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Both sleep duration and sleep efficiency have been associated with risk of Alzheimer’s disease, suggesting that interventions to promote optimal sleep may be a way to reduce Alzheimer’s disease risk. However, studies often focus on average sleep measures, usually from self-report questionnaires, ignoring the role of intra-individual variability in sleep across nights quantified from objective sleep measures. The current cross-sectional study sought to investigate the role of intra-individual variability in accelerometer-based objective sleep duration and sleep efficiency in relation to in vivo Alzheimer’s disease pathology (β-amyloid and tau) using positron emission tomography imaging and cognition (working memory, inhibitory control, verbal memory, visual memory and global cognition). To examine these relationships, we evaluated 52 older adults (age = 66.4 ± 6.89, 67% female, 27% apolipoprotein E4 carriers) with objective early mild cognitive impairment. Modifying effects of apolipoprotein E4 status were also explored. Less intra-individual variability in sleep duration was associated with lower β-amyloid burden, higher global cognition and better inhibitory control, with a trend for lower tau burden. Less intra-individual variability in sleep efficiency was associated with lower β-amyloid burden, higher global cognition and better inhibitory control, but not with tau burden. Longer sleep duration was associated with better visual memory and inhibitory control. Apolipoprotein E4 status significantly modified the association between intra-individual variability in sleep efficiency and β-amyloid burden, such that less sleep efficiency variability was associated with lower β-amyloid burden in apolipoprotein E4 carriers only. There was a significant interaction between sleep duration and apolipoprotein E4 status, suggesting that longer sleep duration is more strongly associated with lower β-amyloid burden in apolipoprotein E4 carriers relative to non-carriers. These results provide evidence that lower intra-individual variability in both sleep duration and sleep efficiency and longer mean sleep duration are associated with lower levels of β-amyloid pathology and better cognition. The relationships between sleep duration and intra-individual variability in sleep efficiency with β-amyloid burden differ by apolipoprotein E4 status, indicating that longer sleep duration and more consistent sleep efficiency may be protective against β-amyloid burden in apolipoprotein E4 carriers. Longitudinal and causal studies are needed to better understand these relationships. Future work should investigate factors contributing to intra-individual variability in sleep duration and sleep efficiency in order to inform intervention studies.

Tau pathology and vascular dysfunction are important contributors to Alzheimer's disease (AD), but vascular–tau associations and their effects on cognition are poorly understood. We investigated these associations in male and female humans by conducting voxelwise comparisons between cerebral blood flow (CBF) and tau positron emission tomography (PET) images in independent discovery [cognitively normal (CN), 19; mild cognitive impairment (MCI) risk, 43; MCI, 6] and replication (CN,73; MCI, 45; AD, 20) cohorts. In a subgroup, we assessed relationships between tau and soluble platelet-derived growth factor β (sPDGFRβ), a CSF marker of pericyte injury. We tested whether CBF/sPDGFRβ–tau relationships differed based on Montreal Cognitive Assessment (MoCA) global cognition performance, or based on amyloid burden. Mediation analyses assessed relationships among CBF/sPDGFRβ, tau, and cognition. Negative CBF–tau correlations were observed predominantly in temporal-parietal regions. In the replication cohort, early negative CBF–tau correlations increased in spatial extent and in strength of correlation with increased disease severity. Stronger CBF–tau and sPDGFRβ–tau correlations were observed in participants with greater amyloid burden and lower MoCA scores. Importantly, when stratifying by amyloid status, stronger CBF–tau relationships in individuals with lower MoCA scores were driven by amyloid+participants. Tau PET was a significant mediator CBF/sPDGFRβ–MoCA relationships in numerous regions. Our results demonstrate vascular–tau associations across the AD spectrum and suggest that early vascular–tau associations are exacerbated in the presence of amyloid, consistent with a two-hit model of AD on cognition. Combination treatments targeting vascular health, as well as amyloid-β and tau levels, may preserve cognitive function more effectively than single-target therapies.SIGNIFICANCE STATEMENTEmerging evidence demonstrates a role for vascular dysfunction as a significant contributor to Alzheimer's pathophysiology. However, associations between vascular dysfunction and tau pathology, and their effects on cognition remain poorly understood. Multimodal neuroimaging data from two independent cohorts were analyzed to provide novelin vivoevidence of associations between cerebral blood flow (CBF), an MRI measure of vascular health, and tau pathology using PET. CBF–tau associations were related to cognition and driven in part by amyloid burden. Soluble platelet-derived growth factor β, an independent CSF vascular biomarker, confirmed vascular–tau associations in a subgroup analysis. These results suggest that combination treatments targeting vascular health, amyloid-β, and tau levels may more effectively preserve cognitive function than single-target therapies.

Background: APOE ɛ4 and sex have been linked to increased risk for conversion to Alzheimer’s disease (AD). However, the relationship between APOE ɛ4 gene dose, sex, and AD biomarkers remains understudied. Objective: To investigate the effect of APOE ɛ4 dose on AD biomarkers in a sample of older adults with mild cognitive impairment (MCI), and to examine whether APOE ɛ4 dose modifies AD risk differently in MCI women and men. Methods: We examined cross-sectional AD biomarkers for participants with MCI (n = 930, 55–96 years old) from three large aging cohorts. Region of interest MRI volumes, global cognition, and episodic memory were analyzed by number of APOE ɛ4 alleles and stratified by sex. Results: Across all participants, number of APOE ɛ4 alleles was associated with smaller hippocampal and amygdala volumes and poorer cognition. When stratified by sex, women showed an APOE ɛ4 dose effect for bilateral hippocampal and left amygdala volumes and cognition. In contrast, men showed an APOE ɛ4 dose effect for hippocampal volumes with a trend in amygdala, but cognition did not differ between men with 1 and 2 APOE ɛ4 alleles. Women with 2 APOE ɛ4 alleles had poorer memory between 65–69 and poorer global cognition between 70–74 compared to men with 2 APOE ɛ4 alleles. Conclusion: APOE ɛ4 confers a dose effect on AD biomarkers in patients with MCI, and the number of APOE ɛ4 alleles has a greater detrimental impact in women than men, which may be specific to a critical time window.

Word production is a complex multi-stage process linking conceptual representations, lexical entries, phonological forms and articulation. Previous studies have revealed a network of predominantly left-lateralized brain regions supporting this process, but many details regarding the precise functions of different nodes in this network remain unclear. In order to better delineate the functions of regions involved in word production, we used event-related functional magnetic resonance imaging (fMRI) to identify brain areas where blood oxygen level-dependent (BOLD) responses to overt picture naming were modulated by three psycholinguistic variables: concept familiarity, word frequency, and word length, and one behavioral variable: reaction time. Each of these variables has been suggested by prior studies to be associated with different aspects of word production. Processing of less familiar concepts was associated with greater BOLD responses in bilateral occipito-temporal regions, reflecting visual processing and conceptual preparation. Lower frequency words produced greater BOLD signal in left inferior temporal cortex and the left temporo-parietal junction, suggesting involvement of these regions in lexical selection and retrieval and encoding of phonological codes. Word length was positively correlated with signal intensity in Heschl's gyrus bilaterally, extending into the mid superior temporal gyrus (STG) and sulcus (STS) in the left hemisphere. The left mid STS site was also modulated by reaction time, suggesting a role in the storage of lexical phonological codes.

Sensory information is critical for movement control, both for defining the targets of actions and providing feedback during planning or ongoing movements. This holds for speech motor control as well, where both auditory and somatosensory information have been shown to play a key role. Recent clinical research demonstrates that individuals with severe speech production deficits can show a dramatic improvement in fluency during online mimicking of an audiovisual speech signal suggesting the existence of a visuomotor pathway for speech motor control. Here we used fMRI in healthy individuals to identify this new visuomotor circuit for speech production. Participants were asked to perceive and covertly rehearse nonsense syllable sequences presented auditorily, visually, or audiovisually. The motor act of rehearsal, which is prima facie the same whether or not it is cued with a visible talker, produced different patterns of sensorimotor activation when cued by visual or audiovisual speech (relative to auditory speech). In particular, a network of brain regions including the left posterior middle temporal gyrus and several frontoparietal sensorimotor areas activated more strongly during rehearsal cued by a visible talker versus rehearsal cued by auditory speech alone. Some of these brain regions responded exclusively to rehearsal cued by visual or audiovisual speech. This result has significant implications for models of speech motor control, for the treatment of speech output disorders, and for models of the role of speech gesture imitation in development.

There has been much debate recently over the functional role played by the planum temporale (PT) within the context of the dorsal auditory processing stream. Some studies indicate that regions in the PT support spatial hearing and other auditory functions, whereas others demonstrate sensory-motor response properties. This multifunctionality has led to the claim that the PT is performing a common computational pattern matching operation, then routing the signals (spatial, object, sensory-motor) into an appropriate processing stream. An alternative possibility is that the PT is functionally subdivided with separate regions supporting various functions. We assess this possibility using a within subject fMRI block design. DTI data were also collected to examine connectivity. There were four auditory conditions: stationary noise, moving noise, listening to pseudowords, and shadowing pseudowords (covert repeti- tion). Contrasting the shadow and listen conditions should activate regions specific to sensory-motor proc- esses, while contrasting the stationary and moving noise conditions should activate regions involved in spatial hearing. Subjects (N ¼ 16) showed greater activation for shadowing in left posterior PT, area Spt, when the shadow and listen conditions were contrasted. The motion vs. stationary noise contrast revealed greater activation in a more medial and anterior portion of left PT. Seeds from these two contrasts were then used to guide the DTI analysis in an examination of connectivity via streamline tractography, which revealed different patterns of connectivity. Findings support a heterogeneous model of the PT, with func- tionally distinct regions for sensory-motor integration and processes involved in auditory spatial percep- tion. Hum Brain Mapp 33:2453-2463, 2012. V C 2011 Wiley Periodicals, Inc.

Efforts to correlate peripheral neurophysiologic function with perceptional deficits seen in autistic disorder (AD) have resulted in mixed findings, reflecting the high degree of heterogeneity observed in these individuals. We used the auditory brainstem response to study the effect of stress (high click presentation rate) on the auditory system in 20 children with AD (7-13 years) and 20 age-matched typically developing (TD) children. We report latency prolongations in children with AD vs. TD at waves I, III, and V that differed by ear of presentation: overall, left ear showed significant prolongations by group while right ear did not. The 'stressed' condition produced prolongations for both groups at each wave. At wave V, children with AD showed significant prolongations vs. TD, particularly for the right ear. For children with AD, wave V latency prolongations corresponded to language outcome as measured by VIQ, with longer prolongations associating with lower VIQ. Preliminary results provide evidence for reduced synaptic efficiency in auditory pathways in children with AD, which may form the neural bases for sensory reactivity and language impairment.

Purpose: determine if language disorder in children with autistic disorder (AD) corresponds to abnormalities in hemispheric asymmetries in auditory language cortex. Methods: MRI morphometric study in children with AD (n = 50) to assess hemispheric asymmetries in auditory language cortex. A key region of interest was the planum temporale (PT), which is larger in the left hemisphere in most healthy individuals. Results: (i) Heschl’s gyrus and planum polare showed typical hemisphere asymmetry patterns; (ii) posterior Superior Temporal Gyrus (pSTG) showed significant rightward asymmetry; and (iii) PT showed a trend for rightward asymmetry that was significant when constrained to right-handed boys (n = 30). For right-handed boys, symmetry indices for pSTG were significantly positively correlated with those for PT. PT asymmetry was age dependent, with greater rightward asymmetry with age. Conclusions: results provide evidence for rightward asymmetry in auditory association areas (pSTG and PT) known to subserve language processing. Cumulatively, our data provide evidence for a differing maturational path for PT for lower functioning children with AD, with both pre- and post-natal experience likely playing a role in PT asymmetry. Electronic supplementary material The online version of this article (doi:10.1007/s11689-009-9010-2) contains supplementary material, which is available to authorized users.