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learn from studying the net effects of specific PDE4D
polymorphisms on enzyme activity. Additional clinicalgenetic analyses may also be able to define the relationship between PDE4D genotype and specific features of
stroke such as functional outcome or risk of stroke recurrence.
Advocates of research into human disease genetics
often point to the possibility that new genes will lead
to new drugs. In the case of PDE4D, these hopes may
be well grounded given the relatively advanced state of
PDE4-related drug design.13 Many fundamental questions will need to be answered before clinical trials can
be considered, however. If PDE4D genotype is indeed
associated with stroke risk, does stroke arise from too
much PDE4D activity, too little activity, or dysfunctional regulation? Does PDE4D affect the genesis of
thromboembolism (dictating some type of chronic preventative treatment) or the brain’s response to acute
ischemic injury (thereby favoring acute abortive treatment)? Though the study by Meschia and colleagues
brings new evidence for a role for PDE4D in stroke,
there are clearly many layers of puzzles to be solved
before this PDE4D puzzlebox can be opened.
11. Barad M, Bourtchouladze R, Winder DG, et al. Rolipram, a
type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci USA 1998;95:
15020 –15025.
12. Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases:
modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 2003;370:1–18.
13. Card GL, Blasdel L, England BP, et al. A family of phosphodiesterase inhibitors discovered by cocrystallography and
scaffold-based drug design. Nat Biotechnol 2005;23:201–207.
14. Leblanc GG, Meschia JF, Stuss DT, Hackinski V. Genetics of
vascular cognitive impairment. The opportunity and the challenges. Stroke 2005:in press.
Steven M. Greenberg, MD, PhD
Jonathan Rosand, MD, MSc
Imaging reorganization of structure–function relationships after stroke has become a major source of excitement and controversy. When functional imaging was
introduced, investigators of poststroke aphasia believed
the methodology would transparently reveal the areas
of brain that assume language functions of the damaged region. But the results of studies that were at least
superficially asking the same question showed different
answers. For example, results of some functional imaging (positron emission tomography [PET] or functional magnetic resonance imaging [fMRI]) studies of
patients who had partially recovered language indicated
that left hemisphere perilesional areas assumed lost language functions,1– 4 whereas others found that right
hemisphere homologues of damaged areas assumed
these functions.5–11 One possible account of the apparently conflicting results is that both right hemisphere
regions and spared left hemisphere regions contribute
to recovery, depending on the extent of left hemisphere
damage, time after onset, and the language function.
For example, the right hemisphere may be capable of
assuming certain language functions, but not others.
However, recent studies have presented more complexities. Some studies have shown that the right hemisphere “activation” seen on functional imaging may be
nonfunctional or even detrimental. Temporarily interfering with function using slow repetitive transcranial
magnetic stimulation (rTMS) of the right hemisphere
sites that show increased BOLD signal on fMRI only
sometimes interferes with language. Such suppression
may even facilitate language, indicating that the observed language-related signal changes in the right
Neurology Clinical Trials Unit
Massachusetts General Hospital
Boston, MA
1. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet Med
2002;4:45– 61.
2. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, et al. The
gene encoding phosphodiesterase 4D confers risk of ischemic
stroke. Nat Genet 2003;35:131–138.
3. Meschia JF, Brott TG, Brown RD, et al. Assessing the roles of
phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating
protein (ALOX5AP) in ischemic stroke. Ann Neurol 2005;58:
4. Bevan S, Porteous L, Sitzer M, Markus HS. Phosphodiesterase
4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis. Stroke 2005;36:949 –953.
5. Lohmussaar E, Gschwendtner A, Mueller JC, et al. ALOX5AP
gene and the PDE4D gene in a central European population of
stroke patients. Stroke 2005;36:731–736.
6. Song Q, Cole J, O’Connell J, et al. Phosphodiesterase 4D polymorphisms and risk of cerebral infarction in a biracial population. The Stroke Prevention in Young Women Study. Stroke
(abs) 2005;36:457.
7. Woo D, Kaushal R, Kissela BM, et al. Haplotype association of
PDE4D with ischemic stroke. Neurology (abs) 2005;P01.092.
8. Rosand J, Altshuler D. Human genome sequence variation and
the search for genes influencing stroke. Stroke 2003;34:
9. Sacco RL. Newer risk factors for stroke. Neurology 2001;57:
10. Byers D, Davis RL, Kiger JA, Jr. Defect in cyclic AMP phosphodiesterase due to the dunce mutation of learning in Drosophila melanogaster. Nature 1981;289:79 – 81.
DOI: 10.1002/ana.20623
Can Shift to the Right Be a
Good Thing?
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
hemisphere may reflect neural activity that interferes
with language.12 Furthermore, results of functional imaging studies in subjects with poststroke aphasia may
be complicated by vascular disease in the left hemisphere. The BOLD effect in fMRI depends on a hemodynamic response to neural activation that is disproportionate to oxygen extraction in that area. In
patients with severe arterial stenosis, impaired vascular
reactivity may preclude the normal hemodynamic response to neural activation.13 In these patients, neural
activity may be associated with no BOLD effect14 or
even a negative BOLD effect, because of increased oxygen extraction without a corresponding increase in
blood flow.
In this issue, Vandenbulke and colleagues report results of an fMRI study of neural activation associated
with semantic association tasks using words or pictures
in 19 patients with primary progressive aphasia (PPA)
compared with 19 patients with mild cognitive impairment and 14 neurologically normal volunteers.15 In
PPA, fMRI results are presumably not complicated by
vascular disease. The investigators found that control
subjects showed left greater than right anterior temporal activation during the semantic task compared with
a visuospatial control task with similar stimuli. In comparison, patients with PPA showed more right than left
anterior temporal task-associated BOLD effect. The
apparent shift in laterality was greater for patients with
word comprehension deficits, who also showed more
left temporal atrophy. There was a strong negative correlation between right anterior temporal responses and
accuracy on several tests of word meaning, including
word comprehension, verbal associative semantic
scores, and naming.
A critical question raised by these results is what
does the right hemisphere activation reflect? One possibility (preferred by the authors) is that it reflects reorganization, a shift of processes involved in word
comprehension from the left to the right hemisphere.
In this case, the right hemisphere would have to be less
competent in this task than the left, because word
comprehension was poorer in those with right hemisphere activation. Another potential explanation is that
the right anterior temporal activation is somehow maladaptive, causing the word comprehension deficit and
poor performance on the semantic tasks. This explanation is implausible. Although right anterior temporal
activation could inhibit left anterior temporal function,
it is unlikely that right anterior temporal activation
would increase as a primary phenomenon in PPA.
A third account is that the right anterior temporal
lobe is normally involved in processing word meaning,
but it represents meaning in a different way that does
not permit discernment between semantically related
words. For example, semantic representations in the
right anterior temporal lobe might specify information
such as the facts that fangs are dangerous and that rattlesnakes, copperheads, and wolves have fangs, but no
information that would specify the difference between
rattlesnakes, copperheads, and wolves. This sort of semantic knowledge would be useful in everyday life, allowing gross generalizations based on perceptual features of unfamiliar stimuli (leading us to avoid contact
with fangs). Semantic representations in the left anterior temporal lobe might represent the distinctions between these animals, required for naming, word comprehension, and the semantic association tasks used by
the authors. Therefore, normally, activation would be
greater in the left hemisphere during this semantic association task (as observed for control subjects). However, when the left anterior temporal lobe is dysfunctional (as indicated by the left anterior temporal
atrophy in the PPA patients with comprehension deficits), the subject would rely more on the relatively
spared right anterior temporal semantic system to attempt the task, accounting for the shift in laterality to
the right in these patients. Reliance on this right hemisphere region would explain frequent errors by PPA
patients on the semantic association test used in the
fMRI study, because a correct response requires the
ability to distinguish between related objects. It would
also account for their frequent semantic paraphasias in
naming and poor word comprehension. On this account, the greater activation of right anterior temporal
cortex in patients with PPA with comprehension deficits would just reflect dysfunction of left anterior temporal cortex, requiring greater reliance on the right
hemisphere semantic system. In this case, the increased
BOLD effect would reflect somewhat beneficial activation, rather than maladaptive or neutral activation.
However, it would not represent reorganization—just a
greater reliance on the normal right anterior temporal
semantic system, which is inadequate to support consistently accurate performance on tasks with semantically related foils.
In short, results reported by Vandenbulke and coworkers raise more questions than they answer. Nevertheless, they provide important new data to complement data from imaging studies of aphasia recovery
after stroke. Longitudinal functional imaging studies of
language deterioration in PPA might provide additional insights. The puzzle is not yet complete, but the
pieces are beginning to form parts of a picture.
Argye E. Hillis, MD, MA
Department of Neurology
Johns Hopkins University School of Medicine
Baltimore, MD
Hillis: Can Shift to the Right Be a Good Thing?
1. Karbe H, Kessler J, Herholz K, et al. Long-term prognosis of
poststroke aphasia studied with positron emission tomography.
Arch Neurol 1995;52:186 –190.
2. Heiss WD, Kessler J, Thiel A, et al. Differential capacity of left
and right hemispheric areas for compensation of post-stroke
aphasia. Ann Neurol 1999;45:430 – 438.
3. Warburton E, Swinburn K, Price CJ, et al. Mechanisms of recovery from aphasia: evidence from positron emission tomographic studies. J Neurol Neurosurg Psychiatry 1999;66:
4. Thiel A, Herholz K, Koyuncu A, et al. Plasticity of language
networks in patients with brain tumors: a positron emission tomography activation study. Ann Neurol 2001;50:620 – 629.
5. Weiller C, Isensee C, Rijntjes M, et al. Recovery from Wernicke’s aphasia: a positron emission tomographic study. Ann
Neurol 1995;37:723–732.
6. Ohyama M, Senda M, Kitamura S, et al. Role of the nondominant hemisphere and undamaged area during word repetition in
poststroke aphasics. A PET activation study. Stroke 1996;27:
7. Cappa SF, Perani D, Grassi F, et al. A PET follow-up study of
recovery after stroke in acute aphasics. Brain Lang 1997;56:
55– 67.
8. Thulborn KR, Carpenter PA, Just MA. Plasticity of languagerelated brain function during recovery from stroke. Stroke
1999;30:749 –754.
9. Musso M, Weiller C, Kiebel S, et al. Training-induced brainplasticity in aphasia. Brain 1999;122:1781–1790.
10. Thompson CK, Fix SC, Gitelman DR, et al. fMRI studies of
agrammatic sentence comprehension before and after treatment.
Brain Lang 2000;74:387–391.
11. Leff A, Crinion J, Scott S, et al. A physiological change in homotopic cortex following left posterior temporal lobe infarction.
Ann Neurol 2002;51:553–558.
12. Naeser MA, Martin PI, Nicholas M, et al. Improved picture
naming in chronic aphasia after TMS to part of right Broca’s
area: an open-protocol study. Brain Lang 2005;93:95–105.
13. Marshall RS. The functional relevance of cerebral
hemodynamics: why blood flow matters to the injured and recovering brain. Curr Opin Neurol 2004;17:705–709.
14. Rossini PM, Altamura C, Ferretti A, et al. Does cerebrovascular
disease affect the coupling between neuronal activity and local
hemodynamics? Brain 2004;127:99 –110.
15. Vandenbulke M, Peeters R, Van Hecke P, et al. Anterior temporal laterality in primary progressive aphasia shifts to the right.
Ann Neurol 2005;58:362–370.
DOI: 10.1002/ana.20621
Cerebral Amyloid
Angiopathy: Both Viper
and Maggot in the Brain
Cerebral amyloid angiopathy (CAA) is characterized by
the accumulation of amyloid ␤ (A␤) and other amyloidogenic peptides in the walls of capillaries and arter-
ies of the brain1,2 and presents with a range of clinical
and pathological features. At the acute end of the neurological spectrum, CAA sits as a “viper” in the brain
waiting to strike as sudden intracerebral hemorrhage
(ICH) in the elderly. This aspect of CAA is emphasized in the article by Rosand and colleagues3 in this
issue of the Annals. The authors analyzed the spatial
distribution of large and small hemorrhages in the
brains of 59 patients with probable CAA-related ICH.
Using gradient-echo magnetic resonance imaging, the
authors attained a more accurate picture of the location
of 321 initial hemorrhages and 24 symptomatic recurrent hemorrhages than can be obtained by clinical or
pathological examinations. The results of the study
show that hemorrhages clustered preferentially in the
temporal and occipital lobes.
At the other end of the neurological spectrum is the
association of CAA with Alzheimer’s disease (AD), a
syndrome that gnaws at the brain like a “maggot” with
slowly progressive decline in cognition, personality, and
To devise effective prevention and therapy for
CAA, we need to know why CAA occurs and how it
relates to ICH and AD. It is clear that at least two
steps are required in the pathogenesis of CAA-related
hemorrhage: first, accumulation of A␤ in the walls of
cerebral vessels, a common feature of aging and of
AD; second, rupture of A␤-laden blood vessels, which
is relatively uncommon and occurs in association with
specific vasculopathic features such as fibrinoid necrosis and formation of microaneurysms. The study by
Rosand and colleagues3 provides important new information about the distribution of CAA-related
hemorrhages in the brain and how cerebral regions
supplied by the posterior circulation (ie, the vertebral
arteries rather than the carotid arteries) seem more
Studies involving transgenic mice5,6 and human
neuropathology7,8 suggest that CAA results largely
from the entrapment of insoluble fibrillary A␤ and
other amyloidogenic peptides in the perivascular
pathways by which interstitial fluid (ISF) drains from
the brain.9
Experimental studies have shown that ISF drains
from the brain along basement membranes of capillaries and arteries10,11 and that this route is effectively
the “lymphatic drainage” of the brain.12 A␤ appears
to drain from the brain along the same perivascular
route as ISF.13 As CAA develops with advancing age,
A␤ is initially deposited as insoluble fibrils of amyloid
in basement membranes of cortical and leptomeningeal arteries.7,14 With increasing severity of CAA, insoluble deposits of A␤ replace basement membranes
and smooth muscle cells in the artery walls2 with two
major effects. First, the artery walls become brittle
and are more likely to rupture and bleed; second, the
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
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