Abstract
Objective: To investigate the patterns of MRI brain atrophy in patients with ALS with and without clinically evident frontotemporal lobar dementia (FTLD) using voxel-based morphometry (VBM).
Methods: Voxel-based morphometry was used to compare T1-weighted MRI images obtained from ten ALS patients with FTLD, ten ALS patients who were cognitively and behaviorally normal, and 22 control subjects. Images from patients and controls were spatially pre-processed using a study-specific, customized template and a priori images. A statistical threshold of p < 0.05 corrected for multiple comparisons determined significance.
Results: A common pattern of gray matter atrophy was seen in both ALS and ALS/FTLD patients when compared to controls that involved the bilateral motor/premotor cortices, the left middle and inferior frontal gyri, the anterior portion of the superior frontal gyri, the superior temporal gyri, the temporal poles and left posterior thalamus. Most of the frontal regions were significantly more atrophied in the ALS/FTLD group than in the ALS group. No significant differences were found in white matter volumes.
Conclusions: Patients with ALS and ALS associated with frontotemporal lobar degeneration exhibit widespread gray matter atrophy in frontotemporal regions. This finding supports the idea of a clinical and anatomic continuum between ALS and frontotemporal lobar degeneration.
It is increasingly recognized that varying degrees of frontal lobe dysfunction are present in ALS, with some patients manifesting no clinical deficits, and others meeting clinical criteria for frontotemporal lobar degeneration (FTLD).1,2 Until recently, the association between ALS and FTLD had been only documented in single cases3 or in small group reports.4 A more recent study of 100 ALS patients screened for dementia found that 50% had executive function deficits, with many meeting Neary research criteria for FTLD.5 FTLD symptoms can either precede or follow ALS manifestations6,7 and in one study 15% of FTLD patients went on to demonstrate signs of motor neuron disease.5 Furthermore, FTLD patients without motor symptoms often show lesions typical of ALS at pathology (motor neuron disease-inclusion dementia or MND-ID).8 Additionally, there are reports of families in which different members presented with ALS, FTLD, or both.9
Neuroimaging can be a useful method to investigate the anatomic basis of the association between ALS and FTLD. Frontal or temporal lobes involvement has been consistently shown in FTLD.10–14 ALS has been associated with reductions in blood flow or metabolism in frontal cortex15,16 but structural MRI has produced inconsistent results.17–21 Only two functional neuroimaging studies investigated ALS/FTLD. One small study showed severe bilateral frontal hypoperfusion in ALS/FTLD.22 The other PET investigation found frontotemporal hypometabolism in both groups and a trend of decreased activity in medial temporal structures in FTLD with motoneuron disease.23
Here we used voxel-based morphometry (VBM) to investigate the patterns of gray and white matter atrophy in a group of patients with ALS prospectively recruited at the UCSF ALS center. We sought to compare regional brain volumes between patients with ALS with normal cognitive and behavioral functions and those who also met clinical criteria for FTLD. We expected to find greater frontotemporal atrophy in patients with ALS/FTLD.
Methods.
Subjects.
Ten patients with ALS with normal cognitive and behavioral functions, 10 patients with ALS/FTLD, and 22 healthy controls participated in the study. All 20 patients with ALS were prospectively evaluated at the UCSF ALS Center. All met World Federation of Neurology criteria for ALS24 and 10 also met Neary criteria for FTLD.2 Of the 10 patients with FTLD, 7 met criteria for the FTD/frontal variant of FTLD, 2 for the semantic dementia/temporal variant, and 1 for the progressive non-fluent aphasia variant. Participants had no history of head injury, psychiatric disease, or a known family history of dementia.
A battery of neuropsychological and neurobehavioral tests that has been described elsewhere5 was administered to all patients. Table 1 reports demographic data, ALS clinical data, and basic neuropsychological findings for ALS and ALS/FTLD patients. One-way analysis of variance (ANOVA) was used to compare demographic and ALS clinical differences between the ALS and ALS/FTLD groups. Since there was a significant age difference between the two groups, these analyses were corrected for age. No significant differences were found in overall severity of ALS between the two groups of patients. In particular, no significant differences existed in the number of months from ALS disease onset, the upper motor neuron/lower motor neuron scores, the number of patients with pseudobulbar affect or bulbar type disease onset, and the ALSFRS disease progression scores. Although no significant differences were found in ALS clinical findings between groups, some trends were observed: more ALS/FTLD patients exhibited bulbar type onset when compared to the ALS group, which had more patients with limb onset. The ALS/FTLD group also had more upper motor neuron involvement (see table 1). In table 1 we report statistical differences between the neuropsychological and behavioral measures between the ALS and ALS/FTLD groups. However, since results of the neuropsychological tests aided the clinical diagnosis of FTLD, we do not emphasize these results. Of note is that the significance between the BNT scores in the two groups was influenced by the particularly poor score (8/15) obtained by the SD patient.
Table 1 Demographics and clinical characteristics of the ALS and ALS/frontotemporal lobar dementia (FTLD) groups
Clinical MRI findings were used only to exclude patients and not to classify them as having ALS only or ALS/FTLD. MRI scans were also obtained from 22 normal control subjects. The control subjects had no previous history of neurologic or mental illness. The group included 12 women and 10 men. The mean age of the neuroimaging control group was 44.5 years (SD ± 10.4).
The study was approved by the UCSF committee on human research. All subjects provided written informed consent before participating.
MRI scanning and voxel-based morphometry.
MRI scans were obtained on a 1.5-T SIGNA system (General Electric, Milwaukee, WI) equipped with a standard quadrature head coil. Structural MRI sequences included a volumetric three-dimensional spoiled fast gradient echo MRI (FSPGR, repetition time/echo time = 27/6 msec) to obtain T1-weighted images of the entire brain with 0.9 mm in-plane, and 3.0 mm thick axial sections. All scans were acquired within a 6-month period from the time of clinical diagnosis.
Voxel-based morphometry (VBM) was used to compare gray and white matter regional volumes in patients who met clinical criteria for ALS alone (ALS) and in patients who met criteria for both ALS and FTLD (ALS/FTLD). VBM is a fully automated, whole-brain technique for detection of regional brain atrophy by voxel-wise comparison of gray and white matter volumes between groups of subjects.25,26 The technique comprises an image spatial preprocessing step (spatial normalization, segmentation, modulation, and smoothing) followed by statistical analysis. Both stages are implemented in the SPM2 software package (www.fil.ion.ucl.ac.uk/spm). Since the template and a priori images provided by SPM are derived from young, healthy brains, ad hoc, age-matched, a priori, and template images were created. Patients' and controls' images were normalized to the common template to allow intersubject comparisons and then segmented into gray, white, and CSF compartments using the latest VBM technique.26 Gray and white matter voxel values were multiplied by the Jacobian determinants derived from the spatial normalization step in order to preserve the initial volumes. Gray and white images were then spatially smoothed with a 12 mm FWHM isotropic Gaussian kernel. Total intracranial volume was used as a confounding covariate in an analysis of covariance (ANCOVA). Age and sex for each subject were entered into the design matrix as nuisance variables. Regionally specific differences in gray and white matter volumes were assessed using the general linear model and the significance of each effect was determined using the theory of Gaussian fields. Specific statistical analyses were performed to investigate the regions of common atrophy in ALS/FTLD and ALS groups compared to controls, and the group differences between the two patient populations. Specifically, the following contrasts were performed: 1) all patients (ALS/FTLD + ALS) vs controls masked inclusively with ALS/FTLD vs controls and ALS vs controls, identified regions of atrophy present in both groups. The inclusive masking procedure limits the main effect contrast (i.e., all patients vs controls) to regions that are also present in each subgroup vs control contrasts; 2) ALS/FTLD vs controls masked inclusively with ALS/FTLD vs ALS, identified regions more atrophied in ALS/FTLD vs ALS and vs controls. In this case, the inclusive masking procedure assured that regions that were more atrophied in ALS/FTLD than ALS were also more atrophied in ALS/FTLD vs controls; and 3) ALS vs controls, masked inclusively with ALS vs ALS/FTLD, identified regions more atrophied in ALS than in ALS/FTLD and controls. These contrasts were performed using gray and white matter images to assess significant volume loss in each partition. We accepted a statistical threshold of p < 0.05 corrected for multiple comparisons for the main contrasts and of p < 0.001 uncorrected for the contrasts used as masks. For contrast 2 we also lowered the inclusive mask to p < 0.05 to illustrate areas that showed a trend for being different in ALS/FTLD vs ALS.
Results.
Voxel-based morphometry: Gray matter.
All ALS vs controls.
This analysis identified regions of significant gray matter atrophy present in both ALS and ALS/FTLD when compared to controls (table 2 and figure 1A). The most significant areas of atrophy were found in the bilateral motor/premotor cortices and anterior portion on the superior frontal gyrus bilaterally. Other areas of atrophy included the left middle and inferior frontal gyri, left posterior thalamus, bilateral superior temporal gyri, and right temporal pole. All these regions were significantly atrophied after correction for multiple comparisons.
Table 2 Regions of significant gray matter atrophy common in ALS/frontotemporal lobar dementia (FTLD) and ALS when compared to controls
ALS/FTLD vs controls and vs ALS.
This analysis identified regions that were more atrophied in ALS/FTLD than in ALS within areas that were also atrophied in the ALS/FTLD contrast compared to controls (see table 3 and figure 1B). Areas of significant greater atrophy in ALS/FTLD than ALS included the left middle frontal gyrus, the left inferior frontal gyrus, and the medial premotor cortex. Atrophy in the middle and inferior frontal gyri was also present in the ALS alone group when compared to controls, but showed more significant or more extended involvement in the ALS/FTLD group (see tables 2 and 3). On the other hand, the medial premotor cortex showed significant atrophy only in the ALS/FTLD group when compared to controls. Motor/premotor cortex, frontal pole, and posterior thalamus showed a trend for being more atrophied in ALS/FTLD vs ALS (inclusive mask p < 0.05).
Table 3 Regions of gray matter atrophy in amyotrophic lateral sclerosis (ALS)/frontotemporal lobar dementia (FTLD) vs ALS
Figure 2A illustrates the relationship between gray matter volumes in the left inferior frontal gyrus and a relevant neuropsychological measure (phonemic fluency) in ALS/FTLD and ALS. Figure 2B illustrates the distribution of gray matter volumes in regions that showed common and different effects in ALS/FTLD and ALS. These two plots highlight the non-binomial distribution of volumes and neuropsychological scores in the two groups and support the idea of a continuum between ALS and ALS/FTLD.
Figure 2. (A) Plot of gray matter volumes (arbitrary units) at -57,20,16 as a function of the score on the phonemic fluency task (FAS); (B) Plot of gray matter volume in regions that showed different and common effects in amyotrophic lateral sclerosis (ALS)/frontotemporal lobar dementia and ALS.
ALS vs controls and vs ALS/FTLD.
This analysis would highlight regions that were more atrophied in ALS than in ALS/FTLD within areas that were also more atrophied against controls. No areas showed greater atrophy in ALS than in ALS/FTLD.
VBM: White matter.
No significant white matter atrophy was found in ALS and ALS/FTLD groups when compared to controls and to each other.
Discussion.
We performed a VBM study that compared patterns of brain atrophy in ALS and ALS/FTLD. The results demonstrated that each patient group showed gray matter atrophy in the motor, premotor, prefrontal, and temporal cortices. However, patients with ALS who also met criteria for FTLD showed more significant volume loss in the same areas, particularly within the left hemisphere. We discuss these results in relation to previous pathologic and neuroimaging studies in ALS and ALS/FTLD and their possible implication in the nature of the association between ALS and FTLD.
The finding of atrophy in frontotemporal regions beyond motor and premotor cortices in ALS is consistent with previous pathologic and neuroimaging studies. Pathologically, the hallmarks of ALS are tau-negative and ubiquitin-positive intraneuronal inclusions (UI). Neuronal loss and gliosis of cortical layers II and III with microvacuolation are also present, similar to that found in FTLD. UI and neuronal loss have been found to extend beyond the motor system (upper and lower motorneurons) and premotor cortex, not only in ALS with dementia, but also in patients with ALS who were cognitively normal.27–29 Consistently, neuroimaging studies in ALS have also confirmed the spread of atrophy and/or hypometabolism to the frontal and temporal cortices in ALS.15,20 In this study, frontal atrophy in ALS/FTLD was more severe than in ALS. These results are consistent with pathologic findings showing greater UI density and superficial spongiosis in ALS/FTLD than in ALS alone.
We found no significant differences between the two groups in the anterior and medial temporal lobe regions, even though pathologic reports of ALS-dementia have shown that typical lesions also extend to medial temporal lobe, including the anterior hippocampus, parahippocampus, and amygdala.30,31 Previous neuroimaging studies have provided inconsistent results regarding the involvement of medial temporal structures in ALS/FTLD. Although no study has explicitly compared ALS/FTLD to ALS, one PET study compared 10 FTLD patients (the term FTD is used in the article) with three ALS/FTLD cases and found decreased glucose uptake in frontal and anterior temporal cortices in both groups23 and a trend for greater medial temporal hypometabolism in ALS/FTLD than in FTLD alone. A SPECT study compared ALS/FTLD to normal controls and showed a bifrontal pattern of reduced cerebral blood flow, with less consistent anterior temporal involvement.22 One possible explanation for the discrepancy between pathologic and neuroimaging findings in the medial temporal lobes is the severity of the dementia syndrome. All patients included in this study had mild to moderate dementia, as testified by the fact that they all (except for one) presented at the ALS center without a previous diagnosis of dementia. In these cases neuronal loss in the medial temporal lobe might not be severe enough to be detected on MRI.
One possible caveat of our study is the age difference between the ALS/FTLD and the ALS and normal control groups. To the degree that age-related variance is not adequately represented in the control group, age-related atrophy in the patient groups will not be adequately controlled for even with age entered as a covariate in the statistical analysis. Thus, although we believe age-related atrophy to be an unlikely explanation for the dramatic frontal atrophy demonstrated in our patients, its impact on our findings cannot be entirely ruled out.
Our results show a remarkable similarity between the frontotemporal pattern of brain atrophy in ALS without dementia and ALS/FTLD, providing evidence for an anatomic continuum between the two syndromes. This result parallels pathologic studies where both ALS and ALS/FTLD patients show neuronal loss and UI, differing only in the severity of the finding. Our neuroimaging results thus provide further evidence in support of the idea of a continuum between ALS and FTLD.32,33 In our two patient groups, the severity of frontal atrophy seems to predict the presence of FTLD symptoms. Duration of illness, age at onset, and other factors seem to mediate the relative involvement of frontal regions in ALS, although few patients seem spared by this process. Recent pathologic evidence showing subclinical anatomic motor system involvement in patients with motor neuron disease-inclusion dementia (MND-ID) further supports this view.34,35 These patients present with pure FTLD clinical syndromes despite evidence at autopsy of upper and lower motor neuron involvement.36 Thus, even at a neuropathologic level there is no clear demarcation between ALS and ALS/FTLD.
While our study provides evidence for the idea of a continuum between ALS and ALS/FTLD, it cannot exclude the alternative hypothesis that the two simply co-occur in some patients. Future pathologic and molecular studies are needed to fully understand the pathogenesis of ALS and FTLD.
Acknowledgment
The authors thank the patients and their families for their commitment to the authors' research.
Footnotes
-
Supported by the ALS Association, The McBean Family Foundation, The Sandler Foundation, the John Douglas French Alzheimer's Association, the National Institute on Aging (5P01 AG019724-02 and 1 P50 AG-03-006-01), the California Department of Health (DHS 04-35516), the UCSF General Clinical Research Center (M01 RR00079), and the National Institute of Neurologic Diseases and Stroke (R01 NS50915).
Received May 27, 2004. Accepted in final form March 29, 2005.
References
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