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

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

10.21203/rs.3.rs-121836/v2 ◽

2020 ◽

Author(s):

Md Nasir Uddin ◽

Abrar Faiyaz ◽

Lu Wang ◽

Yuchuan Zhuang ◽

Kyle D Murray ◽

...

Keyword(s):

White Matter ◽

Hiv Infection ◽

Diffusion Mri ◽

Temporal Evolution ◽

Free Water ◽

Combination Antiretroviral Therapy ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cd4 Counts

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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Serum neurofilament light is sensitive to active cerebral small vessel disease

Neurology ◽

10.1212/wnl.0000000000004645 ◽

2017 ◽

Vol 89 (20) ◽

pp. 2108-2114 ◽

Cited By ~ 49

Author(s):

Thomas Gattringer ◽

Daniela Pinter ◽

Christian Enzinger ◽

Thomas Seifert-Held ◽

Markus Kneihsl ◽

...

Keyword(s):

Single Molecule ◽

Small Vessel Disease ◽

Brain Mri ◽

Cerebral Small Vessel Disease ◽

Community Dwelling ◽

Small Vessel ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Vessel Disease

Objective:To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner.Methods:In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls.Results:Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up.Conclusions:Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.

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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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Plasma Neurofilament Light and Future Declines in Cognition and Function in Alzheimer’s Disease in the FIT-AD Trial

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-210302 ◽

2021 ◽

pp. 1-11

Author(s):

Danni Li ◽

Lin Zhang ◽

Nathaniel W. Nelson ◽

Michelle M. Mielke ◽

Fang Yu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Daily Living ◽

Short Term ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Linear Mixed Effects ◽

Future Studies ◽

Rate Of Decline ◽

And Function

Background: Utilities of blood-based biomarkers in Alzheimer’s disease (AD) clinical trials remain unknown. Objective: To evaluate the ability of plasma neurofilament light chain (NfL) to predict future declines in cognition and activities of daily living (ADL) outcomes in 26 older adults with mild-to-moderate AD dementia from the FIT-AD Trial. Methods: Plasma NfL was measured at baseline and 3 and 6 months. Cognition and ADL were assessed using the AD Assessment Scale-Cognition (ADAS-Cog) and AD Uniform Dataset Instruments and Disability Assessment for Dementia (DAD), respectively, at baseline, 3, 6, 9, and 12 months. Linear mixed effects models were used to examine the associations between baseline or change in plasma NfL and changes in outcomes. Results: Higher baseline plasma NfL was associated with greater rate of decline in ADAS-Cog from baseline to 6 months (standardized estimate of 0.00462, p = 0.02853) and in ADL from baseline to 12 months (standardized estimate of –0.00284, p = 0.03338). Greater increase in plasma NfL in short term from baseline to 3 months was associated with greater rate of decline in memory and ADL from 3 to 6 months (standardized estimate of –0.04638 [0.003], p = 0.01635; standardized estimate of –0.03818, p = 0.0435) and greater rate of decline in ADL from 3 to 12 month (standardized estimate of –0.01492, p = 0.01082). Conclusion: This study demonstrated that plasma NfL might have the potential to predict cognitive and function decline up to 12 months. However, future studies with bigger sample sizes need to confirm the findings.

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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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Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants

Journal of Alzheimer s Disease ◽

10.3233/jad-180025 ◽

2018 ◽

Vol 63 (2) ◽

pp. 479-487 ◽

Cited By ~ 19

Author(s):

Pratishtha Chatterjee ◽

Kathryn Goozee ◽

Hamid R. Sohrabi ◽

Kaikai Shen ◽

Tejal Shah ◽

...

Keyword(s):

Cognitive Performance ◽

Light Chain ◽

Amyloid Β ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cognitively Normal

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The effect of childhood trauma, ApoE genotype and HIV-1 viral protein R variants on change in cognitive performance

BMC Research Notes ◽

10.1186/s13104-019-4869-9 ◽

2019 ◽

Vol 12 (1) ◽

Author(s):

Jacqueline S. Womersley ◽

Lara B. Clauss ◽

Olivette Varathan ◽

Susan Engelbrecht ◽

Sian M. J. Hemmings ◽

...

Keyword(s):

Cognitive Performance ◽

Childhood Trauma ◽

Viral Protein ◽

Apoe Genotype ◽

Risk Scores ◽

Viral Protein R ◽

Gene Environment ◽

Calculated Risk ◽

Neuropsychological Assessments

Abstract Objective Gene–environment interactions contribute to the development of HIV-associated neurocognitive disorders. We examined whether childhood trauma, apolipoprotein E isoforms and viral protein R (Vpr) variants were associated with change in cognitive performance. Seventy-three seropositive women completed neuropsychological assessments at baseline and 1-year follow-up. We conducted genetic analyses using DNA obtained from blood and calculated risk scores based on Vpr amino acid 37, 41 and 55 variants that were previously associated with cognitive performance. Results Global cognitive scores declined significantly over the 1-year study period (p = 0.029). A reduction in global cognitive scores was associated with childhood trauma experience (p = 0.039).

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