dementia), but not for AD. Thus, the deficits evident in PDD appear to develop from imbalanced inhibitory-to-excitatory action control generally inherent to PD. These results specify the concept of dysexecution in PD and differentiate the cognitive profile of PDD from that of AD patients.

A different pattern of lateralised brain activity during processing of loved faces in men and women: a MEG study.

Viewing personally familiar and loved faces evokes a distinct pattern of brain activity as demonstrated by research employing imaging and electrophysiological methods. The aim of the current investigation was to study the perception of loved faces combined with recalling past emotional experiences using whole-head magnetoencephalograpy (MEG). Twenty-eight participants (fourteen female) viewed photographs of their romantic partner as well as of two long-term friends while imagining a positive emotional encounter with the respective person. Face-stimuli evoked a slow and sustained shift of magnetic activity from 300ms post-stimulus onwards which differentiated loved from friends' faces in female participants and left-sided sensors only. This late-latency evoked magnetic field resembled (as its magnetic counterpart) ERP-modulations by affective content and memory, most notably the late positive potential (LPP). We discuss our findings in the light of studies suggesting greater responsiveness to affective cues in women as well as sex differences in autobiographical and emotional memory.

Sex-differences of face coding: evidence from larger right hemispheric M170 in men and dipole source modelling.

The processing of faces relies on a specialized neural system comprising bilateral cortical structures with a dominance of the right hemisphere. However, due to inconsistencies of earlier findings as well as more recent results such functional lateralization has become a topic of discussion. In particular, studies employing behavioural tasks and electrophysiological methods indicate a dominance of the right hemisphere during face perception only in men whereas women exhibit symmetric and bilateral face processing. The aim of this study was to further investigate such sex differences in hemispheric processing of personally familiar and opposite-sex faces using whole-head magnetoencephalography (MEG). We found a right-lateralized M170-component in occipito-temporal sensor clusters in men as opposed to a bilateral response in women. Furthermore, the same pattern was obtained in performing dipole localization and determining dipole strength in the M170-timewindow. These results suggest asymmetric involvement of face-responsive neural structures in men and allow to ascribe this asymmetry to the fusiform gyrus. This specifies findings from previous investigations employing event-related potentials (ERP) and LORETA reconstruction methods yielding rather extended bilateral activations showing left asymmetry in women and right lateralization in men. We discuss our finding of an asymmetric fusiform activation pattern in men in terms of holistic face processing during face evaluation and sex differences with regard to visual strategies in general and interest for opposite faces in special. Taken together the pattern of hemispheric specialization observed here yields new insights into sex differences in face perception and entails further questions about interactions between biological sex, psychological gender and influences that might be stimulus-driven or task dependent.

MEG/EEG sources of the 170-ms response to faces are co-localized in the fusiform gyrus.

The 170-ms electrophysiological processing stage (N170 in EEG, M170 in MEG) is considered an important computational step in face processing. Hence its neuronal sources have been modelled in several studies. The current study aimed to specify the relation of the dipolar sources underlying N170 and M170. Whole head EEG and MEG were measured simultaneously during the presentation of unfamiliar faces. An Independent Component Analysis (ICA) was applied to the data prior to localization. N170 and M170 were then modelled with a pair of dipoles in a four-shell ellipse (EEG)/homogeneous sphere (MEG) arranged symmetrically across midline. The dipole locations were projected onto the individual structural MR brain images. Dipoles were localized in fusiform gyri in ten out of eleven individuals for EEG and in seven out of eleven for MEG. N170 and M170 were co-localized in the fusiform gyrus in six individuals. The ICA shifted some of the single-subject dipoles up from cerebellum to fusiform gyrus mainly due to the removal of cardiac activity. The group mean dipole locations were also found in posterior fusiform gyri, and did not differ significantly between EEG and MEG. The result was replicated in a repeated measurement 3 months later.

Faces as objects of non-expertise: processing of thatcherised faces in congenital prosopagnosia.

Congenital prosopagnosia (cPA) is a severe disorder in recognising familiar faces, a human characteristic that is presumably innate, without any macro-spatial brain anomalies. Following the idea that cPA is based on deficits of configural face processing, we used a speeded grotesqueness decision task with thatcherised faces, since the Thatcher illusion can serve as a test of configural disruption (Lewis and Johnston, 1997 Perception 26 225-227). The time needed to report the grotesqueness of a face in relation to orientation showed dissociate patterns between a group of fourteen people with cPA and a group of matched controls: whereas the RTs of controls followed a strong sigmoid function depending on rotation from the upright orientation, the RTs of people with cPA showed a much weaker sigmoid trend approaching a linear function. The latter result is interpreted as a diagnostic sign of impaired configural processing, being the primary cause of the absence of 'face expertise' in prosopagnosia.

Correlates of implicit memory for words and faces in event-related brain potentials.

Prior research has suggested an ERP correlate of implicit memory for words consisting of a centro-parietal positivity around 400 ms. We attempted (1) to replicate this ERP modulation in a different task, involving only trials with correct responses, and (2) to compare the findings to the domain of faces. Two experiments were conducted with a modified Sternberg task, in which both targets and nontargets were presented repeatedly. In Experiment 1, positive ERP differences between repeated and new nontargets were observed, which were domain-specific in topography and, for words, replicated the previously reported findings. In Experiment 2, the amplitude of the modulation for words, but not for faces, was unaffected by a variation of the level of processing during encoding, supporting the implicitness of the processes underlying the ERP modulation to nontarget words.

Looking for faces: Attention modulates early occipitotemporal object processing.

Looking for somebody's face in a crowd is one of the most important examples of visual search. For this goal, attention has to be directed to a well-defined perceptual category. When this categorically selective process starts is, however, still unknown. To this end, we used magnetoencephalography (MEG) recorded over right human occipitotemporal cortex to investigate the time course of attentional modulation of perceptual processes elicited by faces and by houses. The first face-distinctive MEG response was observed at 160-170 ms (M170). Nevertheless, attention did not start to modulate face processing before 190 ms. The first house-distinctive MEG activity was also found around 160-170 ms. However, house processing was not modulated by attention before 280 ms (90 ms later than face processing). Further analysis revealed that the attentional modulation of face processing is not due to later, for example, back-propagated activation of the M170 generator. Rather, subsequent stages of occipitotemporal object processing were modulated in a category-specific manner and with preferential access to face processing.

Cardiac artifact subspace identification and elimination in cognitive MEG data using time-delayed decorrelation.

To reduce physiological artifacts in magnetoencephalographic (MEG) and electroencephalographic recordings, a number of methods have been applied in the past such as principal component analysis, signal-space projection, regression using secondary information, and independent component analysis. This method has become popular as it does not have constraints such as orthogonality between artifact and signal or the need for a priori information. Applying the time-delayed decorrelation algorithm to raw data from a visual stimulation MEG experiment, we show that several of the independent components can be attributed to the cardiac artifact. Calculating an average cardiac activity shows that physiologically different excitation states of the heart produce similar field distributions in the MEG sensor system. This is equivalent to differing spectral properties of cardiac field distributions in the raw data. As a consequence, the algorithm combines, e.g., the R peak and the T wave of the cardiac cycle into a single component and the one-to-one assignment of each independent component with a physiological source is not justified in this case. To improve the signal quality of visually evoked fields, the multidimensional cardiac artifact subspace is suppressed from the data. To assess the preservation of the evoked signal after artifact suppression, a geometrical and a temporal measure are introduced. The suppression of cardiac and alpha wave artifacts allows, in our experimental setting, the reduction of the number of epochs to one half while preserving the visually evoked signal.