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ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.MethodsFor the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).ResultsIndividual regional W-scores ≥1.96 (corresponding to p0.05).ConclusionsBoth in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

OBJECTIVE: To determine whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aβ burden. PARTICIPANTS AND MEASUREMENTS: We studied 134 clinically normal older adults (age 74.1±6.8 years, 59.7% female, 85.8% white) who underwent Aβ positron emission tomography (Aβ-PET) and who completed the Ohio State University Traumatic Brain Injury Identification questionnaire. We limited participants to those reporting injuries classified as mTBI. A subset (N=30) underwent a second Aβ-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aβ-PET burden, interactions between remote mTBI and age, sex, and APOE status, longitudinal Aβ accumulation, and the interaction between remote mTBI and Aβ burden on memory and executive functioning. RESULTS: Of 134 participants, 48 (36%) reported remote mTBI (0, N=86; 1, N=31, 2+, N=17; mean 37±23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aβ burden (p=.94, η(2)

Background and ObjectivesTraumatic encephalopathy syndrome (TES) has overlapping clinical symptoms with Alzheimer disease (AD). AD pathology commonly co-occurs with chronic traumatic encephalopathy (CTE) pathology. There are currently no validated CTE biomarkers. AD-specific biomarkers such as plasma P-tau181 and P-tau217 may help to identify patients with TES who have AD pathology.MethodsWe measured plasma P-tau181 and P-tau217 (Meso Scale Discovery electrochemiluminescence) in patients with TES, mild cognitive impairment/dementia with biomarker-confirmed AD (“AD”), and healthy controls (“HC”). Patients underwent amyloid-beta (Aβ)-PET and a subset underwent tau-PET using [18F]Flortaucipir. We compared plasma P-tau levels controlling for age and sex and also performed AUC analyses to evaluate the accuracy of group differentiation. In patients with TES, we evaluated associations between plasma P-tau, years of repetitive head impact exposure, and tau-PET. Four TES patients with autopsy-confirmed CTE were described qualitatively.ResultsThe sample included 131 participants (TES, N = 18; AD, N = 65; HC, N = 48). Aβ(+) patients with TES (N = 10), but not Aβ(−) TES, had significantly higher plasma P-tau levels than HC (P-tau181:p< 0.001,d= 1.34; P-tau217:p< 0.001,d= 1.59). There was a trend for Aβ(+) TES having higher plasma P-tau than Aβ(−) TES (P-tau181:p= 0.06,d= 1.06; P-tau217:p= 0.09,d= 0.93). AUC analyses showed good classification of Aβ(+) TES from HC for P-tau181 (AUC = 0.87 [0.71–1.00]) and P-tau217 (AUC = 0.93 [0.86–1.00]). Plasma P-tau217 showed fair differentiation of Aβ(+) TES from Aβ(−) TES (AUC = 0.79 [0.54–1.00],p= 0.04), whereas classification accuracy of P-tau181 was slightly lower and not statistically significant (AUC = 0.71 [0.46–0.96],p= 0.13). Patients with AD had higher tau-PET tracer uptake than Aβ(+) TES and were well differentiated using P-tau181 (AUC = 0.81 [0.68–0.94]) and P-tau217 (AUC = 0.86 [0.73–0.98]). Plasma P-tau correlated with the tau-PET signal in Aβ(+) TES but not in Aβ(−) TES, and there was no association between plasma P-tau and years of repetitive head impact exposure. TES patients with severe CTE and no AD at autopsy had low P-tau181 and P-tau217 levels.DiscussionMeasuring P-tau181 and P-tau217 in plasma may be a feasible and scalable fluid biomarker for identifying AD pathology in TES. Low plasma P-tau levels may be used to increase clinical suspicion of CTE over AD as a primary pathology in TES. Currently, there is no support for P-tau181 or P-tau217 as in vivo biomarkers of CTE tau. Larger studies of patients with pathologically confirmed CTE are needed.Classification of EvidenceThis study provides Class III evidence that (1) among patients with TES and abnormal Aβ-PET scans, elevated plasma P-tau can differentiate between affected individuals and HCs; (2) low plasma P-tau may help identify patients with TES who do not have Alzheimer; and (3) plasma P-tau181 and P-tau217 are not useful biomarkers of patients with TES who do not have AD.

IMPORTANCE: Biomarkers for chronic traumatic encephalopathy (CTE) are currently lacking. The radiotracer fluorine F 18–labeled ((18)F)–flortaucipir (FTP) detects tau pathology in Alzheimer disease, and positron emission tomography (PET) with FTP shows elevated binding in individuals at risk for CTE. No study, however, has assessed the correlation between in vivo FTP PET and postmortem tau in CTE. OBJECTIVE: To assess the regional association between in vivo FTP binding and postmortem tau pathology in a patient with pathologically confirmed CTE. DESIGN, SETTING, AND PARTICIPANTS: A white male former National Football League player with 17 years of US football exposure was clinically diagnosed with traumatic encephalopathy syndrome at a neurology tertiary referral center. (18)F-Fludeoxyglucose, carbon 11–labeled Pittsburgh compound B, and FTP PET were performed 52 months prior to death, and magnetic resonance imaging, 50 months prior to death. Brain images were assessed qualitatively for abnormalities blinded to autopsy data. Autopsy was performed using a neurodegenerative research protocol. The FTP standardized uptake value ratios (inferior cerebellar gray reference region) and W-score (age-adjusted z-score) maps were compared with phosphorylated tau immunohistochemical analysis with monoclonal antibody CP13. MAIN OUTCOMES AND MEASURES: Qualitative and quantitative comparisons between antemortem FTP PET and tau pathology at autopsy. RESULTS: Flortaucipir uptake was distributed in a patchy, frontotemporal-predominant pattern that overlapped with regions showing neurodegeneration on magnetic resonance imaging and hypometabolism on (18)F-fludeoxyglucose PET. Pathological assessment revealed stage 4 CTE; limbic argyrophilic grain disease; stage 2 limbic-predominant, age-related transactive response DNA-binding protein 43 encephalopathy; and Braak neurofibrillary tangle stage 3. (18)F-Flortaucipir W-maps matched areas of high postmortem tau burden in left fusiform and inferior temporal gyri and juxtacortical frontal white matter. High FTP W-scores with low tau burden were found in the basal ganglia, thalamus, motor cortex, and calcarine cortex. No regions with low FTP W-scores corresponded to areas with high pathological tau burden. A modest correlation, which did not reach statistical significance (ρ = 0.35, P = .17), was found between FTP standardized uptake value ratio and tau area fraction at the regional level. CONCLUSIONS AND RELEVANCE: In this patient, FTP PET findings during life showed a modest correspondence with postmortem pathology in CTE. These findings suggest that FTP may have limited utility as a tau biomarker in CTE.

Spinal cord infarctions (SCIs) predominantly affect the anterior spinal artery (ASA) territory and manifest with acute weakness and loss of pain and temperature sensation. In comparison, posterior spinal artery (PSA) infarctions are more rare,1 possibly due to paired PSAs with increased collateral arterial supply; the diagnosis may also be underrecognized.1–5 Reports on clinical and radiologic features and outcomes of PSA infarcts are scant. We sought to describe all PSA infarcts seen at Mayo Clinic (1997–2017) to improve the understanding and awareness of this uncommon myelopathy. All patients consented to use of their medical records for research.

A 75-year-old woman with a history of multiple resolved hemiparetic strokes presented with unilateral ischemic stroke causing sudden loss of volitional control of the musculature crucial for speaking and swallowing. Automatic movements, such as laughter and yawning, were preserved (video 1 and figure). She was diagnosed with Foix-Chavany-Marie syndrome (FCMS). Lesions of the operculum or its projections to brainstem nuclei can cause FCMS.1 Because these muscles receive bilateral innervation, a new unilateral lesion can produce sudden bilateral weakness if an old contralateral lesion was compensated by the intact hemisphere. Spontaneous movements, controlled by extrapyramidal pathways, are preserved.2

Historically, payment for cognitive, nonprocedural care has required provision of face-to-face evaluation and management as part of general ambulatory or inpatient care. Although non-face-to-face patient care (e.g., care via electronic means or telephone) is commonly performed and is integral to patient-centered care, appropriate reimbursement for this type of care is lacking. Beginning in 2017, Centers for Medicare and Medicaid (CMS) has taken a large step forward in reimbursing an increased number of cognitive care and non-face-to-face codes. CMS has also included language indicating that nonphysician providers (i.e., nurse practitioners and physician assistants) can perform many of these services independently. The 2017 and now the 2018 fee schedules thus create new payments for non-face-to-face, patient-centered services, and may allow neurologists to reach out to more patients through nonphysician providers. As health care in the United States moves toward value-based incentives, these newly supported non-face-to-face services will provide neurologists with new tools to deliver sustainable, high-value care.

See Gordon (doi:10.1093/brain/awy052) for a scientific commentary on this article.Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis may account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of 18F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern. We identified impaired participants (Clinical Dementia Rating > 0) with amnestic presentations ≥ 75 years who had MRI and PET imaging with 18F-FDG (glucose metabolism), Pittsburgh compound B (amyloid) and flortaucipir (tau) performed within a year of cognitive assessment. These were stratified into amyloid positive/negative and tau positive/negative according to the A/T/N classification scheme. Our sample included 15 amyloid and tau-positive participants, and nine tau-negative participants (five of whom were amyloid-positive). For the autopsy cohort, sequential cases with antemortem 18F-FDG-PET were screened and those with TDP-43-negative Alzheimer's disease (10 cases) and TDP-43-positive hippocampal sclerosis (eight cases) were included. We compared each group to controls and to each other in a voxel-based analysis, and supplemented this with a region of interest-based analysis comparing medial to inferior temporal metabolism. Tau-positive and negative cases did not differ on neuropsychological testing or structural magnetic resonance biomarkers. Tau-negative cases had focal medial temporal and posterior cingulate/retrosplenial hypometabolism regardless of amyloid status, whereas tau-positive cases had additional lateral parietal and inferior temporal involvement. The inferior/medial temporal metabolism ratio was significantly different between the groups with the tau-negative group having a higher ratio. In the autopsy series, hippocampal sclerosis cases had greater medial temporal hypometabolism than Alzheimer's disease cases, who had more parietal and lateral/inferior temporal hypometabolism. Again, the ratio between temporal regions of interest differed significantly between groups. Two of the tau-negative patients, both of whom had an elevated inferior/medial temporal ratio, came to autopsy during the study and were found to have hippocampal sclerosis. Our finding that tau-negative amnestic mild cognitive impairment and dementia is associated with focal medial temporal and posterior cingulate hypometabolism extends prior reports in amyloid-negative cases. The inferior/medial temporal metabolism ratio can help identify tau-negative cases of amnestic dementia and may serve as a biomarker for hippocampal sclerosis.

ObjectiveTo describe the phenomenon of tau-negative amnestic dementia mimicking Alzheimer disease (AD) clinically and radiologically and to highlight the importance of biomarkers in AD research.MethodsEight participants with amnestic mild cognitive impairment or AD dementia were evaluated by a behavioral neurologist and had a standardized neuropsychological battery performed. All participants completed structural (MRI) and molecular (amyloid and tau PET) imaging. AD-signature thickness and adjusted hippocampal volume served as structural biomarkers, while standardized uptake value ratios (SUVRs) from validated regions of interest for amyloid and tau PET were used to determine molecular biomarker status.ResultsAll participants were thought to have AD as the primary driver of their symptoms before any PET imaging. All participants had hippocampal atrophy, and 2 participants fell below the AD-signature thickness cutoff for elderly controls (2.57), with a further 3 falling below the more stringent cutoff based on young controls (2.67). Four participants were amyloid positive (SUVR >1.42), and all were tau negative (SUVR ConclusionsThe participants presented here were clinically impaired, with structural imaging evidence of neurodegeneration, in the absence of any significant tau accumulation. Therefore, AD is unlikely as a cause of their clinical presentation and neurodegenerative imaging findings. Several implications are discussed, including the need to establish amyloid and tau positivity in N+ participants before enrolling them in trials of disease-modifying therapy agents for AD.

Narcolepsy and idiopathic hypersomnia are commonly treated by sleep specialists and encountered by other medical providers. Although pharmacotherapy with modafinil and traditional stimulants is considered the mainstay of treatment, physicians are often uncomfortable with their prescription because of concerns regarding misuse. The goal of this study was to assess the frequency of stimulant misuse in this population.A retrospective cohort study was performed evaluating patients 18 years and older diagnosed with narcolepsy with and without cataplexy and idiopathic hypersomnia with and without long sleep between 2003-2008. Patients were included if they obtained stimulant prescriptions from and had at least one follow-up visit subsequent to initial diagnosis at our center. Stimulant misuse was defined by multiple prescription sources or early refill requests, which are systematically entered into the record by nursing staff.A total of 105 patients met inclusion criteria for the study; 45 (42%) were male. Mean age at multiple sleep latency test was 42 (± 16). Twelve (11%) patients had a history of illicit substance misuse, and one (1%) patient demonstrated previous stimulant misuse. Fifty-seven (54%) patients carried psychiatric diagnoses, 88% of whom reported depression. Median duration of monitored stimulant therapy was 26 months (range 1-250). None of the 105 patients was found to have evidence of stimulant misuse.This study suggests that the frequency of stimulant misuse in patients with narcolepsy and idiopathic hypersomnia is extremely low. Concerns regarding drug misuse should not leverage decisions to provide long-term therapy.

As humans age there is a decline in most sensory systems including vision, hearing, taste, smell, and tactile acuity. In contrast, the frequency and severity of musculoskeletal pain generally increases with age. To determine whether the density of sensory nerve fibers that transduce skeletal pain changes with age, calcitonin gene related peptide (CGRP) and neurofilament 200 kDa (NF200) sensory nerve fibers that innervate the femur were examined in the femurs of young (4-month-old), middle-aged (13-month-old) and old (36-month-old) male F344/BNF1 rats. Whereas the bone quality showed a significant age-related decline, the density of CGRP(+) and NF200(+) nerve fibers that innervate the bone remained remarkably unchanged as did the severity of acute skeletal fracture pain. Thus, while bone mass, quality, and strength undergo a significant decline with age, the density of sensory nerve fibers that transduce noxious stimuli remain largely intact. These data may in part explain why musculoskeletal pain increases with age.