Treating Traumatic Brain Injury with Minocycline.

Traumatic brain injury (TBI) results in both rapid and delayed brain damage. The speed, complexity, and persistence of TBI present large obstacles to drug development. Preclinical studies from multiple laboratories have tested the FDA-approved anti-microbial drug minocycline (MINO) to treat traumatic brain injury. At concentrations greater than needed for anti-microbial action, MINO readily inhibits microglial activation. MINO has additional pleotropic effects including anti-inflammatory, anti-oxidant, and anti-apoptotic activities. MINO inhibits multiple proteins that promote brain injury including metalloproteases, caspases, calpain, and polyADP-ribose-polymerase-1. At these elevated doses, MINO is well tolerated and enters the brain even when the blood-brain barrier is intact. Most preclinical studies with a first dose of MINO at less than 1 h after injury have shown improved multiple outcomes after TBI. Fewer studies with more delayed dosing have yielded similar results. A small number of clinical trials for TBI have established the safety of MINO and suggested some drug efficacy. Studies are also ongoing that either improve MINO pharmacology or combine MINO with other drugs to increase its therapeutic efficacy against TBI. This review builds upon a previous, recent review by some of the authors (Lawless and Bergold, Neural Regen Res 17:2589-92, 2022). The present review includes the additional preclinical studies examining the efficacy of minocycline in preclinical TBI models. This review also includes recommendations for a clinical trial to test MINO to treat TBI.

A single closed head injury in male adult mice induces chronic, progressive white matter atrophy and increased phospho-tau expressing oligodendrocytes.

Traumatic brain injury (TBI) acutely damages the brain; this injury can evolve into chronic neurodegeneration. While much is known about the chronic effects arising from multiple mild TBIs, far less is known about the long-term effects of a single moderate to severe TBI. We found that a single moderate closed head injury to mice induces diffuse axonal injury within 1-day post-injury (DPI). At 14 DPI, injured animals have atrophy of ipsilesional cortex, thalamus, and corpus callosum, with bilateral atrophy of the dorsal fornix. Atrophy of the ipsilesional corpus callosum is accompanied by decreased fractional anisotropy and increased mean and radial diffusivity that remains unchanged between 14 and 180 DPI. Injured animals show an increased density of phospho-tau immunoreactive (pTau+) cells in the ipsilesional cortex and thalamus, and bilaterally in corpus callosum. Between 14 and 180 DPI, atrophy occurs in the ipsilesional ventral fornix, contralesional corpus callosum, and bilateral internal capsule. Diffusion tensor MRI parameters remain unchanged in white matter regions with delayed atrophy. Between 14 and 180 DPI, pTau+ cell density increases bilaterally in corpus callosum, but decreases in cortex and thalamus. The location of pTau+ cells within the ipsilesional corpus callosum changes between 14 and 180 DPI; density of all cells increases including pTau+ or pTau- cells. >90% of the pTau+ cells are in the oligodendrocyte lineage in both gray and white matter. Density of thioflavin-S+ cells in thalamus increases by 180 DPI. These data suggest a single closed head impact produces multiple forms of chronic neurodegeneration. Gray and white matter regions proximal to the impact site undergo early atrophy. More distal white matter regions undergo chronic, progressive white matter atrophy with an increasing density of oligodendrocytes containing pTau. These data suggest a complex chronic neurodegenerative process arising from a single moderate closed head injury.

Better together? Treating traumatic brain injury with minocycline plus N-acetylcysteine.

Traumatic brain injury has a complex pathophysiology that produces both rapid and delayed brain damage. Rapid damage initiates immediately after injury. Treatment of traumatic brain injury is typically delayed many hours, thus only delayed damage can be targeted with drugs. Delayed traumatic brain injury includes neuroinflammation, oxidative damage, apoptosis, and glutamate toxicity. Both the speed and complexity of traumatic brain injury pathophysiology present large obstacles to drug development. Repurposing of Food and Drug Administration-approved drugs may be a highly efficient approach to get therapeutics to the clinic. This review examines the preclinical outcomes of minocycline and N-acetylcysteine as individual drugs and compares them to the minocycline plus N-acetylcysteine combination. Both minocycline and N-acetylcysteine are Food and Drug Administration-approved drugs with pleiotropic therapeutic effects. As individual drugs, minocycline and N-acetylcysteine are well tolerated, with known pharmacokinetics, and enter the brain through an intact blood-brain barrier. At concentrations greater than needed for anti-microbial action, minocycline is a potent anti-inflammatory minocycline, also acts as an antioxidant and inhibits multiple enzymes that promote brain injury including metalloproteases, caspases, and polyADP-ribose-polymerase-1. N-acetylcysteine alone is also an antioxidant. It increases brain glutathione, prevents lipid oxidation, and protects mitochondria. N-acetylcysteine also acts as an anti-inflammatory as well as increases extracellular glutamate by activating the Xc cystine-glutamate anti-transporter. These multiple actions of minocycline and N-acetylcysteine have made them attractive candidates to treat traumatic brain injury. When first dosed within the one hour after injury, either minocycline or N-acetylcysteine improves a diverse set of therapeutic outcome measures in multiple traumatic brain injury animal models. A small number of clinical trials for traumatic brain injury have established the safety of minocycline or N-acetylcysteine and suggested that either drug has some efficacy. Preclinical studies have shown that minocycline plus N-acetylcysteine have positive synergy resulting in therapeutic effects and a more prolonged therapeutic time window not seen with the individual drugs. This review compares the actions of minocycline and N-acetylcysteine, individually and in combination. Evidence supports that the combination has greater utility to treat traumatic brain injury than the individual drugs.

Assessing Dependency in a Multiethnic Community Cohort of Individuals With Alzheimer's Disease.

BACKGROUND AND OBJECTIVES: Clinic-based studies of patients with Alzheimer's disease (AD) have demonstrated the value of assessing dependence when characterizing patients' functional status. The Dependence Scale, a validated tool to assess level of caregiving needs, is associated with markers of disease severity, cost, and progression, while offering independent functional information about patients. This study examines whether such associations between the Dependence Scale and markers of disease severity demonstrated in clinical cohorts are similarly exhibited in a multiethnic community population of individuals with AD. RESEARCH DESIGN AND METHODS: One hundred fifty four elders with AD enrolled in the Predictors 3 cohort were assessed with the Dependence Scale, modified Mini-Mental State Examination (mMMS), instrumental (IADL) and basic (BADL) activities of daily living, and Clinical Dementia Rating (CDR) Scale, and were assigned an Equivalent Institutional Care (EIC) rating. Cross-sectional associations were examined using bivariate correlations and one-way analysis of variance analyses. Fisher-z tests examined differences in strengths of associations across previous clinic and current community cohorts. RESULTS: Dependence Scale scores were associated with CDR (r = .20, p = .013), mMMS (r = -.23, p = .005), IADL (r = .39, p < .001), BADL (r = .65, p < .001), and EIC (r = .51, p < .001). Dependence was unassociated with ethnicity (F[3,144] = 1.027, p = .3822), age (r = .120, p = .145), and education (r = -.053, p = .519). The strength of the correlations was comparable across cohorts except that BADLs were more strongly associated with dependence (z = -4.60, p < .001) in the community cohort, and living arrangement was not associated with dependence (r = .13, p = .130). DISCUSSION AND IMPLICATIONS: Associations between the Dependence Scale and markers of disease severity in a clinic-based cohort of AD patients are similar to associations in a multiethnic community cohort of individuals diagnosed with AD. The Dependence Scale relates to markers of disease severity rather than demographic factors, and may offer an unbiased assessment of care required in multiethnic and community populations.

Increased Reporting Accuracy of Alzheimer Disease Symptoms in Caribbean Hispanic Informants.

INTRODUCTION: Informant report of symptoms is essential for diagnosing and characterizing Alzheimer disease (AD). Differences in the perception and experience of dementia across ethnicities may influence informant report. Understanding such differences is critical given that among those with AD, Hispanics are disproportionately affected. METHODS: Cross-sectional analyses examined informant report of cognitive and functional symptoms in mild AD across white (n=107) and Caribbean Hispanic (n=71) informants. To explore its accuracy, informant report of symptoms was compared against objective measures of patient performance. RESULTS: Adjusted analyses revealed Hispanics reported more symptoms than white informants. Informant report of symptoms was inversely correlated with patients' global cognition in both ethnic groups. Only Hispanic report of symptoms was significantly associated with memory and language performance. DISCUSSION: Informant report of symptoms was associated with patients' global cognition, reflecting relatively accurate informant reports in both ethnic groups, and was stronger in Hispanics when examining memory and language. Such differences may reflect cultural caregiving practices and perceptions of dementia, having implications for diagnosis and treatment.

The Predictors study: Development and baseline characteristics of the Predictors 3 cohort.

INTRODUCTION: The Predictors study was designed to predict the length of time to major disease outcomes in Alzheimer's disease (AD) patients. Here, we describe the development of a new, Predictors 3, cohort. METHODS: Patients with prevalent or incident AD and individuals at-risk for developing AD were selected from the North Manhattan community and followed annually with instruments comparable to those used in the original two Predictors cohorts. RESULTS: The original Predictors cohorts were clinic based and racially/ethnically homogenous (94% white, 6% black; 3% Hispanic). In contrast, the 274 elders in this cohort are community-based and ethnically diverse (39% white, 40% black, 21% other; 78% Hispanic). Confirming previous observations, psychotic features were associated with poorer function and mental status and extrapyramidal signs with poorer function. DISCUSSION: This new cohort will allow us to test observations made in our original clinic-based cohorts in patients that may be more representative of the general community.