Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration

Brain, Год журнала: 2017, Номер 141(2), С. 459 - 471

Опубликована: Ноя. 22, 2017

Survivors of a traumatic brain injury can deteriorate years later, developing atrophy and dementia. Traumatic triggers chronic microglial activation, but it is unclear whether this harmful or beneficial. A successful chronic-phase treatment for might be to target microglia. In experimental models, the antibiotic minocycline inhibits activation. We investigated effect on activation neurodegeneration using PET, MRI, measurement axonal protein neurofilament light in plasma. Microglial was assessed 11C-PBR28 PET. The relationships measures injury, effects disease progression, were structural diffusion plasma light, cognitive assessment. Fifteen patients at least 6 months after moderate-to-severe received either 100 mg orally twice daily no drug, 12 weeks. At baseline, binding increased compared controls cerebral white matter thalamus, levels elevated. MRI damage highest areas greater binding. Minocycline reduced (mean Δwhite = -23.30%, 95% confidence interval -40.9 -5.64%, P 0.018), levels. Faster rates found with higher baseline medicine study, while increasing marker neurodegeneration. These findings suggest that has reparative phase injury.

Язык: Английский

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Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations

Nature Aging, Год журнала: 2020, Номер 1(1), С. 114 - 123

Опубликована: Ноя. 30, 2020

Язык: Английский

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Plasma biomarker profiles in autosomal dominant Alzheimer’s disease

Brain, Год журнала: 2023, Номер 146(3), С. 1132 - 1140

Опубликована: Янв. 11, 2023

Abstract Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early disease-related abnormalities such as the accumulation amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in CNS can adequately detected by peripheral measurements whether are equally applicable both clinical preclinical phases. Here we aimed explore timing performance mutation carriers compared non-carriers autosomal dominant disease. Samples (n = 164) from 33) 42) a Swedish cohort (APP p.KM670/671NL, APP p.E693G PSEN1 p.H163Y) were included explorative longitudinal analyses. Plasma phosphorylated (P-tau181), total (T-tau), neurofilament light chain (NfL) fibrillary acidic protein (GFAP) concentrations measured with single-molecule array method previously described. additionally correlated core CSF. Results analyses confirmed that P-tau181, NfL GFAP higher non-carriers. This change was observed presymptomatic phase detectable first an increase approximately 10 years before estimated symptom onset, followed increased levels P-tau181 closer expected onset. T-tau Altogether, seem feasible detect different pathologies already individuals. Interestingly, changes prior NfL. Our results suggest reflect pathology upstream tangles The implications these findings need additional validation, particular because limited sample size.

Язык: Английский

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A new enzyme-linked immunosorbent assay for neurofilament light in cerebrospinal fluid: analytical validation and clinical evaluation

Alzheimer s Research & Therapy, Год журнала: 2018, Номер 10(1)

Опубликована: Янв. 23, 2018

Cerebrospinal fluid (CSF) neurofilament light (NfL) is a reliable marker of neuro-axonal damage in different neurological disorders that related to disease severity. To date, all recent studies performed human CSF have used the same enzyme-linked immunosorbent assay (ELISA). confirm large body evidence for NfL, we developed new ELISA method and here present performance characteristics this NfL disorders. We produced two monoclonal antibodies (NfL21 NfL23) directed against core domain, novel sandwich evaluated patients with: 1) inflammatory demyelinating diseases (IDD; n = 97), including multiple sclerosis (MS; 59), clinically isolated syndrome (CIS; 32), radiologically (RIS; 6); 2) Alzheimer’s (AD; 72), mild cognitive impairment due AD (MCI-AD, 36) probable dementia (AD-dem; 36); 3) Parkinson’s (PD; 30); 4) other noninflammatory non-neurodegenerative (OND; 30). Our showed good analytical (inter-plate coefficient variation (CV) < 13%), with no cross-reactivity medium heavy (NfM NfH). With respect available ELISAs, range values strong correlation (r 0.9984, p 0.001) between methods. levels were significantly higher MCI-AD/AD-dem IDD as compared both PD OND patients. The highest discriminative power was obtained (area under curve (AUC) 0.87, 95% confidence interval (CI) 0.80–0.95). Within group, positively correlated several clinical radiological severity parameters. These results show quantification concentrations CSF. confirmed be MS, disease-severity MS

Язык: Английский

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Assessing mouse behaviour throughout the light/dark cycle using automated in-cage analysis tools

Journal of Neuroscience Methods, Год журнала: 2017, Номер 300, С. 37 - 47

Опубликована: Апрель 26, 2017

An important factor in reducing variability mouse test outcomes has been to develop assays that can be used for continuous automated home cage assessment. Our experience shown this most evidenced long-term assessment of wheel-running activity mice. Historically, mice and other rodents have as a robust assay determine, with precision, the inherent period circadian rhythms Furthermore, instrumental dissecting molecular genetic basis mammalian rhythms. In teasing out elements determined its robustness – an unforced behaviour over long time intervals we others investigating whether similar apparatus could accurately discriminate differences distinct behavioural parameters Firstly, using these systems, explored behaviours number inbred strains determine extract biologically meaningful differences. Secondly, tested relevant mutant lines how discriminative were. findings show that, when compared conventional out-of-cage phenotyping, far deeper understanding phenotype established by monitoring one or more light:dark cycles.

Язык: Английский

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Asymmetric effects of activating and inactivating cortical interneurons

eLife, Год журнала: 2016, Номер 5

Опубликована: Окт. 10, 2016

Bidirectional manipulations – activation and inactivation are widely used to identify the functions supported by specific cortical interneuron types. Implicit in much of this work is notion that tonic will both produce valid, internally consistent insights into interneurons’ computational roles. Here, using single-unit recordings auditory cortex awake mice, we show may not generally hold true. Optogenetically manipulating somatostatin-positive (Sst+) or parvalbumin-positive (Pvalb+) interneurons while recording tone-responses showed Sst+ increased response gain, Pvalb+ weakened tuning decreased information transfer, implying these neurons support delineable functions. But activating revealed no such differences. We a simple network model understand asymmetry, how relatively small changes key parameters, as spontaneous activity strength light manipulation, determined whether would paradoxical conclusions regarding

Язык: Английский

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NFL is a marker of treatment response in children with SMA treated with nusinersen

Journal of Neurology, Год журнала: 2019, Номер 266(9), С. 2129 - 2136

Опубликована: Май 23, 2019

Recently, the anti-sense oligonucleotide drug nusinersen was approved for spinal muscular atrophy (SMA) and our aim to find a response marker this treatment.Twelve children with SMA type 1 two copies of SMN2 gene were included in consecutive single-center study. The sampled CSF at baseline every time given intrathecally. neuronal biomarkers NFL tau glial biomarker GFAP measured. Motor function assessed using CHOP INTEND. Eleven similarly aged children, who investigated rule out neurological or infectious disease, used as controls.Baseline levels (4598 ± 981 vs 148 39, P = 0.001), (939 159 404 86, 0.02), (236 44 108 26, 0.02) significantly higher than controls. improved by treatment median 13 points corresponding 5.4 per month (P 0.001). typically normalized ( < 380 pg/ml) between fourth fifth doses [- 879.5 pg/mL/dose, 95% CI (- 1243.4, - 415.6), 0.0001], decreased 112.6 206-7, 18.6), 0.01], minor decreases observed 16.9 22.8, 11.2), 0.02] treatment. Improvement motor correlated reduced concentrations (rho 0.64, 0.03) 0.85, 0.0008) but not GFAP.Nusinersen axonal damage improvement SMA. may, therefore, be novel monitor early disease course.

Язык: Английский

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Blood-based biomarkers for Alzheimer’s disease—An update

Journal of Neuroscience Methods, Год журнала: 2018, Номер 319, С. 2 - 6

Опубликована: Окт. 25, 2018

Язык: Английский

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Divergent Connectivity of Homologous Command-like Neurons Mediates Segment-Specific Touch Responses in Drosophila

Neuron, Год журнала: 2017, Номер 96(6), С. 1373 - 1387.e6

Опубликована: Ноя. 30, 2017

Язык: Английский

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Midbrain dopamine neurons signal aversion in a reward-context-dependent manner

eLife, Год журнала: 2016, Номер 5

Опубликована: Окт. 19, 2016

Dopamine is thought to regulate learning from appetitive and aversive events. Here we examined how optogenetically-identified dopamine neurons in the lateral ventral tegmental area of mice respond events different conditions. In low reward contexts, most were exclusively inhibited by events, expectation reduced neurons’ responses punishment. When a single odor predicted both punishment, that reflected integrated value outcomes. Thus, signal prediction errors (VPEs) integrating information about aversion common currency. contrast, high acquired short-latency excitation masked their VPE signaling. Our results demonstrate importance considering contexts examine representation uncover modes signaling, each which may be adaptive for environments.

Язык: Английский

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