Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer’s disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aβ1-42 pathology (Aβ+/−) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aβ+ compared with Aβ− controls. In MCI-Aβ+ compared with Aβ− controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aβ+ and MCI-Aβ+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.     

Diagnostic value of bright spotty lesions on MRI after a first episode of acute myelopathy

Background and purposeTo determine the diagnostic value of bright spotty lesions (BSLs) for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD^AQP4+), the predictive value of axial-BSLs for AQP4-IgG seropositivity, and the radio-clinical differences in NMOSD^AQP4+ patients with and without axial-BSLs.Materials and methodsRetrospective study that included patients aged ≥ 16 years, with a first acute spinal cord syndrome between 2005 and 2018 and abnormal spinal cord MRI with axial and sagittal T2 sequences. Patients with MRI findings consistent with compressive myelopathy were excluded. All spinal cord MRI were retrospectively evaluated for the presence of BSLs by 2 radiologists blinded to the diagnosis of acute myelopathy.ResultsA total of 82 patients were included; 15 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients (NMOSD^AQP4+), and 67 other patients, considered as the other causes of myelopathy (OM) group. The specificity of axial-BSLs for NMOSD^AQP4+ patients was 94.0% (95% CI [85.6 to 97.7]). The sensitivity was 40.0% (95% CI [19.8 to 64.3]). In the multivariable analysis, the only MRI characteristic associated with AQP4-IgG positivity was the presence of axial-BSLs (OR: 9.2, 95% CI [1.2 to 72.9]; P = 0.022). In NMOSD^AQP4+ patients, the median of cord expansion ratio was higher with axial-BSL (1.2, IQR [1.1–1.3]) than without axial-BSL (1.1, IQR [1.0–1.2]; P = 0.046).ConclusionAfter a first acute spinal cord syndrome, the presence of axial-BSLs on spinal cord MRI seems very specific for NMOSD^AQP4+ and seems to be a predictor radiological marker of AQP4-IgG positivity.     

Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism

The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll‐like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR‐induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti‐inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN‐sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions. GLIA 2015;63:1083–1099     

Characterization of the novel GlyT1 PET tracer [18F]MK‐6577 in humans

Decreased glutamatergic neurotransmission is hypothesized to be involved in the pathophysiology of schizophrenia. Inhibition of glycine transporter Type‐1 (GlyT1) reuptake is expected to increase the glutamatergic neurotransmission and may serve as treatment for cognitive and negative symptoms of schizophrenia. In this article, we present human data from a novel GlyT1 PET tracer, [¹⁸F]MK‐6577. In the process of developing a GlyT1 inhibitor therapeutic, a PET tracer can assist in determining the dose with a high probability of sufficiently testing the mechanism of action. This article reports the human PET studies with [¹⁸F]MK‐6577 for measuring GlyT1 receptor availability at baseline in normal human subjects and occupancy with a GlyT1 inhibitor, MK‐2637. Studies were also performed to measure radiation burden and the baseline test‐retest (T‐RT) variability of the tracer. The effective dose from sequential whole‐body dosimetry scans in three male subjects was estimated to be 24.5 ± 2.9 µSV/MBq (mean ± SD). The time–activity curves from T‐RT scans modeled satisfactorily using a two tissue compartmental model. The tracer uptake was highest in the pons (V_T = 6.7 ± 0.9, BP_ND = 4.1 ± 0.43) and lowest in the cortex (V_T = 2.1 ± 0.5, BP_ND = 0.60 ± 0.23). V_T T‐RT variability measured in three subjects was <12% on average. The occupancy scans performed in a cohort of 15 subjects indicated absence of a reference region. The in vivo potency (Occ₅₀) of MK‐2637 was determined using two methods: A: Lassen plot with a population input function (Occ₅₀ = 106 nM, SE = 20 nM) and B: pseudo reference tissue model using cortex as the pseudo reference region (Occ₅₀ = 141 nM, SE = 21 nM). Synapse 69:33–40, 2015. © 2014 Wiley Periodicals, Inc.     

Cueing the personal future to reduce discounting in intertemporal choice: Is episodic prospection necessary?

How does the ability to imagine detailed future experiences (i.e., episodic prospection) contribute to choices between immediate and delayed rewards? Individuals with amnesia do not show abnormally steep discounting in intertemporal choice, suggesting that neither medial temporal lobe (MTL) integrity nor episodic prospection is required for the valuation of future rewards (Kwan et al. ( ), Hippocampus, 22:1215‐1219; Kwan et al. (2013), J Exp Psychol, 142:1355‐1369 2013). However, hippocampally mediated episodic prospection in healthy adults reduces the discounting of future rewards (Peters and Büchel (2010), Neuron, 66:138‐148; Benoit et al. (2011), J Neurosci, 31:6771‐6779), raising the possibility that MTL damage causes more subtle impairments to this form of decision‐making than noted in previous patient studies. Intertemporal choice appears normal in amnesic populations, yet they may be unable to use episodic prospection to adaptively modulate the value assigned to future rewards. To investigate how the extended hippocampal system, including the hippocampus and related MTL structures, contributes to the valuation of future rewards, we compared the performance of six amnesic cases with impaired episodic prospection to that of 20 control participants on two versions of an intertemporal choice task: a standard discounting task, and a cued version in which cues prompted them to imagine specific personal future events temporally contiguous with the receipt of delayed rewards. Amnesic individuals' intertemporal choices in the standard condition were indistinguishable from those of controls, replicating previous findings. Surprisingly, performance of the amnesic cases in the cued condition indicates that amnesia does not preclude flexible modulation of choices in response to future event cues, even in the absence of episodic prospection. Cueing the personal future to modulate decisions appears to constitute a less demanding or a qualitatively different (e.g., personal semantic) form of prospection that is not as sensitive to MTL damage as prospective narrative generation. © 2015 Wiley Periodicals, Inc.     

Discrete mitochondrial aberrations in the spinal cord of sporadic ALS patients

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post‐mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease.     

Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation

Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntington's disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.     

Combined exercise and cognitive behavioral therapy improves outcomes in patients with heart failure

Objective

The purpose of this study is to compare the effectiveness of a combined 12-week home-based exercise (EX)/cognitive behavioral therapy (CBT) program (n=18) with CBT alone (n=19), EX alone (n=20), and with usual care (UC, n=17) in stable New York Heart Association Class II to III heart failure (HF) patients diagnosed with depression.

Methods

Depressive symptom severity [Hamilton Rating Scale for Depression (HAM-D)], physical function [6-min walk test (6MWT)], and health-related quality of life (HRQOL) (Minnesota Living with Heart Failure Questionnaire) were evaluated at baseline (T1), after the 12-week intervention/control (T2), and following a 3-month telephone follow-up (T3). A repeated measures analysis of variance was used to determine group differences. Depression severity was dichotomized as minor (HAM-D, 11-14) and moderate-to-major depression (HAM-D, ≥15), and group intervention and control responses were also evaluated on that basis.

Results

The greatest reduction in HAM-D scores over time occurred in the EX/CBT group (−10.4) followed by CBT (−9.6), EX (−7.3), and UC (−6.2), but none were statistically significant. The combined group showed a significant increase in 6-min walk distance at 24 weeks (F=13.5, P<.001). Among all groups with moderate-to-major depression, only those in CBT/EX had sustained lower HAM-D scores at 12 and 24 weeks, 6MWT distances were significantly greater at 12 (P=.018) and 24 (P=.013) weeks, and the greatest improvement in HRQOL also occurred.

Conclusions

Interventions designed to improve both physical and psychological symptoms may provide the best method for optimizing functioning and enhancing HRQOL in patients with HF.     

APOE-ε4 associates with hippocampal volume,learning, and memory across the spectrum of Alzheimer's disease and dementia with Lewy bodies

Introduction

Although the apolipoprotein E ε4-allele (APOE-ε4) is a susceptibility factor for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), its relationship with imaging and cognitive measures across the AD/DLB spectrum remains unexplored.