In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease C. Fennema-Notestine, S. L. Archibald, M. W. Jacobson, J. Corey-Bloom, J. S. Paulsen, G. M. Peavy, A. C. Gamst, J. M. Hamilton, D. P. Salmon and T. L. Jernigan Neurology 2004;63;989-995

This information is current as of May 14, 2009

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/cgi/content/full/63/6/989

Neurology® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2004 by AAN Enterprises, Inc. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

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In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease C. Fennema-Notestine, PhD; S.L. Archibald, MA; M.W. Jacobson, PhD; J. Corey-Bloom, MD, PhD; J.S. Paulsen, PhD; G.M. Peavy, PhD; A.C. Gamst, PhD; J.M. Hamilton, PhD; D.P. Salmon, PhD; and T.L. Jernigan, PhD

Abstract—Objective: To investigate the regional pattern of white matter and cerebellar changes, as well as subcortical and cortical changes, in Huntington disease (HD) using morphometric analyses of structural MRI. Methods: Fifteen individuals with HD and 22 controls were studied; groups were similar in age and education. Primary analyses defined six subcortical regions, the gray and white matter of primary cortical lobes and cerebellum, and abnormal signal in the cerebral white matter. Results: As expected, basal ganglia and cerebral cortical gray matter volumes were significantly smaller in HD. The HD group also demonstrated significant cerebral white matter loss and an increase in the amount of abnormal signal in the white matter; occipital white matter appeared more affected than other cerebral white matter regions. Cortical gray and white matter measures were significantly related to caudate volume. Cerebellar gray and white matter volumes were both smaller in HD. Conclusions: The cerebellum and the integrity of cerebral white matter may play a more significant role in the symptomatology of HD than previously thought. Furthermore, changes in cortical gray and cerebral white matter were related to caudate atrophy, supporting a similar mechanism of degeneration. NEUROLOGY 2004;63:989 –995

Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disease that affects the striatum and causes motor, behavioral, and cognitive dysfunction. The genetic mutation linked to HD is an expanded polymorphic trinucleotide (cytosine, adenine, guanine: CAG) repeat located on the short arm of chromosome 4.1,2 Although the mechanism of pathologic effects is not known, crosssectional3-9 and longitudinal10 data from neuropathologic and neuroimaging studies suggest that the earliest changes in HD occur in the caudate nucleus. Other regions of the striatum such as the putamen and globus pallidus are also affected, particularly with disease progression,3,8,10,11 with additional neuropathologic evidence of degeneration in the nucleus accumbens3,12 and substantia nigra11 and neuropathologic and neuroimaging evidence of thalamic changes.6,12,13 Recent evidence from neuropathologic and neuroimaging studies suggests that the neurodegenerative Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 28 issue to find the title link for this article.

changes in HD extend to cortical gray matter and cerebral white matter regions,3,5-7,9,12-23 and the onset and progression of these changes are only beginning to be understood.21,24 Neuropathologic studies of cortical gray matter suggest relatively uniform atrophy.20 Morphometric analyses of neuroimaging data indicate that inferior cortical regions, such as orbitofrontal, temporo-occipital, and mesial temporal areas, may be more affected than more superior cortical regions.6 There is also evidence of thinning of the cortical ribbon in HD.12,16,22 Whether such cortical changes observed in HD are secondary to striatal degeneration or the result of a separate primary pathology remains unknown. While some studies show a relationship between cortical degeneration15,20 or metabolic dysfunction5,17 and severity of striatal pathology, numerous neuropathologic studies suggest that the extent of cortical changes in HD may be independent of the degree of striatal pathology.12,16,18 White matter volume loss has been observed in neuropathologic12,13,20 and neuroimaging studies6,19,23 of HD, and may be more severe than the loss of cortical gray matter.12,13,19 It appears to be relatively uniform across the cerebrum13,20 but this has not

From the Veterans Affairs San Diego Healthcare System (Drs. Fennema-Notestine, Jacobson, and Jernigan, and S.L. Archibald), CA; Laboratory of Cognitive Imaging, Department of Psychiatry (Drs. Fennema-Notestine, Jacobson, and Jernigan, and S.L. Archibald), Department of Neurosciences (Drs. Corey-Bloom, Peavy, Gamst, Hamilton, and Salmon), and Division of Biostatistics (Dr. Gamst), University of California, San Diego, La Jolla; and Departments of Psychiatry and Neurology (Dr. Paulsen), The University of Iowa, Iowa City. Supported by the Office of Research and Development, Department of Veterans Affairs Medical Research Service REAP and Merit Review programs, and a Huntington’s Disease Society of America Research Grant. Presented in part at the annual meeting of the American Academy of Neurology, April 2000. Received July 3, 2003. Accepted in final form May 14, 2004. Address correspondence and reprint requests to Dr. Christine Fennema Notestine, Laboratory of Cognitive Imaging (9151-B), University of California, San Diego, 9500 Gilman Drive MC 9151-B, La Jolla, CA 92093; e-mail: [email protected] Copyright © 2004 by AAN Enterprises, Inc. 989

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been examined in vivo in a systematic manner. In addition to volume loss, neuroimaging also reveals an increased level of abnormal signal changes within the white matter (e.g., hyperintense regions on T2weighted images).6 Such measures of white matter integrity have been shown to be related to changes in motor and cognitive performance in other disorders25, 26 and may be a significant factor in HD. The status of cerebellar gray and white matter volume throughout the course of HD remains largely unknown. Cerebellar tissue loss has been reported in juvenile-onset HD, and in some adult-onset HD cases, there are findings to suggest that the cerebellum is abnormally small.24 However, the results of neuropathologic investigations suggest that the neuronal density in the cerebellar cortex is relatively unaffected, particularly early in the disease.24 In light of previous findings in HD of cerebral white matter degeneration and the possibility of smaller cerebellar volumes, the present study used detailed in vivo MRI morphometric analyses to better characterize the pattern of these changes during the disease. Based on previous work, we anticipated that volume loss would be evident in the striatum of patients with HD, with the caudate nucleus relatively more affected than other subcortical structures. Furthermore, we examined the relationship between caudate atrophy and gray and white matter volume loss in HD for evidence of similar or independent mechanisms of pathology.

Methods. Subjects. Fifteen participants with clinically diagnosed HD were recruited from the University of California, San Diego (UCSD) Huntington’s Research Group and the UCSD Huntington’s Disease Society of America Center of Excellence. HD was diagnosed by a senior neurologist on the basis of family history (or confirmation of the genetic mutation) and the presence of chorea. CAG repeat data were not available for all participants. The Unified Huntington’s Disease Rating Scale (UHDRS27) was administered to 13 of the 15 HD patients within 6 months of each participant’s MRI examination. The motor examination of the UHDRS provides ratings for ocular motor changes, dysarthria, gait, balance, rigidity, bradykinesia, dystonia, and chorea; the total impairment score can range from 0 (no motor symptoms) to 124 (severe, bilateral deficits in all categories). The mean motor impairment score for the HD group is 27.5 (SD ⫽ 14.4; range 5 to 54); this study included participants ranging from very mild to moderate in symptom severity. Twenty-two normal control participants (NC) with no family history of HD were recruited from the community and other ongoing studies. Participants with a history of stroke, tumor, brain surgery, major head injury, substance abuse, or a current major psychiatric illness were excluded. The HD and NC groups did not differ in age (HD mean 46.7, SD ⫽ 11.0; NC mean ⫽ 47.1, SD ⫽ 9.8), sex, or level of education (p ⬎ 0.05; see supplementary table E-1 on the Neurology Web site at www.neurology.org). This study was approved by the UCSD Human Research Protections Program, and informed consent was obtained for all participants. Imaging protocol. Each participant received an MRI scan of the head in a GE 1.5 Tesla scanner. A standard fast spin echo (FSE) protocol was collected consisting of 4 mm proton density (repetition time [TR] ⫽ 3,000 msec, echo time [TE] ⫽ 17 msec, echo train [ET] ⫽ 4) and T2-weighted (TR ⫽ 3,800 msec, TE ⫽ 102 msec, ET ⫽ 8) images through the entire brain with no gaps. In addition, a gradient-echo (SPGR) T1-weighted series with TR ⫽ 24 msec, TE ⫽ 5 msec, number of excitations (NEX) ⫽ 2, flip angle ⫽ 45 degrees, field of view of 24 cm, and contiguous 1.2 mm sections was acquired. For all series, the field of view was 24 cm. As in previous work,28 the combined PD-T2 information provides

Figure 1. Example of six processed images showing structural boundaries for gray matter, white matter, and abnormal white matter regions.

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Table 1 Subcortical gray matter and cerebellum Group effect from regression

Proportional volume Regions

Percent change

Overall subcortical gray Caudate nucleus

NC

␤

HD

t

⫺29.8

0.0324 (0.0036)

0.0227 (0.0038)

⫺0.79

⫺8.3*

⫺49.8

0.0060 (0.0010)

0.0030 (0.0012)

⫺0.81

⫺8.8*

Nucleus accumbens

⫺36.4

0.0018 (0.0004)

0.0012 (0.0003)

⫺0.67

⫺5.7*

Lenticular nucleus

⫺34.4

0.0105 (0.0012)

0.0069 (0.0009)

⫺0.85

⫺10.0*

Thalamus

⫺14.4

0.0094 (0.0011)

0.0080 (0.0017)

⫺0.44

⫺3.0†

Substantia nigra

⫺26.1

0.0010 (0.0003)

0.0007 (0.0003)

⫺0.45

⫺2.9†

Basomesial diencephalon

⫺20.2

0.0036 (0.0006)

0.0029 (0.0004)

⫺0.58

⫺4.8*

⫺3.7

.5914 (0.0296)

0.5695 (0.0324)

⫺0.33

⫺2.2†

Cerebellar gray matter Cerebellar white matter

⫺16.9

0.2302 (0.0317)

0.1913 (0.0325)

⫺0.52

⫺3.8*

Cerebellar CSF

⫹59.4

0.0707 (0.0305)

0.1159 (0.0354)

⫹0.55

⫹4.5*

The percent volume change (⫺ reduction; ⫹ increase) in Huntington disease (HD) relative to normal control (NC) participants; the mean (SD) volume as a proportion of the supratentorial (or infratentorial for cerebellar measures) cranial vault; and regression statistics for group comparisons independent of age (note: negative ␤ represents smaller volumes in HD). * p ⬍ 0.001; † p ⬍ 0.01; ‡ p ⬍ 0.05.

excellent contrast between gray and white matter in both cortical and subcortical regions, a direct measure of CSF and intracranial volume, and estimates of white matter abnormalities; furthermore, the 4 mm resolution allowed for whole-brain analysis. The higher resolution T1-weighted SPGR volume was available for enhanced anatomic visualization. Image analysis. As described in detail previously,28 the image analysis involved supervised isolation of intracranial regions, digital filtering of the image to reduce inhomogeneity artifact, reslicing of the volume into standard orientation, tissue segmentation using semi-automated algorithms, and neuroanatomic region-ofinterest analysis. Trained anatomists who were blind to participant diagnosis, age, or any other identifying information performed these procedures on the FSE images. After filtering, the image datasets were resectioned in a standard coronal plane defined relative to the decussations of the anterior and posterior commissures and the structural midline. Registration of the T1-weighted and fast spin-echo datasets was accomplished so that comparable sections from all three datasets are available to resolve anatomic boundaries. The tissue segmentation procedure was an interactive, supervised process that combined information from the PD and T2-weighted datasets and is described in detail elsewhere.28 For each subject, operators manually designated three sets of tissue samples (gray, white, and CSF) on the resectioned images in standard anatomic locations within regions of homogeneous tissue, avoiding artifacts and tissue abnormalities (such as ischemic damage). Regression analyses of the voxel values from these samples were used to classify the remaining intracranial voxels into gray, white, or CSF voxels. The anatomists then circumscribed a set of standard regions on all tissue-segmented images. Standardized rules were applied for delineating subcortical, cortical, and cerebellar gray matter structures, white matter regions, regions in the white matter with abnormal signal, and CSF. Subcortical structures include cerebral ventricles, caudate nucleus, nucleus accumbens, lenticular nucleus, thalamus, substantia nigra, and a region referred to as basomesial diencephalon (which includes septal nuclei, mamillary bodies and other hypothalamic structures, the bed nucleus of the stria terminalis, and the diagonal band of Broca). Cerebellar gray matter, white matter, and CSF were also measured; the estimate of cerebellar white matter volume includes small deep nuclei, such as the dentate gyrus, that are not detectable with this protocol. Volumes of each tissue type (gray matter, white matter, CSF) were estimated separately within the temporal, frontal, parietal, and occipital lobes. Separate gray matter and CSF measures were obtained for cingulate, insula, and three mesial temporal lobe structures: hippocampus, amygdala (which includes some adja-

cent entorhinal and perirhinal cortex), and parahippocampal gyrus. Cerebral white matter was subdivided into the four major cerebral lobes, as mentioned above, and a deep zone surrounding the basal ganglia and diencephalon that includes the internal capsule. The total amount of white matter in a given region consisted of volumes of normal and abnormal white matter. The regions of abnormal white matter were defined as those voxels clearly neuroanatomically within white matter that had signal values exceeding the sample values for normal white matter. These voxels fell in the distribution of signal values obtained from gray matter voxels and were classified with our tissue segmentation methods as “gray matter.” These voxels were coded as abnormal white matter in the anatomic analysis described above. Representative processed images of a normal brain that illustrate the regional boundaries of the measured brain structures are shown in figure 1. Two anatomists performed region of interest analysis of 10 tissue-segmented brain datasets independently, and high interoperator reliability estimates have been reported previously.28 Statistical methods. All volumetric measurements were proportionalized to the volume of the supratentorial cranial vault (STCN; except for cerebellar measures, proportionalized to the infratentorial cranial vault, ITCN) to control for individual differences in head size. Group comparisons were then carried out using nonparametric Mann-Whitney U test. In light of the known effects of age on regional volumes,28 we also performed regression analyses incorporating age and group as independent variables to predict various volumetric measures. Findings reported were significant for both analyses. For the replication of previous neuroimaging and neuropathologic findings in subcortical and cortical gray matter regions, the variables examined were 1) overall volume of subcortical gray matter and six subcortical regions (see figure 1, table 1); 2) overall volume of cerebral cortical gray matter, and 11 specific cortical regions (see figure 1, supplementary table E-2 on the Neurology Web site at www.neurology.org); and 3) overall volumes of cortical (sulcal) and ventricular CSF. The primary focus of this study explored 1) overall volumes of cerebellar gray matter, white matter, and CSF; and 2) overall volumes of cerebral white matter, abnormal white matter in the cerebrum, and white matter measures in five cerebral regions (see figure 1, table 2). In all cases, the volumes were bilateral. Because significant volume loss occurred in multiple regions in HD patients, exploratory analyses were carried out to compare the relative magnitude of loss across regions. This was done by calculating for each participant the relative proportion of decline (RPD) September (2 of 2) 2004 NEUROLOGY 63 991

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Table 2 Cerebral white matter Group effect from regression

Proportional volume Percent change

Regions Cerebral white matter§

NC

␤

HD

t

⫺16.7

0.3565 (0.0291)

0.2971 (0.0455)

⫺0.63

⫺4.8*

⫺6.3

0.0328 (0.0034)

0.0307 (0.0014)

⫺0.35

⫺2.2‡

Deep Frontal

⫺14.0

0.1387 (0.0126)

0.1193 (0.0154)

⫺0.58

⫺4.2*

Parietal

⫺16.2

0.0892 (0.0077)

0.0748 (0.0153)

⫺0.54

⫺3.7*

Temporal§

⫺21.2

0.0545 (0.0082)

0.0429 (0.0098)

⫺0.54

⫺3.8*

Occipital

⫺30.0

0.0420 (0.0072)

0.0294 (0.0087)

⫺0.63

⫺4.8*

Overall abnormal white matter§ Deep abnormal

⫹45.0

0.0129 (0.0044)

0.0187 (0.0085)

0.41

2.8†

⫹56.5

0.0023 (0.0004)

0.0036 (0.0010)

0.71

5.9*

Frontal abnormal

⫹61.8

0.0034 (0.0016)

0.0055 (0.0030)

0.42

2.9†

Parietal abnormal

⫹38.8

0.0049 (0.0026)

0.0068 (0.0041)

0.26

1.7 NS

Temporal abnormal§

⫹14.3

0.0014 (0.0004)

0.0016 (0.0007)

0.22

1.3 NS

Occipital abnormal

⫹71.4

0.0007 (0.0005)

0.0012 (0.0006)

0.41

2.8†

The percent volume change (⫺ reduction; ⫹ increase) in overall and regionalized cerebral white matter (upper table) or abnormal white matter in Huntington disease (HD) relative to normal control (NC) participants; the mean (SD) volume of cerebral white matter or abnormal white matter as a proportion of the supratentorial cranial vault; and regression statistics for group comparisons independent of age (note: negative ␤ represents smaller volumes in HD). § Based on one fewer HD patient due to MRI artifact in the temporal lobes. * p ⬍ 0.001; † p ⬍ 0.01; ‡ p ⬍ 0.05; NS p ⬎ 0.10. for pairs of regions as follows: RPD ⫽ volume of tissue X/volume of tissue Y. Group t-tests contrasted these RPD measures among subcortical regions (caudate vs lenticular nucleus, caudate vs nucleus accumbens, and lenticular nucleus vs nucleus accumbens), among cortical gray matter regions (comparing all four lobar measures), among cerebral white matter regions (comparing all four lobar measures), between overall cerebral white and gray matter, and between overall cerebellar white and gray matter. For example, to determine whether cerebellar gray or white matter was relatively more affected in HD, the following RPD was calculated

for HD patients and NC participants: RPD ⫽ cerebellar gray matter volume/cerebellar white matter volume. If, in this case, the HD group RPD was significantly higher than that of the NC group, it would indicate that in HD the cerebellar white matter volume loss was relatively greater than their cerebellar gray matter loss.

Results. Figure 2 shows the anatomic segmentation of two sections for representative HD and NC participants. The accompanying tables provide, in addition to the mean,

Figure 2. Example of structural MR analysis displayed for two sections from a 43-year-old control participant (left panel) and a 39-year-old symptomatic Huntington disease patient (right panel). T1-weighted SPGR images are provided for neuroanatomic visualization. See figure 1 for color legend. 992

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SD, and statistical results of the proportionalized values, the percent volume change in the HD group relative to the NC group. This percent volume change was calculated as the proportion of the HD mean to the NC mean, minus 100. Globally, the HD group had significantly more CSF relative to the NC group: cortical (sulcal) ⫹138.9%, cerebellar ⫹59.4, and ventricular ⫹149.5%. Conversely, overall cerebral and cerebellar volumes were significantly smaller than controls. The mean raw cranial vault measures used in the proportionalized measures are as follows: NC STCN ⫽ 321,661, ITCN ⫽ 49,185; HD STCN ⫽ 329,718, ITCN ⫽ 50,785. A more detailed regional analysis is presented below. Subcortical gray matter. Overall subcortical gray matter volume and the volumes of the caudate nucleus, nucleus accumbens, lenticular nucleus, thalamus, substantia nigra, and basomesial diencephalon were significantly smaller in participants with HD than in NC participants (see table 1). The greatest percentage of subcortical gray matter volume loss, relative to normal controls, was in the caudate nucleus, followed by the nucleus accumbens and the lenticular nucleus (see table 1). The RPD analyses revealed that the HD patients had relatively greater volume loss in the caudate nucleus than in the lenticular nucleus (p ⬍ 0.001) or in the nucleus accumbens (p ⬍ 0.005). The extent of volume loss in these latter two nuclei was not significantly different. Cerebral cortical gray matter. Overall cortical gray matter volume and the volumes of frontal and temporal cortical gray matter were smaller in the HD group, relative to the NC group (p ⬍ 0.001; supplementary table E-2). Mesial temporal gray matter volume was also significantly smaller in HD patients than in NC participants, particularly in the hippocampus and parahippocampal gyrus. Patients with HD had significantly smaller volumes of gray matter in the insula and cingulate cortex compared to NC participants. The groups did not differ significantly in gray matter volume of the amygdala, parietal, or occipital cortices. The RPD analyses revealed no significant differences in the relative regional cortical gray matter loss across the four primary lobes. Cerebral white matter. Total white matter volumes (including abnormal white matter) were all significantly smaller in the HD relative to the NC group (see table 2). The overall volume of abnormal white matter and the volume of abnormal white matter in deep, frontal, and occipital regions was greater in patients with HD than in NC participants. Furthermore, the proportion of white matter volume that was abnormal in signal was increased in the HD group (p ⬍ 0.0005). The RPD analyses of lobar white matter regions showed that occipital white matter volume in HD was relatively more affected than in frontal (p ⬍ 0.001) or parietal (p ⬍ 0.001) regions, and that temporal was more affected than frontal white matter (p ⬍ 0.05). No other regional comparisons revealed significant differences. Comparison of cerebral white matter and cerebral gray matter loss. The RPD analyses showed no difference in the relative overall volume loss of cerebral cortical gray matter and cerebral white matter for patients with HD (p ⬎ 0.05). However, white matter loss in HD was proportionately greater than gray matter loss in the occipital (p ⬍ 0.01) and temporal (p ⬍ 0.05) lobes. The HD patients

had similar proportional white and gray matter loss in the parietal and frontal lobes. Cerebellar gray and white matter. Volumes of gray and white matter in the cerebellum were significantly smaller in patients with HD than in NC participants (see table 1). An RPD analysis showed that cerebellar white matter volume loss was greater than cerebellar gray matter volume loss in the HD patients (p ⬍ 0.05). There was no difference in the relative loss of cerebellar and cerebral white matter volumes in the HD participants. Relationship of caudate volume to other global and regional brain volumes. The volume of the caudate nucleus in patients with HD was significantly correlated with the volume of most other subcortical gray matter regions, with overall cortical gray matter volume and the volume of the hippocampus, and with volumes of normal and abnormal cerebral white matter (table 3). Caudate volume was not significantly correlated with cerebellar gray or white matter.

Discussion. Consistent with previous neuropathologic and neuroimaging findings,3-10 the caudate nucleus was severely affected in patients with HD. On average, approximately 50% of caudate nucleus volume was lost in these patients. Extensive volume loss was also evident in the lenticular nucleus (primarily putamen), as has been previously reported,6,12 and in the nucleus accumbens.3,12 This latter finding provides in vivo evidence that supports previous neuropathologic reports of nucleus accumbens degeneration in patients with HD3,12 and a recent in vivo study.23 While the proportion of volume loss was similar in the lenticular nucleus and nucleus accumbens (approximately 35%), both structures were less affected than the caudate nucleus. Previous reports have suggested that the putamen may undergo more Table 3 Correlation between caudate volume and regional brain volumes Caudate volume vs regional volumes, Spearman correlation coefficient (rs)

Regions Caudate nucleus

—

Nucleus accumbens

⫹0.55*

Lenticular nucleus

⫹0.60*

Thalamus

⫹0.59*

Substantia nigra

⫹0.19 NS

Basomesial diencephalon

⫹0.57*

Cortical gray matter

⫹0.56*

Hippocampus

⫹0.82*

Cerebral white matter

⫹0.50*

Abnormal cerebral white matter

⫺0.74*

Cerebellar gray matter

⫹0.28 NS

Cerebellar white matter

⫹0.32 NS

The correlations are based only on individuals with Huntington disease. * p ⬍ 0.05; NS p ⬎ 0.05. September (2 of 2) 2004 NEUROLOGY 63 993

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significant changes over time relative to the caudate.8,10 The present study differs from previous morphometric studies in that the lenticular nucleus measure combines the putamen, claustrum, and globus pallidus. Additional subcortical gray matter loss was observed in the thalamus, substantia nigra, and in an anterior basomesial diencephalic region. These in vivo observations support previous neuropathologic findings of volume loss in the substantia nigra,11 as well as reports of degeneration and altered metabolism in the thalamus of these patients.6,12,13 In addition to extensive subcortical gray matter atrophy, the present study demonstrated significant reductions in the volume of cortical gray matter in the cerebrum of patients with HD that were significantly related to caudate volume loss. Decreased volume of gray matter was specifically observed in the frontal, temporal, and occipital cortices, consistent with previous findings,7,13,19,20 and the cingulate and insular cortices also were reduced in HD. The volume of cortical gray matter in the parietal lobe was not reduced significantly in HD, even though previous neuropathologic studies have found anterior parietal gray matter loss13,20 and reduced cerebral blood flow.7 It may be that these disparate parietal findings are due to less sensitivity in the present study since the full extent of the parietal lobe was examined rather than specific regions of interest. Notably, the significant relationship between the severity of cortical gray matter loss and the degree of caudate atrophy suggests a similar or parallel neurodegenerative mechanism. These findings differ from previous immunohistochemistry reports suggesting that the extent of cortical changes in HD may be independent of the degree of striatal pathology.18,29 An important and novel finding in the present study is in vivo evidence of a significant reduction in the volume of the cerebellum in patients with HD. Although a recent in vivo MRI study reported no significant cerebellar atrophy in HD,23 in the present study, both cerebellar gray and white matter volumes were abnormally low in patients with HD, supporting suggestions made by a previous neuropathologic report.24 Cerebellar white matter loss was relatively greater than the loss of cerebellar gray matter. Neither measure was significantly correlated with the volume of the caudate nucleus, although the present study may lack sufficient power for this analysis. Further understanding of this global characterization of the cerebellum may be limited by the resolution of these data; subsequent studies will employ higher resolution pulse sequence acquisitions tuned for more detailed cerebellar segmentation. It is not known whether this cerebellar atrophy is progressive in nature or a pre-existing condition unrelated to disease stage, and the functional consequences of the cerebellar atrophy observed in patients with HD also remain unknown. Future work with clinically diagnosed patients with HD or genetically at-risk individuals will examine the rela994

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tionship between cerebellar gray and white matter volume and motor and behavioral measures thought to reflect cerebellar function and the number of CAG repeats. Another notable finding in the present study is evidence of extensive cerebral white matter reduction, and an increase in the volume of abnormal cerebral white matter, in patients with HD. This in vivo evidence of significant cerebral white matter pathology is consistent with previous findings24 and tended to be greater than cortical gray matter loss. While the white matter loss was evident in all cerebral lobes, the greatest proportional loss was in the occipital lobe. Greater volumes of abnormal white matter (e.g., hyperintense regions on T2-weighted images) were primarily restricted to the frontal, occipital, and deep cerebral regions; this finding may reflect an active neuropathologic process, such as gliosis or demyelination. The mechanisms responsible for such white matter pathology in HD are not clear. In neuropathologic studies, axons within the subcortical white matter have shown significantly increased huntingtin immunoreactivity compared to controls29-31 and progressive accumulation of reactive microglia in the white matter surrounding the striatum.32 One report29 suggested that the presence of mutant huntingtin could “disrupt axonal transport and cause degeneration.” Additionally, neuropathologic findings in patients with HD support the possibility that the density of oligodendrocytes, cells related to myelin production, may be affected early in life in gene carriers.33 Although one study33 reported evidence of neurodegeneration in the form of decreased neurons and increased astrocytes with the progression of HD, oligodendroglial cell densities were increased in mild HD, and this measure did not change with disease progression. The investigators suggested that the oligodendroglial abnormalities might be related to white matter volume loss. The present findings indicate that HD results not only in marked atrophy of the basal ganglia, but also in significant reductions in cerebral and cerebellar gray and white matter. The degree of caudate atrophy was significantly related to the severity of cerebral gray and white matter loss, suggesting that loss in these regions may be due to a similar mechanism. The volume of abnormal white matter in the cerebrum was also increased, suggesting on-going active pathology that was significantly related to caudate atrophy. Future clinical and neuroimaging studies in individuals genetically confirmed to be at risk for developing HD and those with an early diagnosis may help to elucidate the clinico-pathologic relationship between symptomatology and subcortical, cortical, and cerebellar neurodegeneration. A better understanding of the neuroanatomic changes that occur early in HD could prove important as an early diagnostic tool and as a method to evaluate the effectiveness of therapeutic intervention.

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Acknowledgment Resources and facilities were provided by the VA San Diego Healthcare System, the Veterans Medical Research Foundation, and the University of California, San Diego.

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September (2 of 2) 2004 NEUROLOGY 63 995

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In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease C. Fennema-Notestine, S. L. Archibald, M. W. Jacobson, J. Corey-Bloom, J. S. Paulsen, G. M. Peavy, A. C. Gamst, J. M. Hamilton, D. P. Salmon and T. L. Jernigan Neurology 2004;63;989-995 This information is current as of May 14, 2009 Updated Information & Services

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