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ObjectiveTo evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors.MethodsThis observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49–73 years) from the Alzheimer's and Families (ALFA) study. [18F]flutemetamol-PET standardized uptake value ratios, CSF β-amyloid42/40 ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, APOE ε4, education, and vascular and mental health.ResultsProximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased β-amyloid. FH load and APOE ε4 showed independent contributions to β-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age.ConclusionThe identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions.ClinicalTrials.gov identifierNCT02485730.Classification of evidenceThis study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.

ObjectiveTo quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.MethodsRetrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0–16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.ResultsPatients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.ConclusionTo realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.

Significant progress has been made in expanding our understanding of prodromal Parkinson disease (PD), particularly for recognition of early motor and nonmotor signs and symptoms. Although identification of these prodromal features may improve our understanding of the earliest stages of PD, they are individually insufficient for early disease detection and enrollment of participants in prevention trials in most cases because of low sensitivity, specificity, and positive predictive value. Composite cohorts, composed of individuals with multiple co-occurring prodromal features, are an important resource for conducting prodromal PD research and eventual prevention trials because they are more representative of the population at risk for PD, allow investigators to evaluate the efficacy of an intervention across individuals with varying prodromal feature patterns, are able to produce larger sample sizes, and capture individuals at different stages of prodromal PD. A key challenge in identifying individuals with prodromal disease for composite cohorts and prevention trial participation is that we know little about the natural history of prodromal PD. To move toward prevention trials, it is critical that we better understand common prodromal feature patterns and be able to predict the probability of progression and phenoconversion. Ongoing research in cohort studies and administrative databases is beginning to address these questions, but further longitudinal analyses in a large population-based sample are necessary to provide a convincing and definitive strategy for identifying individuals to be enrolled in a prevention trial.

The diagnosis of multiple sclerosis (MS) can be challenging, with up to 20% of patients who attend subspecialty clinics for a second opinion being misdiagnosed with MS.1,2 Part of this diagnostic challenge relates to the lack of a sensitive and specific biomarker for the diagnosis of MS. To overcome this challenge, diagnostic criteria have been developed with the goal of securing an accurate diagnosis in a timely manner while avoiding misdiagnosis. These criteria have been refined since Charcot's initial description of MS over 150 years ago, with significant changes in diagnostic criteria occurring over the past 30 years. The focus of the most recent iterations of MS diagnostic criteria has been to improve the speed of diagnosis to allow early treatment of appropriate patients in the disease-modifying therapy (DMT) era.

ObjectiveTo determine whether a digital clock-drawing test, DCTclock, improves upon standard cognitive assessments for discriminating diagnostic groups and for detecting biomarker evidence of amyloid and tau pathology in clinically normal older adults (CN).MethodsParticipants from the Harvard Aging Brain Study and the PET laboratory at Massachusetts General Hospital were recruited to undergo the DCTclock, standard neuropsychological assessments including the Preclinical Alzheimer Cognitive Composite (PACC), and amyloid/tau PET imaging. Receiver operating curve analyses were used to assess diagnostic and biomarker discriminability. Logistic regression and partial correlations were used to assess DCTclock performance in relation to PACC and PET biomarkers.ResultsA total of 300 participants were studied. Among the 264 CN participants, 143 had amyloid and tau PET imaging (Clinical Dementia Rating [CDR] 0, Mini-Mental State Examination [MMSE] 28.9 ± 1.2). An additional 36 participants with a diagnosis of mild cognitive impairment or early Alzheimer dementia (CDR 0.5, MMSE 25.2 ± 3.9) were added to assess diagnostic discriminability. DCTclock showed excellent discrimination between diagnostic groups (area under the receiver operating characteristic curve 0.86). Among CN participants with biomarkers, the DCTclock summary score and spatial reasoning subscores were associated with greater amyloid and tau burden and showed better discrimination (Cohen d = 0.76) between Aβ± groups than the PACC (d = 0.30).ConclusionDCTclock discriminates between diagnostic groups and improves upon traditional cognitive tests for detecting biomarkers of amyloid and tau pathology in CN older adults. The validation of such digitized measures has the potential of providing an efficient tool for detecting early cognitive changes along the AD trajectory.Classification of EvidenceThis study provides Class II evidence that DCTclock results were associated with amyloid and tau burden in CN older adults.

ObjectivesTo investigate which baseline neuropsychological profile predicts the risk of developing dementia in early-stage Parkinson disease (PD).MethodsWe retrospectively reviewed detailed medical records of 350 drug-naive patients with early-stage PD (follow-up >3 years) who underwent a detailed neuropsychological test at initial assessment. Factor analysis was conducted to determine cognitive profiles that yielded 4 cognitive function factors: factor 1, visual memory/visuospatial; factor 2, verbal memory; factor 3, frontal/executive; and factor 4, attention/working memory/language. Subsequently, we assessed the effect of these cognitive function factors on the risk for dementia conversion. We also constructed a nomogram to calculate the risk for developing dementia over a 5-year follow-up period based on these cognitive profiles.ResultsCox regression analysis demonstrated that a higher composite score of factor 1 (hazard ratio [HR] 0.558, 95% confidence interval [CI] 0.427–0.730), factor 2 (HR 0.768, 95% CI 0.596–0.991), and factor 3 (HR 0.425, 95% CI 0.305–0.593) was associated with a lower risk for dementia conversion, while factor 3 had the most predictive power. The nomogram had a fair ability (Heagerty integrated area under the curve 0.763) to estimate the risk for dementia conversion within 5 years. The composite scores of factor 3 contributed more to the occurrence of dementia in PD than those of the other cognitive function factors.ConclusionsThese findings suggest that these factor analysis–derived cognitive profiles can be used to predict dementia conversion in early-stage PD. In addition, frontal/executive dysfunction contributes most to the occurrence of dementia in PD.

Objective:To compare the accuracy of Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and CT perfusion to detect established infarction in acute anterior circulation stroke.Methods:We performed an observational study in 59 acute anterior circulation ischemic stroke patients who underwent brain noncontrast CT, CT perfusion, and MRI within 100 minutes from CT imaging. ASPECTS scores were calculated by 4 blinded vascular neurologists. The accuracy of ASPECTS and CT perfusion core volume to detect an acute MRI diffusion lesion of ≥70 mL was evaluated using receiver operating characteristics analysis and optimum cutoff values were calculated using Youden J.Results:Median ASPECTS score was 8 (interquartile range [IQR] 5–9). Median CT perfusion core volume was 22 mL (IQR 10.4–71.9). Median MRI diffusion lesion volume was 24.5 mL (IQR 10–63.9). No significant difference was found between the accuracy of CT perfusion and ASPECTS (c statistic 0.95 vs 0.87, p value for difference = 0.17). The optimum ASPECTS cutoff score to detect a diffusion-weighted imaging lesion ≥70 mL was R = 0.88; R2 = 0.77).Conclusions:We found no significant difference between the accuracy of CT perfusion and ASPECTS to predict hyperacute MRI lesion volume in ischemic stroke.

ObjectiveTo investigate whether the patterns of striatal dopamine depletion on dopamine transporter (DAT) scans could provide information on the long-term prognosis in Parkinson disease (PD).MethodsWe enrolled 205 drug-naive patients with early-stage PD, who underwent 18F-FP-CIT PET scans at initial assessment and received PD medications for 3 or more years. After quantifying the DAT availability in each striatal subregion, factor analysis was conducted to simplify the identification of striatal dopamine depletion patterns and to yield 4 striatal subregion factors. We assessed the effect of these factors on the development of levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and dementia during the follow-up period (6.84 ± 1.80 years).ResultsThe 4 factors indicated which striatal subregions were relatively preserved: factor 1 (caudate), factor 2 (more-affected sensorimotor striatum), factor 3 (less-affected sensorimotor striatum), and factor 4 (anterior putamen). Cox regression analyses using the composite scores of these striatal subregion factors as covariates demonstrated that selective dopamine depletion in the sensorimotor striatum was associated with a higher risk for developing LID. Selective dopamine loss in the putamen, particularly in the anterior putamen, was associated with early development of wearing-off. Selective involvement of the anterior putamen was associated with a higher risk for dementia conversion. However, the patterns of striatal dopamine depletion did not affect the risk of FOG.ConclusionsThese findings suggested that the patterns of striatal dopaminergic denervation, which were estimated by the equation derived from the factor analysis, have a prognostic implication in patients with early-stage PD.

ObjectiveTo evaluate the point of view of patients with Parkinson disease (PD) on early detection and risk disclosure in the prodromal phase of PD and to derive recommendations for an ethical framework for the recruitment of prodromal PD cohorts.MethodsA standardized questionnaire to evaluate the patients' perception on early diagnosis in PD was designed by an interdisciplinary study group. After testing in a preliminary feasibility study (n = 20), the survey was performed retrospectively with patients from our clinic.ResultsA total of 101 patients with PD answered the questions. The majority of patients reported that time from onset of motor symptoms to diagnosis was burdensome, including false diagnoses and many consultations of various medical specialists. However, most of the patients evaluated early risk disclosure with skepticism. Freedom of choice and the potential of changes in lifestyle were rated as important.ConclusionAlthough patients with PD reported the time to diagnosis retrospectively as burdensome, the majority was skeptical regarding early disclosure of risk, especially with regard to the lack of pharmacologic options. Circumstances under which early detection and disclosure would have been approved by the majority of patients were (1) advice on lifestyle changes (exercise, nutrition) as potentially disease course–modifying therapy; (2) the establishment of an early diagnosis “culture,” including early clarification of the patients' wish to know; and (3) regular support and follow-up of individuals after risk disclosure.

OBJECTIVE: The huntingtin gene is critical for the formation and differentiation of the CNS, which raises questions about the neurodevelopmental effect of CAG expansion mutations within this gene (mHTT) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of mHTT exhibit different brain growth compared to peers without the mutation by conducting structural MRI in youth who are at risk for HD. We also explored whether the length of CAG expansion affects brain development. METHODS: Children and adolescents (age 6–18) with a parent or grandparent diagnosed with HD underwent MRI and blinded genetic testing to confirm the presence or absence of mHTT. Seventy-five individuals were gene-expanded (GE) and 97 individuals were gene-nonexpanded (GNE). The GE group was estimated to be on average 35 years from clinical onset. Following an accelerated longitudinal design, age-related changes in brain regions were estimated. RESULTS: Age-related striatal volume changes differed significantly between the GE and GNE groups, with initial hypertrophy and more rapid volume decline in GE. This pattern was exaggerated with CAG expansion length for CAG > 50. A similar age-dependent group difference was observed for the globus pallidus, but not in other major regions. CONCLUSION: Our results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with mHTT may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.

ObjectiveEarly biomarkers for dementia with Lewy bodies (DLB) are lacking. To determine whether EEG differentiates the prodromal phase of DLB from other causes of mild cognitive impairment (MCI) and whether EEG is predictive for time to conversion from MCI to DLB, we compared EEGs and clinical follow-up of patients with MCI due to DLB with those of patients with MCI due to Alzheimer disease (MCI-AD).MethodsWe compared 37 patients with MCI who developed DLB during follow-up or had an abnormal 123I-PF-CIT SPECT scan (MCI-DLB) with 67 age-matched patients with MCI-AD. EEGs were assessed visually with a score of increasing abnormality (range 1–5). We performed fast Fourier transform to analyze the power spectrum. With survival analyses, EEG characteristics were related to time to progression to dementia.ResultsThe visual EEG score was higher in MCI-DLB (score >2 in 60%) compared to MCI-AD (score >2 in 8%, p < 0.001). We found frontal intermittent delta activity in 22% of MCI-DLB, not in MCI-AD. Patients with MCI-DLB had a lower peak frequency (7.5 [6.0–9.9] Hz vs 8.8 [6.8–10.2] in MCI-AD, p < 0.001) and more slow-wave activity. Several individual EEG measures showed good performance to discriminate MCI-DLB from MCI-AD (areas under the curve up to 0.94). In MCI-DLB, high visual EEG score, diffuse abnormalities, and low α2 power were related to time to progression to dementia (hazard ratios 4.1, 9.9, 5.1, respectively).ConclusionsProfound EEG abnormalities are already present in the prodromal stage of DLB and have diagnostic and prognostic value.Classification of evidenceThis study provides Class III evidence that EEG abnormalities are more common in MCI-DLB than MCI-AD.

ObjectiveTo determine the temporal sequence of objectively defined subtle cognitive difficulties (Obj-SCD) in relation to amyloidosis and neurodegeneration, the current study examined the trajectories of amyloid PET and medial temporal neurodegeneration in participants with Obj-SCD relative to cognitively normal (CN) and mild cognitive impairment (MCI) groups.MethodA total of 747 Alzheimer's Disease Neuroimaging Initiative participants (305 CN, 153 Obj-SCD, 289 MCI) underwent neuropsychological testing and serial amyloid PET and structural MRI examinations. Linear mixed effects models examined 4-year rate of change in cortical 18F-florbetapir PET, entorhinal cortex thickness, and hippocampal volume in those classified as Obj-SCD and MCI relative to CN.ResultAmyloid accumulation was faster in the Obj-SCD group than in the CN group; the MCI and CN groups did not significantly differ from each other. The Obj-SCD and MCI groups both demonstrated faster entorhinal cortical thinning relative to the CN group; only the MCI group exhibited faster hippocampal atrophy than CN participants.ConclusionRelative to CN participants, Obj-SCD was associated with faster amyloid accumulation and selective vulnerability of entorhinal cortical thinning, whereas MCI was associated with faster entorhinal and hippocampal atrophy. Findings suggest that Obj-SCD, operationally defined using sensitive neuropsychological measures, can be identified prior to or during the preclinical stage of amyloid deposition. Further, consistent with the Braak neurofibrillary staging scheme, Obj-SCD status may track with early entorhinal pathologic changes, whereas MCI may track with more widespread medial temporal change. Thus, Obj-SCD may be a sensitive and noninvasive predictor of encroaching amyloidosis and neurodegeneration, prior to frank cognitive impairment associated with MCI.

Objective: To evaluate the diagnostic accuracy of clinical diagnosis of Parkinson disease (PD) reported in the last 25 years by a systematic review and meta-analysis. Methods: We searched for articles published between 1988 and August 2014. Studies were included if reporting diagnostic parameters regarding clinical diagnosis of PD or crude data. The selected studies were subclassified based on different study setting, type of test diagnosis, and gold standard. Bayesian meta-analyses of available data were performed. Results: We selected 20 studies, including 11 using pathologic examination as gold standard. Considering only these 11 studies, the pooled diagnostic accuracy was 80.6% (95% credible interval [CrI] 75.2%–85.3%). Accuracy was 73.8% (95% CrI 67.8%–79.6%) for clinical diagnosis performed mainly by nonexperts. Accuracy of clinical diagnosis performed by movement disorders experts rose from 79.6% (95% CrI 46%–95.1%) of initial assessment to 83.9% (95% CrI 69.7%–92.6%) of refined diagnosis after follow-up. Using UK Parkinson9s Disease Society Brain Bank Research Center criteria, the pooled diagnostic accuracy was 82.7% (95% CrI 62.6%–93%). Conclusion: The overall validity of clinical diagnosis of PD is not satisfying. The accuracy did not significantly improve in the last 25 years, particularly in the early stages of disease, where response to dopaminergic treatment is less defined and hallmarks of alternative diagnoses such as atypical parkinsonism may not have emerged. Misclassification rate should be considered to calculate the sample size both in observational studies and randomized controlled trials. Imaging and biomarkers are urgently needed to improve the accuracy of clinical diagnosis in vivo.

There are approximately 1,000 genes involved in odor recognition and 347 that code for functional receptors. This enables our distinguishing of approximately 4,000–10,000 distinct odorous ligands, a scientific discovery that earned a Nobel Prize in 2004.1 The olfactory nerve (CN1) contains 6–10 million receptor cells whose ciliated dendrites and cell bodies are contained within a specialized (neuro)epithelium located within the posterior nasal cavity (figure).2 These olfactory receptor cells are interspersed with sustentacular cells for stability of the epithelium and basal cells (stem cells) that provide a regenerative capacity. Also in residence are the Bowman glands, which secrete and maintain the mucous layer upon the cilia that float just beneath the (neuro)epithelium. This mucous contains several proteins that may help metabolize xenobiotics and support epithelial integrity (e.g., mucin, lysozyme, amylase, immunoglobulin G).2 Once an odorant enters the nose, it interacts with the receptors located on the surface of the olfactory cilia and a chemical signature generates a crescendo of action potentials in the olfactory neuron axon (figure). These project to higher brain regions involved in conscious thought processes and the limbic system, generating the emotional, motivational, and memory context.3 Olfactory dysfunction presenting as hyposmia impairs the satisfaction gained from foods and inhibits the detection of environmental hazards (e.g., toxins, fire, spoiled foods, and natural gas leaks). Diminished olfactory inputs also dampen the neural/cephalic phase of digestion responsible for stimulating exocrine secretions in the mouth (e.g., amylase), stomach (e.g., hydrochloric acid, digestive enzymes), and small intestine (e.g., lipase).4,5 These secretions facilitate the absorption and assimilation of micronutrients and fatty acids and contribute to the nature of the microbiome in the host by governing the gut pH.6

Human prion diseases are highly heterogeneous and rare disorders. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form,1 with an average annual age-adjusted incidence of 1.1 cases per million individuals in the United States in 2016 (Larry Schonberger, Center for Disease Control, Atlanta, GA, personal communication, May 2, 2018). Prion diseases may, however, be underdiagnosed. An early and accurate clinical diagnosis of sCJD is challenging due to the substantial overlap with other rapidly progressive dementias. A more accurate diagnosis of sCJD strains is expected to improve surveillance efforts and selection of patients in therapeutic trials once effective drugs become available.

Considerable neurologic injury has already occurred by the time the first symptom appears in amyotrophic lateral sclerosis (ALS) and, although it is one of the most rapidly progressive of the neurodegenerative diseases, the average time from symptom onset to diagnosis is approximately 9 to 12 months.1,2 Unfortunately, every month of diagnostic delay equates to worsening motor neuron damage and diminished chances that experimental therapies might be effective. The diagnosis of ALS remains a clinical one, supported by electrodiagnostic and other testing, and ALS diagnostic criteria require evidence of both upper motor neuron (UMN) and lower motor neuron (LMN) signs. Because LMN signs are often easier to detect, and UMN signs may not appear until later in the disease course, early diagnosis is challenging, and may be made more so by the fact that progressive LMN weakness can be caused by so many other pure motor disorders (e.g., motor radiculopathy, multifocal motor neuropathy, myasthenia gravis, and the inflammatory myopathies).

ObjectivesTo clarify diagnostic accuracy and consequences of misdiagnosis in the admission evaluation of stroke-code patients in a neurologic emergency department with less than 20-minute door-to-thrombolysis times.MethodsAccuracy of admission diagnostics was studied in an observational cohort of 1,015 stroke-code patients arriving by ambulance as candidates for recanalization therapy between May 2013 and November 2015. Immediate admission evaluation was performed by a stroke neurologist or a neurology resident with dedicated stroke training, primarily utilizing CT-based imaging.ResultsThe rate of correct admission diagnosis was 91.1% (604/663) for acute cerebral ischemia (ischemic stroke/TIA), 99.2% (117/118) for hemorrhagic stroke, and 61.5% (144/234) for stroke mimics. Of the 150 (14.8%) misdiagnosed patients, 135 (90.0%) had no acute findings on initial imaging and 100 (67.6%) presented with NIH Stroke Scale score 0 to 2. Misdiagnosis altered medical management in 70 cases, including administration of unnecessary treatments (thrombolysis n = 13, other n = 24), omission of thrombolysis (n = 5), delays to specific treatments of stroke mimics (n = 13, median 56 [31–93] hours), and delays to antiplatelet medication (n = 14, median 1 [1–2] day). Misdiagnosis extended emergency department stay (median 6.6 [4.7–10.4] vs 5.8 [3.7–9.2] hours; p = 0.001) and led to unnecessary stroke unit stay (n = 10). Detailed review revealed 8 cases (0.8%) in which misdiagnosis was possible or likely to have worsened outcomes, but no death occurred as a result of misdiagnosis.ConclusionsOur findings support the safety of highly optimized door-to-needle times, built on thorough training in a large-volume, centralized stroke service with long-standing experience. Augmented imaging and front-loaded specialist engagement are warranted to further improve rapid stroke diagnostics.

Objective: To identify predictors and the optimal time point for the early prediction of the presence and severity of spasticity in the upper limb 12 months poststroke. Methods: In total, 117 patients in the Gothenburg area who had experienced a stroke for the first time and with documented arm paresis day 3 poststroke were consecutively included. Assessments were made at admission and at 3 and 10 days, 4 weeks, and 12 months poststroke. Upper limb spasticity in elbow flexion/extension and wrist flexion/extension was assessed with the modified Ashworth Scale (MAS). Any spasticity was regarded as MAS ≥1, and severe spasticity was regarded as MAS ≥2 in any of the muscles. Sensorimotor function, sensation, pain, and joint range of motion in the upper limb were assessed with the Fugl-Meyer assessment scale, and, together with demographic and diagnostic information, were included in both univariate and multivariate logistic regression analysis models. Seventy-six patients were included in the logistic regression analysis. Results: Sensorimotor function was the most important predictor both for any and severe spasticity 12 months poststroke. In addition, spasticity 4 weeks poststroke was a significant predictor for severe spasticity. The best prediction model for any spasticity was observed 10 days poststroke (85% sensitivity, 90% specificity). The best prediction model for severe spasticity was observed 4 weeks poststroke (91% sensitivity, 92% specificity). Conclusions: Reduced sensorimotor function was the most important predictor both for any and severe spasticity, and spasticity could be predicted with high sensitivity and specificity 10 days poststroke.

Objective: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. Methods: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. Results: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies ( p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia ( p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD ( p ≤ 0.0003). Conclusions: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

Objective:To elucidate early skin denervation in hereditary transthyretin (TTR) amyloidosis and iatrogenic TTR amyloidosis.Methods:We investigated intraepidermal nerve fiber density (IENFD) and clinical findings in 32 patients with hereditary TTR amyloidosis, 11 asymptomatic mutation carriers, 6 patients with iatrogenic TTR amyloidosis, and 23 healthy volunteers.Results:IENFD values were reduced in patients with the V30M mutation (1.9 ± 2.1 per 1 mm), patients with non-V30M mutations (5.8 ± 3.2 per 1 mm), and patients with iatrogenic TTR amyloidosis (3.5 ± 1.8 per 1 mm) compared with healthy volunteers (11.8 ± 3.2 per 1 mm) (p < 0.01). Skin denervation also occurred, even in presymptomatic V30M mutation carriers (5.0 ± 2.2 per 1 mm). The IENFD was correlated with disease duration (ρ = −0.533, p = 0.002) and various peripheral neuropathy parameters such as sensory impairment in the Kumamoto clinical score (ρ = −0.575, p = 0.001), heat-pain detection threshold (ρ = −0.704, p < 0.001), and sural sensory nerve action potential (ρ = 0.481, p = 0.005). TTR amyloid deposits frequently occurred in connective tissues and vessels of the dermal reticular layer in patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis.Conclusions:Patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis may show early skin denervation even in the presymptomatic stage. IENFD may thus be useful for early diagnosis and may serve as a biomarker in clinical trials for hereditary and iatrogenic TTR amyloidosis.

Objective:To detect and quantify lesions of the small-caliber sural nerve (SN) in symptomatic and asymptomatic transthyretin familial amyloid polyneuropathy (TTR-FAP) by high-resolution magnetic resonance neurography (MRN) in correlation with electrophysiologic and histopathologic findings.Methods:Twenty-five patients with TTR-FAP, 10 asymptomatic carriers of the mutated transthyretin gene (mutTTR), and 35 age- and sex-matched healthy controls were prospectively included in this cross-sectional case-control study. All participants underwent 3T MRN with high-structural resolution (fat-saturated, T2-weighted, and double-echo sequences). Total imaging time was ≈45 minutes per patient. Manual SN segmentation was performed from its origin at the sciatic nerve bifurcation to the lower leg with subsequent evaluation of quantitative microstructural and morphometric parameters. Additional time needed for postprocessing was ≈1.5 hours per participant. Detailed neurologic and electrophysiologic examinations were conducted in the TTR group.Results:T2 signal and proton spin density (ρ) reliably differentiated between TTR-FAP (198.0 ± 13.3, 429.6 ± 15.25), mutTTR carriers (137.0 ± 16.9, p = 0.0009; 354.7 ± 21.64, p = 0.0029), and healthy controls (90.0 ± 3.4, 258.2 ± 9.10; p < 0.0001). Marked differences between mutTTR carriers and controls were found for T2 signal (p = 0.0065) and ρ (p < 0.0001). T2 relaxation time was higher in patients with TTR-FAP only (p = 0.015 vs mutTTR carriers, p = 0.0432 vs controls). SN caliber was higher in patients with TTR-FAP vs controls and in mutTTR carriers vs controls (p < 0.0001). Amyloid deposits were histopathologically detectable in 10 of 14 SN specimens.Conclusions:SN injury in TTR-FAP is detectable and quantifiable in vivo by MRN even in asymptomatic mutTTR carriers. Differences in SN T2 signal between controls and asymptomatic mutTTR carriers are derived mainly from an increase of ρ, which overcomes typical limitations of established diagnostic methods as a highly sensitive imaging biomarker for early detection of peripheral nerve lesions.Classification of evidence:This study provides Class III evidence that MRN accurately identifies asymptomatic mutTTR carriers.

Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ 42 , tau, and phosphorylated tau. Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ 42 and CSF phosphorylated tau/Aβ 42 , after adjustment for common fall risk factors. Results: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios ( p Conclusions: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

China's population restriction, known across the globe as the 1-child policy, has been in place since 1981, with variations to allow some couples a second child.1,2 In response to social challenges arising from this policy, the Chinese government announced in 2015 that it would transition to a new 2-child policy, encouraging couples since January 1, 2016, to have 2 children.3 This transition accompanies a focus on population quality (i.e., improvements in health, education, and social welfare) in newborns to the large Chinese elderly population, with an initiative to reform the Chinese health care system and increase disease screening and prevention. These changes provide an opportunity to improve the treatment of neurologic disease in China, specifically identification of disease through newborn screening (NBS) and disease treatment/prevention through education, patient registries, and improvement in primary care access.

Objective: To determine the time of acceleration in white matter hyperintensity (WMH) burden, a common indicator of cerebrovascular pathology, in relation to conversion to mild cognitive impairment (MCI) in the elderly. Methods: A total of 181 cognitively intact elderly volunteers from the longitudinal, prospective, Oregon Brain Aging Study underwent yearly evaluations, including brain MRI, and cognitive testing. MRIs were analyzed for imaging markers of neurodegeneration: WMH and ventricular CSF (vCSF) volumes. The time before MCI, when the changes in WMH and vCSF burden accelerate, was assessed using a mixed-effects model with a change point for subjects who developed MCI during follow-up. Results: During a follow-up duration of up to 19.6 years, 134 subjects converted to MCI. Acceleration in %WMH volume increase occurred 10.6 years before MCI onset. On average, the annual rate of change in %WMH increased an additional 3.3% after the change point. Acceleration in %vCSF volume increase occurred 3.7 years before the onset of MCI. Out of 63 subjects who converted to MCI and had autopsy, only 28.5% had Alzheimer disease (AD) as the sole etiology of their dementia, while almost just as many (24%) had both AD and significant ischemic cerebrovascular disease present. Conclusions: Acceleration in WMH burden, a common indicator of cerebrovascular disease in the elderly, is a pathologic change that emerges early in the presymptomatic phase leading to MCI. Longitudinal changes in WMH may thus be useful in determining those at risk for cognitive impairment and for planning strategies for introducing disease-modifying therapies prior to dementia onset.

Objective: Natalizumab, a therapy for multiple sclerosis (MS), has been associated with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS associated with the JC virus. We assessed clinical outcomes and identified variables associated with survival in 35 patients with natalizumab-associated PML. Methods: Physicians provided Karnofsky scores and narrative descriptions of clinical status. Data were supplemented by the natalizumab global safety database. Results: At the time of analysis, 25 patients (71%) had survived. Survivors were younger (median 40 vs 54 years) and had lower pre-PML Expanded Disability Status Scale scores (median 3.5 vs 5.5) and a shorter time from symptom onset to diagnosis (mean 44 vs 63 days) compared with individuals with fatal cases. Of patients with nonfatal cases, 86% had unilobar or multilobar disease on brain MRI at diagnosis, whereas 70% of those with fatal cases had widespread disease. Gender, MS duration, natalizumab exposure, prior immunosuppressant use, and CSF JC viral load at diagnosis were comparable. Most patients were treated with rapid removal of natalizumab from the circulation. The majority of patients developed immune reconstitution inflammatory syndrome and were treated with corticosteroids. Among survivors with at least 6 months follow-up, disability levels were evenly distributed among mild, moderate, and severe, based on physician-reported Karnofsky scores. Conclusions: Natalizumab-associated PML has improved survival compared with PML in other populations. Disability in survivors ranged from mild to severe. A shorter time from symptom onset to diagnosis and localized disease on MRI at diagnosis were associated with improved survival. These data suggest that earlier diagnosis through enhanced clinical vigilance and aggressive management may improve outcomes.

Background: The definite diagnosis of acute Lyme neuroborreliosis (LNB) requires detection of an increased Borrelia burgdorferi –specific antibody index (AI). The B burgdorferi AI, however, is negative in up to 20% of patients with early LNB and can remain elevated for years after adequate therapy; both of these factors can make the diagnosis difficult. Recent retrospective studies suggested the chemokine CXCL13 as a potential biomarker for LNB. To evaluate its diagnostic value, we conducted a prospective study. Methods: From March 2008 to August 2009, CSF and serum samples from all patients in whom a B burgdorferi– specific AI was requested (n = 692) and CSF analysis revealed CSF pleocytosis (n = 192) were included in the study. Because of the low number of patients with untreated LNB, 13 additional retrospectively selected samples of patients with untreated LNB were added. CXCL13 concentrations were measured by ELISA and receiver operating characteristic curves were generated. Results: CSF CXCL13 was highly elevated in all patients with untreated acute LNB (mean = 15,149 pg/mL) compared with that in the patients without LNB (mean = 247 pg/mL). At a cutoff of 1,229 pg/mL, the sensitivity of CXCL13 was 94.1%, which is higher than the AI (85.7%). Only 7 patients (5 with a CNS lymphoma and 2 with bacterial meningitis) had a CXCL13 level above the cutoff, resulting in a specificity equal to the AI of 96.1%. Conclusions: CXCL13 shows high sensitivity and specificity for acute, untreated LNB. This novel marker appears to be helpful in clinically atypical cases and, in particular, in early stages of the disease when the B burgdorferi AI is (still) negative.

Background: Guillain-Barre syndrome (GBS) has a highly diverse clinical course and outcome, yet patients are treated with a standard therapy. Patients with poor prognosis may benefit from additional treatment, provided they can be identified early, when nerve degeneration is potentially reversible and treatment is most effective. We developed a clinical prognostic model for early prediction of outcome in GBS, applicable for clinical practice and future therapeutic trials. Methods: Data collected prospectively from a derivation cohort of 397 patients with GBS were used to identify risk factors of being unable to walk at 4 weeks, 3 months, and 6 months. Potential predictors of poor outcome (unable to walk unaided) were considered in univariable and multivariable logistic regression models. The clinical model was based on the multivariable logistic regression coefficients of selected predictors and externally validated in an independent cohort of 158 patients with GBS. Results: High age, preceding diarrhea, and low Medical Research Council sumscore at hospital admission and at 1 week were independently associated with being unable to walk at 4 weeks, 3 months, and 6 months (all p 0.05-0.001). The model can be used at hospital admission and at day 7 of admission, the latter having a better predictive ability for the 3 endpoints; the area under the receiver operating characteristic curve (AUC) is 0.84-0.87 and at admission the AUC is 0.73-0.77. The model proved to be valid in the validation cohort. Conclusions: A clinical prediction model applicable early in the course of disease accurately predicts the first 6 months outcome in GBS. Neurology (R) 2011;76:968-975

Tyrosine hydroxylase deficiency (THD) is an autosomal recessive disorder resulting in severe dopamine depletion, with fewer than 70 patients diagnosed worldwide.1 Most of the reported cases of THD belong to 2 phenotypes: an infantile progressive hypokinetic-rigid syndrome with dystonia (type A) and a neonatal/early-onset severe encephalopathy (type B).1 Given the early onset, the extensive involvement of neurologic development, and the limited response to dopaminergic medications, prognosis for THD type B is poor.1–6 Twenty patients with THD type B have been described so far, with no data on long-term outcome.1,2 We report follow-up lasting 17 years with serial video recordings of the index case of THD type B.1,2,7 Acknowledgment: The authors thank Dr. Carlo Dionisi-Vici, Unit of Metabolism, Bambino Gesu Children's Hospital, Rome, for his contribution to the clinical management of the patient and Dr. Claudia Carducci, Department of Experimental Medicine, Sapienza University of Rome, who performed all the biochemical investigations.

Objective: A consistently identified risk factor for Alzheimer disease (AD) is family history of dementia, with maternal transmission significantly more frequent than paternal transmission. A history of maternal AD may be related to AD-like glucose consumption in cognitively healthy subjects. In this cross-sectional study, we tested whether cognitively healthy people with a family history of AD have less gray matter volume (GMV), an endophenotype for late-onset AD, than individuals with no family history, and whether decreases in GMV are different in subjects with a maternal family history. Methods: As part of the Kansas University Brain Aging Project, 67 cognitively intact individuals with a maternal history of late-onset AD (FHm, n = 16), a paternal history of AD (FHp, n = 8), or no parental history of AD (FH−, n = 43), similar in age, gender, education, and Mini-Mental State Examination score, were scanned at 3 T. We used voxel-based morphometry to examine GMV differences between groups, controlling for age, gender, and apoE4. Results: Cognitively healthy individuals with a family history of late-onset AD had significantly decreased GMV in the precuneus, middle frontal, inferior frontal, and superior frontal gyri compared with FH− individuals. FHm subjects had significantly smaller inferior frontal, middle frontal, precuneus, and lingual gyri compared with FH− and FHp subjects. Conclusions: Overall, maternal family history of Alzheimer disease (AD) in cognitively normal individuals is associated with lower gray matter volume in AD-vulnerable brain regions. These data complement and extend reports of cerebral metabolic differences in subjects with a maternal family history.