Table 1.
Aged Animal studies of TBI
| Reference | TBI model | Species / Strain | Age and sex | Resultsa - Neuropathology and Physiology | Resultsa - Functional Outcomes |
|---|---|---|---|---|---|
| Hamm, 199191 | Central FPI | Rat / Fischer-344 | 3 mo and 20 mo males | No difference in acute hypertension, plasma glucose elevation, or histopathology. | Higher mortality and greater acute neurological deficits |
| Hamm, 199292 | Central FPI | Rat / Fischer-344 | 3 mo and 20 mo males | No results reported | More severe motor and cognitive deficits |
| Maughan, 200093 | Weight drop | Rat / not specified | 2–3 mo and 20–23 mo males | Forebrain synaptosomal choline uptake decreased in aged but not young | Greater cognitive deficits and slower recovery |
| Nakagawa, 200094 | Lateral CCI | Mouse / heterozygote PDAPP mice and WT littermates | 22–24 mo females | Decrease in abundance of Ab deposits in hippocampus of PDAPP mice ipsilateral to the site of CCI | No results reported |
| Uryu, 200395 | Lateral CCI | Mouse / wild type with B6D2F1 background; alpha-synuclein knockout | 4 mo and 24 mo (wild type); 16 mo (knockouts); sex not reported. | Transient increase of alpha- and beta-synuclein in neuropil and induction of gamma-synuclein in subcortical axons in aged mice | No results reported |
| Shimamura, 200496 | Lateral FPI | Rat / Sprague-Dawley | 3–4 mo and 22–25 mo males | Greater hippocampal expression of BDNF and p21, lower expression of regenerative and repair genes | No results reported |
| Moor, 200697 | Weight drop | Rat / Wistar | 5–6 week and 19–20 mo males | Lower antioxidant mobilization of ascorbate and urate in hippocampus; more severe cell loss and axonal degeneration | No results reported |
| Shah, 200698 | Lateral FPI | Mouse / C57BL/6 | 5–6 mo and 22–25 mo males | Higher basal expression of BDNF, IL-1beta, and caspase-3, but no trauma-related differences | Higher mortality |
| Shao, 200699 | Lateral CCI | Rat / Fischer-344 | 3 mo, 12 mo, and 22 mo males | Higher lipid peroxidation, lower antioxidant activity, and greater tissue loss | No results reported |
| Cutler, 2007100 | Bilateral frontal CCI | Rat / Fischer-344 | 20 mo males | Progesterone treatment after TBI decreased expression of inflammatory and apoptotic factors (COX-2, IL-6, and NFkappaB) | Improved short-term locomotor recovery after TBI and progesterone treatment |
| Onyszchuk, 200884 | Lateral CCI | Mouse / C57BL/6 | 5–6 mo and 21–24 mo males | Prolonged cerebral edema, increased opening of BBB, more neurodegeneration | Worse sensorimotor recovery |
| Sandhir, 200884 | Lateral CCI | Mouse / C57BL/6 | 5–6 mo and 21–24 mo males | Enhanced and prolonged elevation of markers of reactive astrocytes and microglia | No results reported |
| Anderson, 200986 | Lateral CCI | Mouse / C57BL/6 | 5–6 mo and 23–24 mo males | Attenuated injury response in HIF-1alpha and related neuroprotective genes | No results reported |
| Kasturi, 2009101 | Bilateral frontal CCI | Rat / Fischer-344 | 30 mo and 20 mo ovariectomize d females | Post-traumatic edema reduction lower in aged rats with progesterone treatment | No results reported |
| Gilmer, 2010102 | Lateral CCI | Rat / Fischer-344 | 3–5 mo and 22–24 mo males | Greater post-injury dysfunction and oxidative stress in synaptic mitochondrial fraction | No results reported |
| Sandhir, 2010103 | Lateral CCI | Mouse / C57BL/6 | 5–6 mo and 22–24 mo males | Differential expression of pro-inflammatory regulators C/EBP beta, delta, and CHOP | No results reported |
| Cekic, 2011104 | Bilateral frontal CCI | Rat / Fischer-344 | 22 mo males | Increased baseline brain inflammation, exacerbated injury response, and attenuated benefits of progesterone after TBI in Vitamin-D deficient rats | Progesterone + vitamin D rescued post-injury deficits on open field activity test |
| Wali, 2011105 | Bilateral frontal CCI | Rat / Fischer-344 | 20 mo males | Lesion cavity size not affected by progesterone treatment in aged rats | Progesterone improved locomotor and cognitive recovery in aged rats after TBI |
| Lee, 201258 | Lateral CCI | Mouse / C57BL/6 | 4–6 mo and 21–14 mo males | Greater BBB permeability and matrix metalloproteinase activity, impaired BBB repair responses | No results reported |
| Li, 2012106 | Lateral CCI | Rat / Wistar | 20 mo males | Improved hippocampal LTP; increased endothelial progenitor cells, increased blood vessel density after TBI and progesterone treatment | Progesterone improved mNSS and water maze performance after TBI in aged rats |
| Timaru-Kast, 2012107 | Lateral CCI | Mouse / C57BL/6 | 2 mo and 21 mo males | Greater cerebral edema and altered pattern of neuroinflammation; no difference in contusion volumes | Higher mortality and worse mNSS |
| Itoh, 201387 | Lateral CCI | Rat / Wistar | 10 week and 24 mo males | Larger lesion size, greater increase in markers of oxidative damage and apoptosis | Greater cognitive deficit on water maze |
| Itoh, 2013108 | Lateral CCI | Rat / Wistar | 10 week and 24 mo males | Decreased NSC proliferation and increased level of lipid peroxidation | No results reported |
| *Gupta, 2013109 | Weight drop | Mouse (short lifespan AKR strain) | 20 week and 70 week malesa | Earlier post-TBI decrease in expression of potassium channel and glutamate transporter-1 expression | No results reported |
| Hawkins, 2013110 | Lateral FPI plus hemorrhagic hypotension | Rat / Sprague-Dawley | 4–6 and 20–24 mo males | Greater reduction in MAP and CBF; no age difference in hippocampal neuronal injury | No results reported |
| Kumar, 2013111 | Lateral CCI | Mouse / C57BL/6 | 3 mo and 24 mo males | Pro-inflammatory microglia/macrophage activation state in cortex and sub-cortical regions; larger lesion volume and greater neuronal loss in hippocampus and thalamus | No results reported |
| Sun, 2013112 | Lateral FPI | Rat / Sprague-Dawley | 1mo and 24 mo males | Higher number of TUNEL(+) cells in aged hippocampal dentate gyrus | No results reported |
| *Ojo, 2013113 | Single or repetitive closed head mild CCI | Mouse / Human Tau mice on a C57BL/6 background | 18 mo males and females | Increased phosphortau immunoreactivity and astrocyte / microglia activation after repetitive mild TBI, but not single mild TBI; no perivascular tau pathology, neuritic threads, orastrocytic tangles | No results reported |
| Tajiri, 2014114 | Lateral CCI | Rat / Fischer-344 | 6 mo and 20 mo males | Reduced efficacy for sparing cortical damage and hippocampal cell loss in aged rats treated with stem cells | Reduced efficacy in motor and cognitive recovery after TBI in aged rats treated with stem cells |
| Gupta, 2016115 | Weight drop | Mouse / (short lifespan AKR strain) | 20 week and 70 week malesb | Interactions of NF-κB and N-myc with GLT-1/EAAT2 promoter sequences in ipsilateral cortex of aged mice initiated immediately | No results reported |
| Morganti, 2016116 | Lateral CCI | Mouse / C56BL6/J (wild type); Dbl-Het | 3mo and 23 mo males and females | Greater accumulation of peripherally derived CCR2(+) macrophages | No results reported |
| *Wang, 2016117 | Lateral CCI | Mouse / C57BL/6 | 2–4 mo and 16–18 mo males | Reduced neuronal damage, oxidative stress response, mitochondrial dysfunction, and SIRT3 expression in aged mice with TBI and treatment with fucoidan | Reduced deficits on beam walk and Barnes maze after TBI and treatment with fucoidan |
| Portbury, 2017118 | Lateral CCI | Mouse / C57BL/6 | 24 mo males | Elevated iron and copper levels after TBI; delayed reduction in zinc | No results reported |
| Chou, 2018119 | Lateral CCI | Mouse / Dbl-Het; CCR2RFP/+; CCR2RFP/RFP | 3–6 mo and 20–25 mo males | Enhanced and prolonged brain elevation of peripherally-derived monocytes after TBI | Greater cognitive deficit on radial arm water maze |
| *Krukowski, 2018120 | Lateral CCI | Mouse / C57BL6/J (wild type); C3−/− | 19 mo males and females | Prolonged brain inflammatory response measured at 30 days post TBI | Blockade of complement pathway prevented cognitive deficits after TBI in aged mice. |
| Gupte, 2019121 | Lateral CCI | Rat / Fischer-344 | 20–22 mo males | Treatment with taurine did not significantly reduce brain tissue damage after TBI | Treatment with taurine did not improve sensorimotor function after TBI |
| *Ritzel, 201955 | Lateral CCI | Mouse / C57BL/6 | 3 mo and 18 mo males | Exaggerated microglial response and increased leukocyte invasion | More severe motor deficits, spontaneous locomotor activity, and anxiety-like behavior |
a
In studies with different age groups or with different strains, results refer to older cohorts in comparison to younger cohorts. or transgenic strains in comparison to wild-type strains.
b
While mice in the Gupta, et al., 2013 study were only 70 weeks, this strain has a relatively short lifespan of only 75 ± 5 weeks, and thus, is included.
Abbreviations: BBB: Blood-brain barrier; BDNF: Brain-derived neurotrophic factor; CBF: Cerebral blood flow; CCI: Controlled cortical impact; ; C/EBP: CCAAT/enhancer binding protein; CHOP: CCAAT/enhancer binding protein homologous protein; COX: Cyclooxygenase; Dbl-Het: (mouse strain): CX3CR1GFP/+CCR2RFP/+ (double heterozygous); FPI: Fluid percussion injury; HIF-1alpha: Hypoxia-induced factor-1 alpha; IL: Interleukin; MAP: Mean arterial pressure; mNSS: modified neurological severity score; NFkappaB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NSC: Neural stem cell; PDAPP: transgenic (TG) mice with a mutant human Ab precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter resulting in overexpression of mutant APP (V717F); TBI: traumatic brain injury; TNF: Tumor necrosis factor.
*
Studies using animals 18–19 mo of age in italics.