Framework and baseline examination of the German National Cohort (NAKO).

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years.

Early Aß reduction prevents progression of cerebral amyloid angiopathy.

OBJECTIVE: Clinical trials targeting ß-amyloid peptides (Aß) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aß being the wrong target. Targeting Aß to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aß for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aß deposition. METHODS: APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aß in cerebrospinal fluid (CSF) and brain. RESULTS: CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aß increased with aging followed by a decrease of both Aß40 and Aß42 upon CAA onset, supporting the idea that combined reduction of CSF Aß40 and Aß42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aß reduction in CSF and largely prevented CAA progression and associated pathologies. INTERPRETATION: This is the first study showing that Aß reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aß-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.

[Assessment of self-reported cardiovascular and metabolic diseases in the German National Cohort (GNC, NAKO Gesundheitsstudie): methods and initial results]. / Erfassung selbst berichteter kardiovaskulärer und metabolischer Erkrankungen in der NAKO Gesundheitsstudie: Methoden und erste Ergebnisse.

BACKGROUND: Data on self-reported cardiovascular and metabolic diseases are available for the first 100,000 participants of the population-based German National Cohort (GNC, NAKO Gesundheitsstudie). OBJECTIVES: To describe assessment methods and the frequency of self-reported cardiovascular and metabolic diseases in the German National Cohort. MATERIALS AND METHODS: Using a computer-based, standardized personal interview, 101,806 participants (20-75 years, 46% men) from 18 nationwide study centres were asked to use a predefined list to report medical conditions ever diagnosed by a physician, including cardiovascular or metabolic diseases. For the latter, we calculated sex-stratified relative frequencies and compared these with reference data. RESULTS: With regard to cardiovascular diseases, 3.5% of men and 0.8% of women reported to have ever been diagnosed with a myocardial infarction, 4.8% and 1.5% with angina pectoris, 3.5% and 2.5% with heart failure, 10.1% and 10.4% with cardiac arrhythmia, 2.7% and 1.8% with claudicatio intermittens, and 34.6% and 27.0% with arterial hypertension. The frequencies of self-reported diagnosed metabolic diseases were 8.1% and 5.8% for diabetes mellitus, 28.6% and 24.5% for hyperlipidaemia, 7.9% and 2.4% for gout, and 10.1% and 34.3% for thyroid diseases. Observed disease frequencies were lower than reference data for Germany. CONCLUSIONS: In the German National Cohort, self-reported cardiovascular and metabolic diseases diagnosed by a physician are assessed from all participants, therefore representing a data source for future cardio-metabolic research in this cohort.

Herpes zoster incidence in Germany - an indirect validation study for self-reported disease data from pretest studies of the population-based German National Cohort.

BACKGROUND: Until now, herpes zoster (HZ)-related disease burden in Germany has been estimated based on health insurance data and clinical findings. However, the validity of self-reported HZ is unclear. This study investigated the validity of self-reported herpes zoster (HZ) and its complication postherpetic neuralgia (PHN) using data from the pretest studies of the German National Cohort (GNC) in comparison with estimates based on health insurance data. METHODS: Data of 4751 participants aged between 20 and 69 years from two pretest studies of the GNC carried out in 2011 and 2012 were used. Based on self-reports of physician-diagnosed HZ and PHN, age- and sex-specific HZ incidence rates and PHN proportions were estimated. For comparison, estimates based on statutory health insurance data from the German population were considered. RESULTS: Eleven percent (95%-CI, 10.4 to 12.3, n = 539) of the participants reported at least one HZ episode in their lifetime. Our estimated age-specific HZ incidence rates were lower than previous estimates based on statutory health insurance data. The PHN proportion in participants older than 50 years was 5.9% (1.9 to 13.9%), which was in line with estimates based on health insurance data. CONCLUSION: As age- and sex-specific patterns were comparable with that in health insurance data, self-reported diagnosis of HZ seems to be a valid instrument for overall disease trends. Possible reasons for observed differences in incidence rates are recall bias in self-reported data or overestimation in health insurance data.

Conversion of Synthetic Aß to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model.

UNLABELLED: The aggregation of amyloid-ß peptide (Aß) in brain is an early event and hallmark of Alzheimer's disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral ß-amyloidosis by establishing a long-term hippocampal slice culture (HSC) model. While no Aß deposition was noted in untreated HSCs of postnatal Aß precursor protein transgenic (APP tg) mice, Aß deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic Aß. Seeded Aß deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic Aß species determined the conformational characteristics of HSC Aß deposition. HSC Aß deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic Aß, homogenates of Aß deposits containing HSCs induced cerebral ß-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic Aß into a potent in vivo seeding-active form. SIGNIFICANCE STATEMENT: In this study, we report the seeded induction of Aß aggregation and deposition in long-term hippocampal slice cultures. Remarkably, we find that the biological activities of the largely synthetic Aß aggregates in the culture are very similar to those observed in vivo This observation is the first to show that potent in vivo seeding-active Aß aggregates can be obtained by seeded conversion of synthetic Aß in a living (wild-type) cellular environment.

An acoustic study on non-local anticipatory effects of Italian length contrast.

The present study investigates non-local temporal adjustments before an upcoming length contrast in Italian minimal pairs that differ only in the length of the medial consonant (e.g., geminate word palla "ball" vs singleton word pala "shovel"). This contrast is reportedly signaled by the duration of the singleton/geminate consonant and of the preceding vowel. Here, it is shown that the duration adjustment extends further to the word-initial consonant, e.g., the [p] in palla is significantly longer than that in pala (experiment 1). In experiment 2, an effect of syllable structure is ruled out, an unavoidable confound when comparing singleton and geminate words. The comparison of geminate words with cluster words (e.g., as palco "stage"), both of which have a closed first syllable, shows a similar lengthening. Implications for models of speech production are discussed.

The limits of metrical segmentation: intonation modulates infants' extraction of embedded trochees.

We tested German nine-month-olds' reliance on pitch and metrical stress for segmentation. In a headturn-preference paradigm, infants were familiarized with trisyllabic words (weak-strong-weak (WSW) stress pattern) in sentence-contexts. The words were presented in one of three naturally occurring intonation conditions: one in which high pitch was aligned with the stressed syllable and two misalignment conditions (with high pitch preceding vs. following the stressed syllable). Infants were tested on the SW unit of the WSW carriers. Experiment 1 showed recognition only when the stressed syllable was high-pitched. Intonation of test items (similar vs. dissimilar to familiarization) had no influence (Experiment 2). Thus, German nine-month-olds perceive stressed syllables as word onsets only when high-pitched, although they already generalize over different pitch contours. Different mechanisms underlying this pattern of results are discussed.

Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish ß-Amyloid or Tau Polymorphic Aggregates.

The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the existence of distinct aggregated morphotypes has been suggested to explain the heterogeneous phenotype reported for these diseases. Thus, the development of molecular probes able to distinguish such morphotypes is essential. We report an anionic tetrameric oligothiophene compound that can be utilized for spectral assignment of different morphotypes of ß-amyloid or tau aggregates present in transgenic mice at distinct ages. The ability of the ligand to spectrally distinguish between the aggregated morphotypes was reduced when the spacing between the anionic substituents along the conjugated thiophene backbone was altered, which verified that specific molecular interactions between the ligand and the protein aggregate are necessary to detect aggregate polymorphism. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between different morphotypes of protein aggregates.

Divergent Age-Dependent Conformational Rearrangement within Aß Amyloid Deposits in APP23, APPPS1, and AppNL-F Mice.

Amyloid plaques composed of fibrils of misfolded Aß peptides are pathological hallmarks of Alzheimer's disease (AD). Aß fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aß fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how Aß fibril structures in situ differ in Aß plaque of different mouse models expressing familial mutations in the AßPP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and Aß-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and AppNL-F have different fibril structures within Aß-amyloid plaques depending on the AßPP-processing genotype. Co-staining with Aß-specific antibodies showed that individual plaques from APP23 mice expressing AßPP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact Aß40 fibrils, and the corona region is dominated by diffusely packed Aß40 fibrils. Conversely, the AßPP knock-in mouse AppNL-F, expressing the AßPP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact Aß42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice >12 months, appears strongly promoted by Aß40 and was hence minuscule in AppNL-F. These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.

Label-free imaging of cerebral ß-amyloidosis with extended-focus optical coherence microscopy.

We demonstrate label-free imaging of cerebral ß-amyloidosis ex vivo and in a living mouse model of Alzheimer's disease using extended-focus Fourier domain optical coherence microscopy (xfOCM). xfOCM provides 3D, high-resolution images of individual ß-amyloid plaques in the brain parenchyma and vasculature and requires no staining of the alzheimeric sample under investigation. xfOCM also opens the possibility to perform minimally invasive studies of ß-amyloid pathology in vivo, without the use of labeling methods, which potentially confound experimental findings.

Spectral discrimination of cerebral amyloid lesions after peripheral application of luminescent conjugated oligothiophenes.

In vivo imaging of pathological protein aggregates provides essential knowledge of the kinetics and implications of these lesions in the progression of proteopathies, such as Alzheimer disease. Luminescent conjugated oligothiophenes are amyloid-specific ligands that bind and spectrally distinguish different types of amyloid aggregates. Herein, we report that heptamer formyl thiophene acetic acid (hFTAA) passes the blood-brain barrier after systemic administration and specifically binds to extracellular ß-amyloid deposits in the brain parenchyma (Aß plaques) and in the vasculature (cerebral ß-amyloid angiopathy) of ß-amyloid precursor protein transgenic APP23 mice. Moreover, peripheral application of hFTAA also stained intracellular lesions of hyperphosphorylated Tau protein in P301S Tau transgenic mice. Spectral profiling of all three amyloid types was acquired ex vivo using two-photon excitation. hFTAA revealed a distinct shift in its emission spectra when bound to Aß plaques versus Tau lesions. Furthermore, a spectral shift was observed for Aß plaques versus cerebral ß-amyloid angiopathy, indicating that different amyloid types and structural variances of a specific amyloid type can be distinguished. In conclusion, by adding spectral signatures to amyloid lesions, our results pave the way for a new area of in vivo amyloid imaging, allowing in vivo differentiation of amyloid (sub)types and monitoring changes of their structure/composition over time.

Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease.

Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuroinflammation, and neurofibrillary tangles, hallmark characteristics remarkably similar to those in Alzheimer's disease (AD). We have generated transgenic (tg) mouse models of familial Danish dementia that exhibit the age-dependent deposition of ADan throughout the brain with associated amyloid angiopathy, microhemorrhage, neuritic dystrophy, and neuroinflammation. Tg mice are impaired in the Morris water maze and exhibit increased anxiety in the open field. When crossed with TauP301S tg mice, ADan accumulation promotes neurofibrillary lesions, in all aspects similar to the Tau lesions observed in crosses between beta-amyloid (Abeta)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and Abeta peptides, the lack of codeposition of the two peptides in crosses between ADan- and Abeta-depositing mice points also to distinguishing properties of the peptides. Our results support the concept of the amyloid hypothesis for AD and related dementias, and suggest that different proteins prone to amyloid formation can drive strikingly similar pathogenic pathways in the brain.

Intonational means to mark Verum focus in German and French.

German and French differ in a number of aspects. Regarding the prosody-pragmatics interface, German is said to have a direct focus-to-accent mapping, which is largely absent in French--owing to strong structural constraints. We used a semi-spontaneous dialogue setting to investigate the intonational marking of Verum Focus, a focus on the polarity of an utterance in the two languages (e.g. the child IS tearing the banknote as an opposite claim to the child is not tearing the banknote). When Verum Focus applies to auxiliaries, pragmatic aspects (i.e. highlighting the contrast) directly compete with structural constraints (e.g. avoiding an accent on phonologically weak elements such as monosyllabic function words). Intonational analyses showed that auxiliaries were predominantly accented in German, as expected. Interestingly, we found a high number of (as yet undocumented) focal accents on phrase-initial auxiliaries in French Verum Focus contexts. When French accent patterns were equally distributed across information structural contexts, relative prominence (in terms of peak height) between initial and final accents was shifted towards initial accents in Verum Focus compared to non-Verum Focus contexts. Our data hence suggest that French also may mark Verum Focus by focal accents but that this tendency is partly overridden by strong structural constraints.

Long-term in vivo imaging of ß-amyloid plaque appearance and growth in a mouse model of cerebral ß-amyloidosis.

Extracellular deposition of the amyloid-ß peptide (Aß) in the brain parenchyma is a hallmark lesion of Alzheimer's disease (AD) and a predictive marker for the progression of preclinical to symptomatic AD. Here, we used multiphoton in vivo imaging to study Aß plaque formation in the brains of 3- to 4-month-old APPPS1 transgenic mice over a period of 6 months. A novel head fixation system provided robust and efficient long-term tracking of single plaques over time. Results revealed an estimated rate of 35 newly formed plaques per cubic millimeter of neocortical volume per week at 4-5 months of age. At later time points (i.e., in the presence of increasing cerebral ß-amyloidosis), the number of newly formed plaques decreased. On average, both newly formed and existing plaques grew at a similar growth rate of 0.3 µm (radius) per week. A solid knowledge of the dynamics of cerebral ß-amyloidosis in mouse models provides a powerful tool to monitor preclinical Aß targeting therapeutic strategies and eases the interpretation of diagnostic amyloid imaging in humans.

Amyloid plaque formation precedes dendritic spine loss.

Amyloid-beta plaque deposition represents a major neuropathological hallmark of Alzheimer's disease. While numerous studies have described dendritic spine loss in proximity to plaques, much less is known about the kinetics of these processes. In particular, the question as to whether synapse loss precedes or follows plaque formation remains unanswered. To address this question, and to learn more about the underlying kinetics, we simultaneously imaged amyloid plaque deposition and dendritic spine loss by applying two-photon in vivo microscopy through a cranial window in double transgenic APPPS1 mice. As a result, we first observed that the rate of dendritic spine loss in proximity to plaques is the same in both young and aged animals. However, plaque size only increased significantly in the young cohort, indicating that spine loss persists even many months after initial plaque appearance. Tracking the fate of individual spines revealed that net spine loss is caused by increased spine elimination, with the rate of spine formation remaining constant. Imaging of dendritic spines before and during plaque formation demonstrated that spine loss around plaques commences at least 4 weeks after initial plaque formation. In conclusion, spine loss occurs, shortly but with a significant time delay, after the birth of new plaques, and persists in the vicinity of amyloid plaques over many months. These findings hence give further hope to the possibility that there is a therapeutic window between initial amyloid plaque deposition and the onset of structural damage at spines.

How experience with tone in the native language affects the L2 acquisition of pitch accents.

This paper tested the ability of Mandarin learners of German, whose native language has lexical tone, to imitate pitch accent contrasts in German, an intonation language. In intonation languages, pitch accents do not convey lexical information; also, pitch accents are sparser than lexical tones as they only associate with prominent words in the utterance. We compared two kinds of German pitch-accent contrasts: (1) a "non-merger" contrast, which Mandarin listeners perceive as different and (2) a "merger" contrast, which sounds more similar to Mandarin listeners. Speakers of a tone language are generally very sensitive to pitch. Hypothesis 1 (H1) therefore stated that Mandarin learners produce the two kinds of contrasts similarly to native German speakers. However, the documented sensitivity to tonal contrasts, at the expense of processing phrase-level intonational contrasts, may generally hinder target-like production of intonational pitch accents in the L2 (Hypothesis 2, H2). Finally, cross-linguistic influence (CLI) predicts a difference in the realization of these two contrasts as well as improvement with higher proficiency (Hypothesis 3, H3). We used a delayed imitation paradigm, which is well-suited for assessing L2-phonetics and -phonology because it does not necessitate access to intonational meaning. We investigated the imitation of three kinds of accents, which were associated with the sentence-final noun in short wh-questions (e.g., Wer malt denn Mandalas, lit: "Who draws PRT mandalas?" "Who likes drawing mandalas?"). In Experiment 1, 28 native speakers of Mandarin participated (14 low- and 14 high-proficient). The learners' productions of the two kinds of contrasts were analyzed using General Additive Mixed Models to evaluate differences in pitch accent contrasts over time, in comparison to the productions of native German participants from an earlier study in our lab. Results showed a more pronounced realization of the non-merger contrast compared to German natives and a less distinct realization of the merger contrast, with beneficial effects of proficiency, lending support to H3. Experiment 2 tested low-proficient Italian learners of German (whose L1 is an intonation language) to contextualize the Mandarin data and further investigate CLI. Italian learners realized the non-merger contrast more target-like than Mandarin learners, lending additional support to CLI (H3).

Are there sustained psychological impacts in women diagnosed with in-situ or early invasive breast cancers?

Purpose: The detection of a ductal carcinoma in-situ (DCIS) or an early invasive breast cancer (EIBC), particularly by population-wide mammography-screening-programs, is controversial as an unknown proportion of these cases may be due to overdiagnosis. We investigated whether women with such potentially overdiagnosed breast cancers suffer from sustained adverse psycho-social consequences. Methods: Standardized questionnaires were mailed to 900 survivors, diagnosed with either DCIS or EIBC, requesting self-reports on quality of life using EORTC Quality of Life Questionnaire C-30. Levels of anxiety and depression were assessed using the HADS questionnaires. Item score values in the study group were compared to reference data obtained from normative studies in the German female reference population. Results: The 577 women who returned completed questionnaires had a mean age of 65.1 years, 387 (67%) had been diagnosed by mammography screening. Median time since diagnosis was 5.9 years. There were no substantial differences between the study sample and the reference population for most of the items. While most score values were even slightly more favorable in the study group, the scores for cognitive function were moderately lower, especially among younger patients. Score values for anxiety were generally higher among younger women (50 to 59 years) from the study group, while depression scores were lower irrespective of age. Conclusions: This study indicates that the diagnosis of DCIS or EIBC, which is predominantly a result of screening, does not seem to induce sustained, adverse psychological impacts in affected women when compared with the respective general female population. Only anxiety levels remained elevated among younger women.

In vivo targeting and multimodal imaging of cerebral amyloid-ß aggregates using hybrid GdF3 nanoparticles.

Aim: To propose a new multimodal imaging agent targeting amyloid-ß (Aß) plaques in Alzheimer's disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer's disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood-brain barrier status. Nevertheless, multimodal imaging showed successful Aß targeting in both transgenic mice and Aß fibril-injected rats.

The design and study of a new contrast agent targeting amyloid-ß (Aß) plaques in Alzheimer's disease (AD) is proposed. Aß plaques are the earliest pathological sign of AD, silently appearing in the brain decades before the symptoms of the disease are manifested. While current detection of Aß plaques is based on nuclear medicine (a technique using a radioactive agent), a different kind of contrast agent is here evaluated in animal models of AD. The contrast agent consists of a nanoparticle made of gadolinium and fluorine ions (core), and decorated with a molecule previously shown to bind to Aß plaques (grafting). The core is detectable with MRI and x-ray imaging, while the grafting molecule is detectable with fluorescence imaging, thus allowing different imaging methods to be combined to study the pathology. In this work, the structure, stability and properties of the contrast agent have been verified in vitro (in tubes and on brain sections). Then the ability of the contrast agent to bind to Aß plaques and provide a detectable signal in MRI, x-ray or fluorescence imaging has been demonstrated in vivo (in rodent models of AD). This interdisciplinary research establishes the proof of concept that this new class of versatile agent contrast can be used to target pathological processes in the brain.

Perceiving unstressed vowels in foreign-accented English.

This paper investigated how foreign-accented stress cues affect on-line speech comprehension in British speakers of English. While unstressed English vowels are usually reduced to /ə/, Dutch speakers of English only slightly centralize them. Speakers of both languages differentiate stress by suprasegmentals (duration and intensity). In a cross-modal priming experiment, English listeners heard sentences ending in monosyllabic prime fragments--produced by either an English or a Dutch speaker of English--and performed lexical decisions on visual targets. Primes were either stress-matching ("ab" excised from absurd), stress-mismatching ("ab" from absence), or unrelated ("pro" from profound) with respect to the target (e.g., ABSURD). Results showed a priming effect for stress-matching primes only when produced by the English speaker, suggesting that vowel quality is a more important cue to word stress than suprasegmental information. Furthermore, for visual targets with word-initial secondary stress that do not require vowel reduction (e.g., CAMPAIGN), resembling the Dutch way of realizing stress, there was a priming effect for both speakers. Hence, our data suggest that Dutch-accented English is not harder to understand in general, but it is in instances where the language-specific implementation of lexical stress differs across languages.

Aren't Prosody and Syntax Marking Bias in Questions?

As first observed by Ladd in 1981, English polar questions with high negation (e.g., Aren't they adding a menu item?) can be used both to check the speaker's belief that the proposition p is true (e.g., p = they are adding a menu item) and to check the addressee's belief that p is not true (¬p). We hypothesized that this ambiguity can be disambiguated prosodically. We further hypothesized that the prosodic disambiguation is absent in German, because the checked proposition can be marked morpho-syntactically, with questions with high negation checking p and low negation questions (e.g., Are they not adding a menu item?) checking ¬p.A production study tested these hypotheses with 24 speakers of Western Canadian English and German each (764 and 767 total utterances, respectively). The results showed that, when the speaker originally believed p and the addressee implied ¬p, English speakers preferred questions with high negation over low negation questions, confirming Ladd's observation, and used intonation to mark whose proposition they were checking, as hypothesized. By contrast, German speakers marked this distinction morpho-syntactically, realizing mostly questions with high negation to check their own proposition and low negation questions to check the addressee's proposition. Their prosody, in turn, was largely determined by the morpho-syntactic question form. The study further manipulated the speaker's certainty of the checked proposition, but, in contrast to studies on Romance languages, found that certainty itself was not marked.