The long-term goal of our research is to develop
more effective methods for the prevention and
treatment of stroke. Our group uses clinical,
neuroimaging and genetic characterization of
patients with stroke in order to improve understanding
of the risk and clinical course of cerebrovascular
disease. In addition to our broad-based genetic
studies, we continue to enroll patients with
hemorrhagic and ischemic stroke in longitudinal
studies of stroke outcome. All or our efforts
involve collaborations with other groups, within
the Department of Neurology, the Center for
Human Genetic Research, the Broad Institute,
the Martinos Center for Biomedical Imaging,
and the University of Cincinnati.
Genetic studies
Accumulating data suggest that genetic variation
plays a substantial role in stroke risk. Research
in our group is directed at discovering those
so-called “culprit” genetic variants.
A major thrust of our group is the application
of genome-wide association studies in patients
with ischemic and hemorrhagic stroke. We are
founding members of the International Stroke
Genetics Consortium (www.strokegenetics.org),
and our genome-wide association studies are
all conducted in collaboration with Consortium
members. An additional focus of our work is
on the application of genetic discoveries to
bedside decision-making.
Selected references
Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir
S, Holm H, Sigurdsson A, Jonasdottir A, Baker
A, Thorleifsson G, Kristjansson K, Palsson A,
Blondal T, Sulem P, Backman VM, Hardarson GA,
Palsdottir E, Helgason A, Sigurjonsdottir R,
Sverrisson JT, Kostulas K, Ng MC, Baum L, So
WY, Wong KS, Chan JC, Furie KL, Greenberg SM,
Sale M, Kelly P, Macrae CA, Smith EE, Rosand
J, Hillert J, Ma RC, Ellinor PT, Thorgeirsson
G, Gulcher JR, Kong A, Thorsteinsdottir U, Stefansson
K. Variants conferring risk of atrial fibrillation
on chromosome 4q25. Nature. 2007;448:353-357
Rosand J, Bayley N, Rost N, de
Bakker PIW. Many hypotheses but no replication
for the association between pde4d and stroke.
Nat Genet. 2006;38:1091
Eckman MH, Wong LKS, Soo YOY,
Lam W, Yang SR, Greenberg SM, Rosand J. Patient-specific
decision making for warfarin therapy in nonvalvular
atrial fibrillation: How will screening with
genetics and imaging help? . Stroke. 2008;in
press
White matter hyperintensity
The chronic small vessel diseases that lead
to symptomatic stroke can be detected as radiographic
white matter hyperintensity (WMH). WMH, visible
on CT scan and MRI, is the most common manifestation
of cerebrovascular disease in the elderly. Twin,
sibling and pedigree studies have consistently
demonstrated a powerful genetic contribution
to WMH. The volume of WMH measured on MRI strongly
predicts risk of symptomatic stroke and cognitive
decline as well as gait deterioration and late-life
depression. Effective prevention of WMH progression
therefore holds the promise of transforming
the human aging process and markedly reducing
age-related disability for future generations.
Work in our group is directed at discovering
the genetic variants that govern WMH severity
in patients with stroke as well characterizing
the role of WMH in the brain’s response
to ischemic stroke.
Selected References
Ay H, Arsava EM, Rosand J, Furie KL, Singhal
AB, Schaefer PW, Wu O, Gonzalez RG, Koroshetz
WJ, Sorensen AG. Severity of leukoaraiosis and
susceptibility to infarct growth in acute stroke.
Stroke. 2008:STROKEAHA.107.501932
Arsava EM, Rahman RM….Stroke
2009 in press
Intracerebral hemmorhage
Intracerebral hemorrhage (ICH) is the sudden
acute manifestation of chronic progressive diseases
of the cerebral small vessels. The most devastating
type of stroke, it is fatal in up to 50% of
patients, and leaves the majority of survivors
with substantial life-long disability. In a
long-standing cohort study of patients with
ICH, we use data from neuroimaging, clinical
and genetic analyses to identify the biological
underpinnings of ICH, identify those patients
at greatest risk for ongoing hemorrhage and
neurological deterioration in the Emergency
Department, and improve the care currently provided
to ICH patients.
Selected References
Greenberg SM, Eng JA, Ning MM, Rosand J. Microhemorrhages
predict recurrent symptomatic hemorrhage and
clinical decline following lobar hemorrhage.
Stroke. 2004;35:333-333
Rosand J, Muzikansky A, Kumar
A, Wisco JJ, Smith EE, Betensky RA, Greenberg
SM. Spatial clustering of hemorrhages in probable
cerebral amyloid angiopathy. Ann Neurol. 2005;58:459-462
Goldstein JN, Fazen LE, Snider
R, Schwab K, Greenberg SM, Smith EE, Lev MH,
Rosand J. Contrast extravasation on ct angiography
predicts hematoma expansion in intracerebral
hemorrhage. Neurology. 2007;68:889-894
Rost NS, Smith EE, Chang Y, Snider
RW, Chanderraj R, Schwab K, FitzMaurice E, Wendell
L, Goldstein JN, Greenberg SM, Rosand J. Prediction
of functional outcome in patients with primary
intracerebral hemorrhage. The FUNC score. Stroke.
2008:in press.
Kumar…..Rosand. Crit Care Med 2009 in
press
Anticoagulation and ICH
As the most feared complication of chronic anticoagulation,
ICH plays a major role in decision-making for
those patients at high risk for thromboembolic
stroke. Anticoagulation increases the risk of
ICH and worsens the severity of the hemorrhage
when it occurs. Decision modeling suggests that
an individual’s risk for ICH powerfully
affects the risk-benefit balance of anticoagulation.
Work in our group seeks to clarify the risk
factors for anticoagulant-related ICH, the effect
of anticoagulation on ICH severity as well as
identify ways to improve care.
Selected References
Rosand J, Eckman MH, Knudsen KA, Singer DE,
Greenberg SM. The effect of warfarin and intensity
of anticoagulation on outcome of intracerebral
hemorrhage. Arch Intern Med. 2004;164:880-884
Flibotte JJ, Hagan N, O'Donnell
J, Greenberg SM, Rosand J. Warfarin, hematoma
expansion, and outcome of intracerebral hemorrhage.
Neurology. 2004;63:1059-1064
Goldstein JN, Thomas SH, Frontiero
V, Joseph A, Engel C, Snider R, Smith EE, Greenberg
SM, Rosand J. Timing of fresh frozen plasma
administration and rapid correction of coagulopathy
in warfarin-related intracerebral hemorrhage.
Stroke. 2006;37:151-155
Levine JM, Snider R, Finkelstein
D, Gurol ME, Chanderraj R, Smith EE, Greenberg
SM, Rosand J. Early edema in warfarin-related
intracerebral hemorrhage. Neurocrit Care. 2007;7:58-63
Goldstein JN, Rosand J. Te events.
Neurocrit Care. 2008;in press
