A Hypnic Hypothesis of Alzheimer's Disease

Background: Understanding the pathophysiology of Alzheimer's disease (AD) is of fundamental importance for improved diagnosis, monitoring and ultimately, treatment. Objective: A role for the sleep-wake cycle in the pathogenesis of AD has been proposed, but remains to be worked out in detail. Methods: Here we draw together several lines of previous work to outline a ‘hypnic hypothesis' of AD. Results: We propose that altered function of brainstem neurotransmitter pathways associated with sleep, promotes regionally specific disintegration of a cortico-subcortical ‘default mode' brain network that is selectively vulnerable in AD. Conclusion: The formation of a dynamic toxic state within this vulnerable network linked to sleep-wake disruption, would in turn lead to failure of synaptic repair, increased transmission of pathogenic misfolded proteins and a self-amplifying neurodegenerative process. We consider the evidence for this hypnic hypothesis and the implications that follow on from it

Thomas Jefferson Health System Medical Legal Partnership

Introduction: Medical-legal partnerships (MLPs) provide civil legal services in concert with healthcare services to mitigate complex social conditions with health-harming effects. Currently, there are 333 MLPs in 46 states. Thomas Jefferson Health System (TJHS) does not have a systemwide MLP. (Magee Rehabilitation Hospital does have an MLP used by qualifying Magee patients). This project sought to identify the core components of an MLP and to demonstrate the value an MLP would provide TJHS. Methods: Assessed existing literature. Interviewed an existing MLP director. Patients from the Jefferson Hospital Ambulatory Practice (JHAP) clinic completed a written survey regarding health-harming social-legal issues. Entered survey data into Excel and analyzed using descriptive statistics. Results: Six common core components of all MLPs were identified. Existing MLPs have demonstrated a reduction in readmission rates, decreased inpatient and emergency department visits, and recovery of payments for unreimbursed clinical services. Patients report improved health when unmet civil legal needs are addressed. Results of the JHAP clinic survey are pending, but preliminarily many patients appear to have social-legal issues. Conclusions: This project demonstrates that a TJHS MLP program could improve patient health and reduce overutilization of the health system. Over time the cost of the program would potentially be offset by the recovery of healthcare dollars. TJHS patients appear to have social-legal issues that negatively impact their health and could be addressed through legal remedies. Based on the analysis, an Opportunity Assessment was generated. Critical next steps are to draft a business plan and identify potential funding

Brain disorders and the biological role of music

Despite its evident universality and high social value, the ultimate biological role of music and its connection to brain disorders remain poorly understood. Recent findings from basic neuroscience have shed fresh light on these old problems. New insights provided by clinical neuroscience concerning the effects of brain disorders promise to be particularly valuable in uncovering the underlying cognitive and neural architecture of music and for assessing candidate accounts of the biological role of music. Here we advance a new model of the biological role of music in human evolution and the link to brain disorders, drawing on diverse lines of evidence derived from comparative ethology, cognitive neuropsychology and neuroimaging studies in the normal and the disordered brain. We propose that music evolved from the call signals of our hominid ancestors as a means mentally to rehearse and predict potentially costly, affectively laden social routines in surrogate, coded, low-cost form: essentially, a mechanism for transforming emotional mental states efficiently and adaptively into social signals. This biological role of music has its legacy today in the disordered processing of music and mental states that characterizes certain developmental and acquired clinical syndromes of brain network disintegration

Temporal Variant Frontotemporal Dementia Is Associated with Globular Glial Tauopathy

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disorder associated with atrophy of the frontal and temporal lobes. Most patients with focal temporal lobe atrophy present with either the semantic dementia subtype of FTD or the behavioral variant subtype. For patients with temporal variant FTD, the most common cause found on post-mortem examination has been a TDP-43 (transactive response DNA-binding protein 43 kDa) proteinopathy, but tauopathies have also been described, including Pick’s disease and mutations in the microtubule-associated protein tau (MAPT) gene. We report the clinical and imaging features of 2 patients with temporal variant FTD associated with a rare frontotemporal lobar degeneration pathology known as globular glial tauopathy. The pathologic diagnosis of globular glial tauopathy should be considered in patients with temporal variant FTD, particularly those who have atypical semantic dementia or an atypical parkinsonian syndrome in association with the right temporal variant

Intelligence quotient in paediatric sickle cell disease: a systematic review and meta-analysis

AIM: Sickle cell disease (SCD) is the commonest cause of childhood stroke worldwide. Magnetic resonance imaging (MRI) is routinely used to detect additional silent cerebral infarction (SCI), as IQ is lower in SCI as well as stroke. This review assesses the effect of infarction on IQ, and specifically whether, compared to healthy controls, IQ differences are seen in children with SCI with no apparent MRI abnormality. METHOD: A systematic review was conducted to include articles with an SCD paediatric population, MRI information, and Wechsler IQ. A meta-analysis of 19 articles was performed to compare IQ in three groups: stroke vs SCI; SCI vs no SCI; and no SCI vs healthy controls. RESULTS: Mean differences in IQ between all three groups were significant: stroke patients had lower IQ than patients with SCI by 10 points (six studies); patients with SCI had lower IQ than no patients with SCI by 6 points (17 studies); and no patients with SCI had lower IQ than healthy controls by 7 points (seven studies). INTERPRETATION: Children with SCD and no apparent MRI abnormality have significantly lower IQ than healthy controls. In this chronic condition, other biological, socioeconomic, and environmental factors must play a significant role in cognition

Two cases of food aversion with semantic dementia

Accounts of altered eating behavior in semantic dementia generally emphasize gluttony and abnormal food preferences. Here we describe two female patients with no past history of eating disorders who developed early prominent aversion to food in the context of an otherwise typical semantic dementia syndrome. One patient (aged 57) presented features in line with anorexia nervosa while the second patient (aged 58) presented with a syndrome more suggestive of bulimia nervosa. These cases add to the growing spectrum of apparently dichotomous behavior patterns in the frontotemporal dementias and illustrate a potentially under-recognized cause of eating disorders presenting in later life

Anatomy and lateralization of the human corticobulbar tracts: an fMRI-guided tractography study

The left hemisphere lateralization bias for language functions, such as syntactic processing and semantic retrieval, is well known. Although several theories and clinical data indicate a link between speech motor execution and language, the functional and structural brain lateralization for these functions has never been examined concomitantly in the same individuals. Here we used functional MRI during rapid silent syllable repetition (/lalala/, /papapa/ and /pataka/, known as oral diadochokinesis or DDK) to map the cortical representation of the articulators in 17 healthy adults. In these same participants, functional lateralization for language production was assessed using the well established verb generation task. We then used DDK-related fMRI activation clusters to guide tractography of the corticobulbar tract from diffusion-weighted MRI. Functional MRI revealed a wide inter-individual variability of hemispheric asymmetry patterns (left and right dominant, as well as bilateral) for DDK in the motor cortex, despite predominantly left hemisphere dominance for language-related activity in Broca’s area. Tractography revealed no evidence for structural asymmetry (based on fractional anisotropy) within the corticobulbar tract. To our knowledge, this study is the first to reveal that motor brain activation for syllable repetition is unrelated to functional asymmetry for language production in adult humans. In addition, we found no evidence that the human corticobulbar tract is an asymmetric white matter pathway. We suggest that the predominance of dysarthria following left hemisphere infarct is probably a consequence of disrupted feedback or input from left hemisphere language and speech planning regions, rather than structural asymmetry of the corticobulbar tract itself

Structural connectivity of the amygdala in young adults with autism spectrum disorder

Autism spectrum disorder (ASD) is characterized by impairments in social cognition, a function associated with the amygdala. Subdivisions of the amygdala have been identified which show specificity of structure, connectivity, and function. Little is known about amygdala connectivity in ASD. The aim of this study was to investigate the microstructural properties of amygdala-cortical connections and their association with ASD behaviours, and whether connectivity of specific amygdala subregions is associated with particular ASD traits. The brains of 51 high-functioning young adults (25 with ASD; 26 controls) were scanned using MRI. Amygdala volume was measured, and amygdala-cortical connectivity estimated using probabilistic tractography. An iterative 'winner takes all' algorithm was used to parcellate the amygdala based on its primary cortical connections. Measures of amygdala connectivity were correlated with clinical scores. In comparison with controls, amygdala volume was greater in ASD (F(1,94) = 4.19; p = .04). In white matter (WM) tracts connecting the right amygdala to the right cortex, ASD subjects showed increased mean diffusivity (t = 2.35; p = .05), which correlated with the severity of emotion recognition deficits (rho = -0.53; p = .01). Following amygdala parcellation, in ASD subjects reduced fractional anisotropy in WM connecting the left amygdala to the temporal cortex was associated with with greater attention switching impairment (rho = -0.61; p = .02). This study demonstrates that both amygdala volume and the microstructure of connections between the amygdala and the cortex are altered in ASD. Findings indicate that the microstructure of right amygdala WM tracts are associated with overall ASD severity, but that investigation of amygdala subregions can identify more specific associations