NNS 2015 Program & Abstract Book

Intro:

In 1977, Torch et al. (NEUROLOGY 27:1157) described

LATND in a 64 y.o. man who died after an 8-yr history of progressive

behavioral-cognitive encephalopathy associated with sleep & auto-

nomic disturbance, memory loss, dementia, & left temporal EEG

slowing. At autopsy a large old left hippocampal cystic infarct was

noted with atrophy of the ipsilateral 1) fimbria/fornix [Fx], 2) mam-

milary body [MB] & hypothalamus [HT], 3) mammillothalamic tract

[MTT], anterior thalamus [AT], and 4) cingulum (Papez Circuit).

Clinical decline was attributed to 1

, 2

& 3

LATND. To determine its

prevalence in adult & childhood, 128 published autopsy cases of hip-

pocampal injury in 4 major categories were reviewed: Group A) stroke

[49 cases]; Group B) TBI/surgical [24 cases]; Group C) encephalitis [41

cases]; Group D) kernicturus [14 cases]. 24 additional cases included:

E) hippocampal sclerosis with TLE; F) neoplasm & carcinomatous-

vasculitis; G) hyperinsulin-induced hypoglycemia; H) neurodegenera-

tive child- & adult-onset Atypical & Familial Alzheimer’s Disease, and

Dementia Infantilis with schizophrenic-autistic features.

Methodology:

Etiology, rate & degree of LATND, using a grad-

uated scale of microscopic to grossly visible atrophy, was tabulated

with symptomatology, as a function of survival time (ST, the period

time from symptom-onset to death).

Results:

Uni- and/or bilateral 1

- 3

LATND was observed following

uni- or bilateral: A) hippocampal stroke [14L:14R:12L/R]; B) progres-

sive boxing-induced TBI/CTE (dementia-pugilistica) & temporal lobe

surgery/fornicotomy [1L:5R:18L/R]; C) limbic enchephalitis & carci-

nomatous vasculits [3L:1R:37L/R]; D) kernicterus/hypoxemia [14L/R].

Limbic degeneration was identified in 65% of stroke-, 75% of TBI-, 37%

of encephalitis-, and 21% of kernicterus-affected hemispheres [a total of

194 hemispheres]. Average age of symptom-onset was: infarction, 59y;

TBI, 38y; encephalitis, 36y; kernicterus, 2.5d. In most cases the extent &

degree of symetrical or asymetrical LATNDwas linearly related to ST. In

stroke, rate of progression was: Fx, 4mos; MB, 6–8mos; HT, 1.5 yr;

MTT-AT, 3y 8mos-5 yrs; in TBI: Fx, 4–5mos; MB, 1–2.5 yr; HT, 5–

11 yr; MTT-AT, 12–15 yrs. Rates of LATND progressed in the order:

encephalitis

kernicterus

stroke

TBI, where mean ST was: ker-

nicterus (2y), encephallitis (3.4y), infarction (3.9y), TBI (13.3y). Mem-

ory loss was most common in left or bilateral stroke, with apathy or

emotional mood-related agitation & lability occurring in early LATND,

with hallucinatory, paranoid, psychotic schizophrenic behavior & de-

mentia 2–4 yrs later associated with degeneration of the anterior thala-

mus. TBI-dementia was seen after 5–10 y; encephalitic-dementia, after

3mos-2y; kernicterus-related retardation after 1.5–2 y, also correlating

with advancing anterior thalamic diencephalic degeneration.

Conclusion:

LATND is commonly over-looked because of inade-

quate brain-sectioning & microscopic inspection, or lack of awareness

of the process. LATND may account for early ‘‘positive’’ & later

‘‘negative’’ symptoms, as in ‘‘burned-out’’ stages of schizophrenia

(e.g., dementia praecox), where early symptoms reflect hippocampal-

diencephalic deafferentation, denervation-hypesensitivity or dysinhi-

bition, followed by progressive LATND.

Future Research:

Literature review of high-resolution CT, MRI,

DTI, fMRI, PET, SPECT, MEG studies performed to-date, demon-

strates that LATND may be a valid radiological biomarker in various

hippocampal-sensitive conditions (e.g., AD, FTL/tau/prion & other

human dementias, sports & military-related TBI/CTE, hypoxemia,

hypo-glycemia, vasculitis, physical abuse/neglect with secondary cor-

tisol/stress-induced PTSD). LATND, as a human & animal bio-model,

holds future research promise in developing novel pharmacological and

neuro-protective strategies for its prevention or reversal, including

better helmet design for contact sports (e.g., boxing, football).

Keywords: Traumatic Brain and Other Hippocampal Injury,

Hippocampal-Limbic Trans-neuronal Degeneration, Progressive Co-

gnitive Dementia, Chronic Traumatic Encephalopathy, Traumatic and

other Hippocampal Injury

B2-04

EMERGING ROLE OF GAPDH IN TBI INDUCED AMYLOI-

DOSIS

Tiffany Greco

, David Hovda, Mayumi Prins

UCLA, Neurosurgery, Los Angeles, USA

TBI is a risk factor for developing Alzheimer’s disease (AD), but TBI-

induced mechanisms initiating AD are unknown and controversial.

Oxidative stress (ROS) plays a role in AD and TBI. Many critical pro-

teins are susceptible to oxidative modification, including GAPDH. It’s

known for its role as a redox-sensitive enzyme in glycolysis. However,

it’s a multifunctional protein involved in several cellular pathways. In-

jury or disease induced post-translational modifications alter its structure

and activity allowing it to perform new and likely aberrant roles. These

pathologic functions are not understood in disease generation or pro-

gression. In AD models, GADPH binds with beta-amyloid precursor

protein (BAPP) and amyloid beta (AB) and is found in plaques, sug-

gesting a role in amyloidosis, yet it’s not known where in the pathway it

acts. We hypothesize oxidative modification of GADPH facilitates

translocation to and binding of BAPP and AB formation. Contusion-

injured PND35 male rats were fed standard (STD) or ketogenic diet

(KD). Ipsilateral cortex was isolated at 1, 3, 6 and 24 hrs post-injury and

the following were quantified: GAPDH S-nitrosylation (GAPDH-SNO),

coimmunoprecipitation of GAPDH, BAPP and AB, and cytosolic AB.

STD animals show peak GAPDH-SNO at 1 hr followed by increased

interaction between GAPDH and BAPP by 3 hrs. As interaction between

GAPDH and BAPP decreased, those between GAPDH and AB increased

in tandem with cytosolic AB. By 6 hrs, KD decreased production of AB.

At 24 hrs, KD prevented increased interaction between both GAPDH,

BAPP and AB. This is the first study to show GAPDH is involved in the

immediate molecular cascade of events that may trigger AD. Once bound

to BAPP, GAPDH may recruit or activate

-secretase. GAPDH may

facilitate AB plaque formation as it can dimerize and form aggregates

similar to AB. If these events are regulated by ROS generation, it would

be expected to see inhibition of this pathway with antioxidant adminis-

tration. Our study is limited by KD ad-lib feeding which takes several

hours for ketones to reach the brain. This is seen at 6 hrs, where little

effect of KD was shown compared to 24 hrs. Future studies utilizing

intravenous administration of ketones would resolve this. In summary,

this study highlights the need to maintain redox balance post-injury as

pathological amounts of ROS induce pathological signaling pathways.

Acknowledgments

NFL Charities, UCLA BIRC, Anderson Fellowship, NS058489-01,

NS27544

Keywords: traumatic brain injury, GAPDH, amyloid beta, Alzhei-

mer’s Disease, oxidative stress

B2-05

HIPPOCAMPAL DEGENERATION AFTER TRAUMATIC

BRAIN INJURY: THE ROLES OF THE PGE2 EP1 RECEPTOR

Alexander V Glushakov, Jennifer M Galvis, Somantha L Solaski,

Sylvain Dore

University of Florida, Anesthesiology, Gainesville, USA

Over the past decade, PGE2 EP1 receptor blockers have been studied

as a promising strategy for the treatment of neurological disorders and

as a potential safer alternative to the cyclooxygenase-2 inhibitors.

Preclinical data have demonstrated their efficacy in the treatment of

ischemic and excitotoxic conditions by improving behavioral and

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