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A 6-year-old boy presented for evaluation after a new onset focal seizure. CT demonstrated a large right hemispheric mass with midline shift ([figure 1A][1]). MRI confirmed a T2 hyperintense tumour with reduced diffusivity, minimal enhancement on postgadolinum sequences, and linear calcifications on

Brain organoids recapitulate in vitro the specific stages of in vivo human brain development, thus offering an innovative tool by which to model human neurodevelopmental disease. We review here how brain organoids have been used to study neurodevelopmental disease and consider their potential for both technological advancement and therapeutic development.

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.

Background Facial baroparesis is a palsy of the seventh cranial nerve resulting from increased pressure compressing the nerve along its course through the middle ear cavity. It is a rare condition, most commonly reported in barotraumatic environments, in particular scuba diving and high-altitude air travel. We report here an unusual case of highly frequent baroparesis, workup, and successful treatment. Case presentation A 57-year-old Caucasian male frequent commercial airline traveler presented with a 4-year history of recurrent episodes of right-sided facial paralysis and otalgia, increasing in both frequency and severity. Incidents occurred almost exclusively during rapid altitude changes in aircraft, mostly ascent, but also during rapid altitude change in an automobile. Self-treatment included nasal and oral decongestants, nasal corticosteroids, and warm packs. Temporal bone computed tomography (CT) scan revealed possible right-sided dehiscence of the tympanic bone segment; audiogram and magnetic resonance imaging of the internal auditory canals were unremarkable. After a diagnosis of facial nerve baroparesis was made, the patient underwent myringotomy with insertion of a pressure equalization tube (PET) into the right tympanic membrane. Despite re-exposure to altitude change multiple times weekly post-treatment, the patient reported being symptom-free for more than 6 months following intervention. Conclusions Prompt PET insertion may represent the preferred treatment for individuals who suffer recurrent episodes of facial baroparesis. Education regarding this rare condition may prevent unnecessary testing and treatment of affected patients. Future studies should explore the pathophysiology and risk factors, compare therapeutic options, and provide follow-up data to optimize the management of affected patients.

A 12-year-old boy with Down syndrome (DS), myeloproliferative disorder and autism spectrum disorder presented for new-onset seizures. The patient did not report any headaches, weakness, nausea or vomiting, and neurological examination was non-focal. MRI revealed a mixed solid and cystic 13 mm mass

A 14-year-old girl presented with 10 months of worsening headaches with associated nausea and 1 month of visual impairment, including blurry and double vision. Her headaches initially occurred monthly but increased in frequency and became intractable to medical management. Physical examination was

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p 8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5–25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

In 2010, an estimated 4.7% of people aged 60+ had dementia (Sosa-Ortiz, Acosta-Castillo, & Prince, 2012), leading to a global economic burden estimated at $604 billion (Wimo, Jonsson, Bond, Prince, & Winblad, 2013). The greatest predictor of dementia is increasing age (Plassman et al., 2007); as the number of older adults in the population continues to grow (Sosa-Ortiz, Acosta-Castillo, & Prince, 2012), early identification of neurodegenerative disease is increasingly essential. The rise in dementia prevalence creates the need for parallel improvements in treatment and palliative care. Research investment in the early characterization and treatment of dementia is an important public health goal. One challenge related to the early detection of dementia continues to be the identification of subtle cognitive changes in what is considered its “pre-clinical” phase. These subtle cognitive deficits may occur years before a clinical diagnosis is made, as biomarker evidence suggests that Alzheimer’s disease (AD) and related pathologies accumulate decades before clinical diagnosis (Albert et al., 2011; Howieson et al., 2008; Sperling et al., 2011). Detection of the earliest and most subtle cognitive changes should coincide with detection of the earliest and most subtle functional changes, which affect an individual’s ability to perform daily tasks in the natural environment (Chaytor & Schmitter-Edgecombe, 2003). A promising area for additional research in this field involves the latent dementia construct referred to as “δ” by Royall and colleagues (Royall & Palmer, 2012; Royall, Palmer, & O’Bryant, 2012), which may represent a recent advancement toward the goal of detecting early and subtle cognitive changes and concomitant functional decline. This construct, which is derived from Spearman’s general intelligence factor g (Spearman, 1904), represents a further subdivision of Spearman’s g into the two independent factors g’ (g prime) and δ. Royall et al. describe the δ construct, the focus of the current investigation, as representing the “cognitive correlates of functional status” (Royall et al., 2007; Royall & Palmer, 2012); as such, g’ reflects the component of one’s general cognitive ability that is separate from the functional decline caused by neurodegenerative disease. The δ and g’ constructs differ only slightly. Though both are thought to represent the latent variables underlying cognitive task performance, only δ is theorized to underlie one’s ability to function independently and perform activities of daily living (ADL). According to Royall and colleagues, g’ explains the largest proportion of the variance in cognitive test results, but δ most strongly correlates with dementia severity (Royall & Palmer, 2012). Most approaches to cognitive assessment of dementia focus on observed scores, which contain measurement error. In contrast, the latent variable modeling approach taken by Royall, which utilizes confirmatory factor analysis (CFA), can be used to quantify dementia severity with error in estimation but not in measurement (McArdle, 2009; Weston & Gore, 2006;). Latent variable models that fit the data well can be interpreted as providing evidence for a latent trait underlying observed test scores. The model proposed by Royall and colleagues should not be dependent upon the use of specific cognitive tests to measure the construct of dementia, which has a categorical latent structure (Gavett & Stern, 2012). If the model proposed by Royall and colleagues provides a valid representation of the latent dementia phenotype, then δ represents an important construct that could advance neurodegenerative disease research, especially as it pertains to the use of cognitive tests to aid in the detection of the earliest co-occurring changes in cognition and ADLs (Albert et al., 2011; Howieson et al., 2008; Sperling et al., 2011). To ensure that the δ construct is invariant to sample and assessment methods (i.e., cognitive test battery), Royall and colleagues’ model for δ requires validation in other samples and with different cognitive tests. The hypothesized model, which treats δ and g’ as independent constructs, has been validated in demented individuals (Royall, Palmer, & O’Bryant, 2012), cognitively healthy adults (Royall & Palmer, 2012) and in an ethnically diverse sample (Royall & Palmer, 2013). The goal of the current study is to further cross-validate the δ construct in a national clinical case series of older adult participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) (Beekly, Ramos, & Lee, 2007; Morris et al., 2006; Weintraub et al., 2009), both cross-sectionally and longitudinally. The UDS, maintained by NACC, contains longitudinal assessment data that reflect both the cognitive and functional changes that occur in healthy aging and as a result of AD, mild cognitive impairment (MCI), and other neurodegenerative diseases (Morris et al., 2006). As such, the UDS provides a unique opportunity for cross-validation of the δ construct through use of its large, diverse, and cognitively heterogeneous sample. In addition, the UDS includes a different battery of neuropsychological and functional tests than Royall’s initial δ validations (Royall & Palmer, 2012; Royall & Palmer, 2013; Royall, Palmer, & O’Bryant, 2012) and maintains approximately annual data relevant to ADLs and multiple cognitive domains, including attention, speed of processing, executive function, episodic memory, language, and behavioral symptoms (Weintraub et al., 2009). In validating the δ construct cross-sectionally, we hypothesize that the Royall et al. (Royall & Palmer, 2012; Royall, Palmer & O’Bryant, 2012) model, where δ represents the latent variable underling both cognitive and functional status and g’ represents the latent variable underlying the component of cognitive ability not related to functional decline, will fit the baseline data from the NACC UDS well. In cross-validating the δ construct longitudinally, we hypothesize that participants’ latent dementia status, as measured by δ on an approximately annual basis, will change in conjunction with participants’ latent dementia status as measured approximately annually by the Clinical Dementia Rating Sum of Boxes (CDR-SB), one of the most commonly used methods of rating an individual’s cognitive and functional status in the context of a neurodegenerative disease (O’Bryant et al., 2010).

Neuropsychological research frequently uses non-clinical undergraduate participants to evaluate neuropsychological tests. However, a recent study by An and colleagues (2012, Archives of Clinical Neuropsychology, 27, 849-857) called into question that the extent to which the interpretation of these participants' performance on neuropsychological tests is valid. This study found that in a sample of 36 participants, 55.6% exhibited performance invalidity at an initial session and 30.8% exhibited performance invalidity at a follow-up session. The current study attempted to replicate these findings in a larger, more representative sample using a more rigorous methodology. Archival data from 133 non-clinical undergraduate research participants were analyzed. Participants were classified as performance invalid if they failed any one PVT. In the current sample, only 2.26% of participants exhibited performance invalidity. Thus, concerns regarding insufficient effort and performance invalidity when using undergraduate research participants appear to be overstated.

Introduction Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as “at risk” for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE. Methods Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE. Results We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology. Conclusions The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.