Page 37 - NNS 2014 Program & Abstract Book

quantify select pro- (IL-1ß, IL-6, IFN-

c

, TNF-

a

) and anti- (IL-4, IL-10)

inflammatory cytokines. After normalizing each cytokine to baseline

levels per patient, hierarchical clustering was used to generate den-

drogram heat maps using Pearson correlated row distance measures and

pairwise average-linkage clustering. Each cytokine dendrogram heat

map was examined to determine if rows (patients) stratified according

to treatment group.

Hierarchal clustering and dendrogram heat map generation identi-

fied IL-1

b

, IL-4 and TNF-

a

as cytokines where the dendrogram pat-

tern correlated with the assigned treatment groups. The dendrogram

clustering also demonstrated a treatment dose dependent reduction for

the pro-inflammatory cytokines (IL-1

b

and TNF-

a

) and increase for

the anti-inflammatory cytokine (IL-4) levels from 24–96 hours.

Our study suggests that hierarchical clustering and dendrogram

heat mapping may be used to identify plasma cytokines associated

with the treatment effect of cell therapy. The treatment effect of intra-

venous autologous bone marrow mononuclear cells for TBI in the

acute setting appears to be most associated with the reduction of pro-

inflammatory IL-1

b

and TNF-

a

levels and increase of anti-inflammatory

IL-4 levels.

Key words

biomarker, cell therapy, clincal trial, inflammasome, inflammation

T1-09

INVERSE NEUROVASCULAR COUPLING TO CORTICAL

SPREADING DEPOLARIZATIONS IN SEVERE BRAIN

TRAUMA

Hinzman, J.M.

1

, Andaluz, N.

1

, Shutter, L.A.

2

, Okonkwo, D.O.

2

,

Pahl, C.

3

, Strong, A.J.

3

, Dreier, J.P.

4

, Hartings, J.A.

1

University of Cincinnati, Cincinnati, United States

2

University of Pittsburgh, Pittsburgh, United States

3

Kings College, London, UK

4

Charite University, Berlin, Germany

Cortical spreading depolarization (CSD) causes breakdown of elec-

trochemical gradients following TBI, but also elicits dynamic changes

in regional cerebral blood flow (rCBF) that range from physiologic

neurovascular coupling (hyperemia) to pathological inverse coupling

(hypoperfusion). The purpose of this study was to determine whether

pathological inverse neurovascular coupling occurs as a mechanism of

secondary injury. In 24 TBI patients requiring craniotomy, CSDs were

monitored with subdural electrode strips and rCBF was measured with

a parenchymal thermal diffusion probe. The status of cerebrovascular

autoregulation was monitored as a correlation between blood pressure

and rCBF. The rCBF response to CSD was obtained for 196 events in

5 patients. In one patient with intact cerebrovascular autoregulation,

CSD induced only hyperemic responses (794% increase), while an-

other patient with impaired autoregulation exhibited only the inverse

(hypoperfusion) response (

-

24% decrease). By contrast, three pa-

tients exhibited dynamic changes in neurovascular coupling to CSDs

through the course of monitoring. One exhibited increasing severity of

the pathological inverse response (

-

14%,

-

29%,

-

79% decrease,

p

<

0.05) that coincided with progressive worsening of cerebro-

vascular autoregulation (Pearson coefficient 0.04, 0.14, 0.28,

p

<

0.05). Another exhibited a transformation from physiological

hyperemic coupling (44% increase) to pathological inverse cou-

pling (

-

30% decrease) (p

<

0.05) that coincided with a loss of

autoregulation (Pearson coefficient 0.19

/

0.32, p

<

0.05). Patho-

logic inverse coupling was only observed with electrodes placed in

or adjacent to evolving lesions. Patients with good 6-month out-

comes had higher perfusion (46.8

–

6.5 ml/100 g/min) than patients

with poor outcomes (32.3

–

3.7 ml/100 g/min) (p

<

0.05). These re-

sults establish inverse neurovascular coupling to CSD as a novel

mechanism of secondary injury in TBI and suggest that CSD, the

neurovascular response, cerebrovascular autoregulation, and is-

chemia are critical processes to monitor and target therapeutically

in the management of brain injury.

Key words

cortical spreading depolarization, ischemia, neurovascular coupling,

regional cerebral blood flow

T1-10

GENETICALLY-MODIFIED NEURAL PROGENITOR CELL

TRANSPLANTATION FOR THE TREATMENT OF TRAU-

MATIC BRAIN INJURY

Blaya, M.O.

, Tsoulfas, P., Furones-Alonso, O., Bramlett, H.M.,

Dietrich, W.D.

University of Miami Miller School of Medicine, Miami, USA

Traumatic brain injury (TBI) represents a serious public health

problem as there are no clinically-available treatments to mitigate

the functional consequences experienced by patients. Neural pro-

genitor cells (NPCs) hold significant promise as a potential treatment

strategy for TBI due to the numerous intrinsic advantages of the

cells, including the secretion of neurotrophic factors. Neurotrophins

are critical for neuronal repair and survival, but their clinical use

after injury is limited by differential binding specificities, short half-

lives, and complicated delivery issues. We hypothesized that peri-

contusional transplantation of NPCs that were genetically modified

to secrete a synthetic, human multineurotrophin (MNTS1) would

overcome some of the limitations of traditional neurotrophin ther-

apy. MNTS1 is a multifunctional, multitargeting neurotrophin that

recapitulates the combined biological activity of three neurotrophins

and induces the prosurvival signaling activity of all three tropomyosin-

related kinase (Trk) receptors. NPCs were obtained from Sprague-

Dawley fetuses at embryonic stage E15 and transduced with either

GFP and MNTS1 constructs (MNTS1-NPCs) or with a GFP con-

struct alone (control GFP-NPCs). Adult rats received moderate fluid

percussion-induced TBI or sham surgery. Animals were transplanted

1 week later with either control GFP-NPCs, MNTS1-NPCs, or in-

jected with saline (vehicle). Five weeks after surgery, animals were

evaluated for hippocampal-dependent spatial memory and then sac-

rificed for immunohistochemical analyses. Six weeks after TBI, we

observed significant survival and neuronal differentiation of MNTS1-

NPCs, as well as injury-activated migration towards contused brain

regions. NPCs displayed long processes with spine-like formations

that extended into cortical and subcortical structures, including the

hippocampus and contralateral hemisphere. Transplanted NPCs, ir-

respective of transduction profile, conferred significant preservation of

pericontusional host tissues and enhanced endogenous hippocampal

neurogenesis in the posttraumatic brain. Furthermore, NPC transplan-

tation significantly improved spatial memory capacity on the hippo-

campal-dependent Morris water maze task. Transplant recipients

exhibited escape latencies approximately half that of injured vehicle

controls. Our findings support the potential of NPC transplantation and

multineurotrophin therapy to enhance endogenous neuroreparative re-

sponses, and therefore may be an effective treatment for TBI.

Key words

adult hippocampal neurogenesis, learning and memory, neural pro-

genitor cell transplantation, neuroprotection, traumatic brain injury

A-5