Linking Neuroinflammation and Extracellular Free Water in HIV Infection: A Longitudinal Study

Abstract Initiation of combination antiretroviral therapy (cART) reduces inflammation in HIV-infected (HIV+) individuals. Recent studies demonstrated that diffusion MRI based extracellular free water (FW) modeling can be sensitive to neuroinflammation. Here, we investigate the FW in HIV-infection, its temporal evolution, and its association with blood markers, and cognitive scores. Using 96 age-matched participants, we found that FW was significantly elevated in grey and white matter in cART-naïve HIV+ compared to healthy controls (HIV-) at baseline. Similarly, at baseline, HIV+ participants had increased neurofilament light chain (NfL) values that correlated with FW and CD4 counts. FW in grey and white matter, as well as NfL decreased in the HIV+ after 12 weeks of cART treatment. No significant FW differences were noted between the HIV+ and HIV- cohorts at 1 and 2-year follow-up. Results suggest that FW elevation in cART-naïve HIV+ participants is likely due to neuroinflammation. The correlation between FW and NfL and the improvement in both FW and NfL after 12 weeks of cART treatment further reinforces this conclusion. The longer follow-up at 1 and 2 years suggests that cART helped control neuroinflammation as inferred by FW. Therefore, FW could be used as a biomarker to monitor HIV-associated neuroinflammation.

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A longitudinal analysis of brain extracellular free water in HIV infected individuals

Scientific Reports ◽

10.1038/s41598-021-87801-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Md Nasir Uddin ◽

Abrar Faiyaz ◽

Lu Wang ◽

Yuchuan Zhuang ◽

Kyle D. Murray ◽

...

Keyword(s):

White Matter ◽

Antiretroviral Therapy ◽

Diffusion Mri ◽

Temporal Evolution ◽

Free Water ◽

Combination Antiretroviral Therapy ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cd4 Counts

AbstractInitiation of combination antiretroviral therapy (cART) reduces inflammation in HIV-infected (HIV+) individuals. Recent studies demonstrated that diffusion MRI based extracellular free water (FW) modeling can be sensitive to neuroinflammation. Here, we investigate the FW in HIV-infection, its temporal evolution, and its association with blood markers, and cognitive scores. Using 96 age-matched participants, we found that FW was significantly elevated in grey and white matter in cART-naïve HIV+ compared to HIV-uninfected (HIV−) individuals at baseline. These increased FW values positively correlated with neurofilament light chain (NfL) and negatively correlated with CD4 counts. FW in grey and white matter, as well as NfL decreased in the HIV+ after 12 weeks of cART treatment. No significant FW differences were noted between the HIV+ and HIV− cohorts at 1 and 2-year follow-up. Results suggest that FW elevation in cART-naïve HIV+ participants is likely due to neuroinflammation. The correlation between FW and NfL, and the improvement in both FW and NfL after 12 weeks of cART treatment further reinforces this conclusion. The longer follow-up at 1 and 2 years suggests that cART helped control neuroinflammation as inferred by FW. Therefore, FW could be used as a biomarker to monitor HIV-associated neuroinflammation.

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Linking Neuroinflammation and Extracellular Free Water in HIV Infection: A Longitudinal Study

10.21203/rs.3.rs-121836/v1 ◽

2020 ◽

Author(s):

Md Nasir Uddin ◽

Abrar Faiyaz ◽

Lu Wang ◽

Yuchuan Zhuang ◽

Kyle D Murray ◽

...

Keyword(s):

White Matter ◽

Hiv Infection ◽

Cognitive Performance ◽

Brain Mri ◽

Free Water ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Linear Mixed Effects ◽

Neuropsychological Assessments

Abstract Background Initiation of combination antiretroviral therapy (cART) reduces inflammation in HIV-infected (HIV+) individuals. Recent studies demonstrated that diffusion MRI based extracellular free water (FW) modeling can be sensitive to neuroinflammation. However, no studies to date have investigated the FW in HIV infection, its temporal evolution, nor its association with brain-derived blood markers. Methods Ninety-six age-matched participants underwent brain MRI and clinical and neuropsychological assessments at baseline. HIV- participants underwent follow-up evaluation annually for two years while HIV + participants were seen 12 weeks after initiating cART and annually thereafter. Whole brain grey and white matter FW measures were compared between groups and correlated with clinical characteristics and cognitive scores. In addition, several pre-specified subcortical grey and white matter regions-of-interest (ROIs) were explored. Results At baseline, FW was significantly elevated in grey and white matter in cART-naïve HIV + participants compared to HIV- participants. Similarly, at baseline, HIV + participants had increased neurofilament light chain (NfL) values that correlated with FW and CD4 count, and decreased cognitive performance compared to HIV- participants. FW decreased in grey and white matter in HIV + participants after 12 weeks of cART treatment. 12-week cART treatment was also associated with a decrease in NfL and improvement in cognitive performance. Linear mixed effects regression models also revealed that FW was significantly reduced in most ROIs after 12 weeks of cART treatment. No significant FW differences were noted between the HIV + and HIV- participants at 1 and 2-year follow-up. Conclusions FW elevation in cART-naïve HIV + participants is likely due to neuroinflammation. The correlation between FW and NfL and the improvement in both FW and NfL after 12 weeks of cART treatment further reinforces this conclusion. The longer follow-up at 1 and 2 years suggests that cART helped control neuroinflammation as inferred by FW. Therefore, FW could be used as a biomarker to monitor HIV-associated neuroinflammation.

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Relationship between serum neurofilament light chain levels and cognitive decline over 9-years follow-up in patients after first demyelinating event suggestive of MS

10.26226/morressier.5b75785e5aff7400151f3465 ◽

2018 ◽

Author(s):

Tomas Uher ◽

Dana Horakova

Keyword(s):

Cognitive Decline ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light

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Characterizing Extracellular White Matter Pathologies Using Free Water Imaging Across the Schizophrenia Illness Course: A Multi-Site Harmonized Diffusion MRI Study

Biological Psychiatry ◽

10.1016/j.biopsych.2021.02.226 ◽

2021 ◽

Vol 89 (9) ◽

pp. S85

Author(s):

Suheyla Cetin-Karayumak ◽

Ofer Pasternak ◽

Fan Zhang ◽

Johanna Seitz ◽

Doron Elad ◽

...

Keyword(s):

White Matter ◽

Diffusion Mri ◽

Free Water ◽

Mri Study

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Fatigue in Patients With Multiple System Atrophy

Neurology ◽

10.1212/wnl.0000000000012968 ◽

2021 ◽

Vol 98 (1) ◽

pp. e73-e82

Author(s):

Lingyu Zhang ◽

Bei Cao ◽

Yanbing Hou ◽

Xiaojing Gu ◽

Qian-Qian Wei ◽

...

Keyword(s):

Multiple System Atrophy ◽

Regression Model ◽

Rating Scale ◽

Early Stage ◽

Progression Rate ◽

Nonmotor Symptoms ◽

Binary Logistic Regression Model ◽

Neurofilament Light Chain ◽

Neurofilament Light

Background and ObjectivesNonmotor symptoms are common in patients with multiple system atrophy (MSA), but there is limited knowledge regarding fatigue in MSA. This study aimed to investigate the frequency and evolution of fatigue and the factors related to fatigue and its progression in patients with MSA at an early stage.MethodsPatients with probable MSA were comprehensively evaluated at both baseline and the 1-year follow-up, including their motor and nonmotor symptoms. Fatigue and anxiety were assessed using the Fatigue Severity Scale (FSS) and Hamilton Anxiety Rating Scale (HARS), respectively. Orthostatic hypotension (OH) was defined as a decrease in the systolic or diastolic blood pressure by at least 30 and 15 mm Hg, respectively. The binary logistic regression model and linear regression model were used to analyze the factors related to fatigue and its progression, respectively.ResultsThis study enrolled 146 patients with MSA. The frequency of fatigue was 60.3%, 55.1%, and 64.9% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. The frequency of fatigue and the FSS score in patients with MSA increased from baseline to the 1-year follow-up (p < 0.05). Young age (odds ratio [OR] 0.939, 95% confidence interval [CI] 0.894–0.987), OH (OR 2.806, 95% CI 1.253–6.286), and high HARS score (OR 1.014, 95% CI 1.035–1.177) were associated with fatigue in MSA. OH was associated with fatigue in MSA-P (OR 3.391, 95% CI 1.066–10.788), while high HARS score was associated with fatigue in MSA-C (OR 1.159, 95% CI 1.043–1.287). In addition, only low FSS scores at baseline were associated with the annual progression rate of FSS scores in MSA, MSA-P, and MSA-C (p < 0.05). Neurofilament light chain, α-synuclein, glial fibrillary acidic protein, brain-derived neurotrophic factor, and triggering receptor expressed on myeloid cell-2 were not significantly associated with fatigue and its progression in MSA.DiscussionFatigue was prevalent in early-stage MSA, and it increased and remained persistent over time. This study demonstrated that OH and anxiety were associated with fatigue in patients with MSA.

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Prediagnostic Neurofilament Light Chain Levels in Amyotrophic Lateral Sclerosis

Neurology ◽

10.1212/wnl.0000000000012632 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012632

Author(s):

Kjetil Bjornevik ◽

Eilis J. O'Reilly ◽

Samantha Molsberry ◽

Laurence N. Kolonel ◽

Loic Le Marchand ◽

...

Keyword(s):

Light Chain ◽

Conditional Logistic Regression ◽

Disease Diagnosis ◽

Health Study ◽

Plasma Samples ◽

Blood Draw ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Rate Ratios

Objective:To assess whether plasma neurofilament light chain (NfL) levels are elevated before ALS diagnosis and to evaluate whether pre-diagnostic NfL levels are associated with metabolic alterations.Methods:We conducted a matched case-control study nested in three large prospective US cohorts (the Nurses’ Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study), and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels.Results:Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 standard deviation [SD] increase: 2.68, 95% CI: 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI: 0.78-1.73). A total of 21 metabolites were correlated with pre-diagnostic NfL levels in ALS cases (p < 0.05), but none of these remained significant after multiple comparison adjustments.Conclusions:Plasma NfL levels were elevated in pre-diagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease.Classification of Evidence:This study provides Class II evidence that plasma NfL levels are elevated in pre-diagnostic ALS patients.

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White-matter free-water diffusion MRI in schizophrenia: a systematic review and meta-analysis

Neuropsychopharmacology ◽

10.1038/s41386-022-01272-x ◽

2022 ◽

Author(s):

Inês Carreira Figueiredo ◽

Faith Borgan ◽

Ofer Pasternak ◽

Federico E. Turkheimer ◽

Oliver D. Howes

Keyword(s):

White Matter ◽

Healthy Volunteers ◽

Diffusion Mri ◽

Clinical Symptoms ◽

Free Water ◽

Brain Regions ◽

Water Levels ◽

First Episode ◽

Whole Brain ◽

Illness Duration

AbstractWhite-matter abnormalities, including increases in extracellular free-water, are implicated in the pathophysiology of schizophrenia. Recent advances in diffusion magnetic resonance imaging (MRI) enable free-water levels to be indexed. However, the brain levels in patients with schizophrenia have not yet been systematically investigated. We aimed to meta-analyse white-matter free-water levels in patients with schizophrenia compared to healthy volunteers. We performed a literature search in EMBASE, MEDLINE, and PsycINFO databases. Diffusion MRI studies reporting free-water in patients with schizophrenia compared to healthy controls were included. We investigated the effect of demographic variables, illness duration, chlorpromazine equivalents of antipsychotic medication, type of scanner, and clinical symptoms severity on free-water measures. Ten studies, including five of first episode of psychosis have investigated free-water levels in schizophrenia, with significantly higher levels reported in whole-brain and specific brain regions (including corona radiata, internal capsule, superior and inferior longitudinal fasciculus, cingulum bundle, and corpus callosum). Six studies, including a total of 614 participants met the inclusion criteria for quantitative analysis. Whole-brain free-water levels were significantly higher in patients relative to healthy volunteers (Hedge’s g = 0.38, 95% confidence interval (CI) 0.07–0.69, p = 0.02). Sex moderated this effect, such that smaller effects were seen in samples with more females (z = −2.54, p < 0.05), but antipsychotic dose, illness duration and symptom severity did not. Patients with schizophrenia have increased free-water compared to healthy volunteers. Future studies are necessary to determine the pathological sources of increased free-water, and its relationship with illness duration and severity.

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