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J Neurol (2006) 253 : 861–868 DOI 10.1007/s00415-006-0045-y
Elizabeth Coulthard Michael Firbank Philip English John Welch Daniel Birchall John O’Brien Timothy D. Griffiths
Received: 3 June 2005 Received in revised form: 2 September 2005 Accepted: 15 September 2005 Published online: 17 July 2006
E. Coulthard, MRCP · M. Firbank, PhD · P. English, DCR · J. Welch, PhD, CPsychol · D. Birchall, MD, FRCR · J. O’Brien, DM, FRCPsych · T. D. Griffiths, DM, FRCP () Newcastle General Hospital Westgate Road Newcastle upon Tyne, NE4 6BE, UK Tel.: +44-(0)191/2323224 E-Mail:
[email protected] D. Birchall, MD, FRCR · J. O’Brien, DM, FRCPsych · T. D. Griffiths, DM, FRCP University College London, UK T. D. Griffiths, DM, FRCP Institute of Neurology University College London, UK
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ORIGINAL COMMUNICATION
Proton magnetic resonance spectroscopy in frontotemporal dementia
■ Abstract This study of frontotemporal dementia (FTD) was carried out to determine whether MR spectroscopy can provide an in vivo marker for the neuronal loss and gliosis that occur in this condition. We compared spectra in frontal and temporal regions known to be affected early in the course of the disease with spectra in the parietal lobe that is spared until late stages of FTD. We were interested in the relative concentrations of two compounds, NAA (a marker of neuronal integrity) and mI (a marker of gliosis), expressed as ratios to creatine (a relatively stable brain constituent). MR spectroscopy was performed on the temporal, parietal, and anterior cingulate cortices of five patients with the established semantic dementia form of FTD, two patients
Introduction
■ Key words frontotemporal dementia · proton magnetic resonance spectroscopy · semantic dementia · N-acetyl aspartate · myoinositol
behavioural abnormalities [10]. Structural imaging can demonstrate frontal atrophy in those with established disease. Post mortem pathological studies of patients with FTD show great heterogeneity [6, 7, 18]. All pathological subtypes are characterized by frontal and or temporal neuronal loss and a variable degree of gliosis that occurs in the cortex and subcortical white matter [17]. Proton magnetic resonance spectroscopy is a technique that allows in vivo, non-invasive estimation of brain metabolites [5]. The spectra produced show several peaks thought to correspond to specific compounds within and around neurons. Two of these in particular are thought to be relevant to neurodegenerative disorders [16]. N-acetyl aspartate (NAA) is predominantly in-
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Frontotemporal dementia (FTD) describes a group of clinical syndromes caused by pathological processes affecting predominantly the frontal and temporal lobes [6, 10]. In the semantic (left temporal) form of FTD, patients have isolated loss of conceptual knowledge and present with difficulties in naming and problems in understanding the meaning of words and objects. Structural imaging reveals atrophy in the anterolateral temporal lobes more marked on the left than the right [12, 15]. Patients with the frontal lobe variant of FTD present with
with the frontal form of FTD and 13 age matched controls. Structural MRI and neuropsychometry were also performed. Patients with FTD had reduced NAA/Cr in frontal and temporal, but not parietal lobes. The two patients with the frontal form of FTD had increased mI/Cr in their cingulate cortices. These data show for the first time that MR spectroscopy can reveal regionally selective abnormalities in patients with FTD. This opens up the possibility of using MR spectroscopy as a clinical tool to identify earlier presentations of the condition.
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tracellular and thought to reflect metabolic activity of neurons as well as density. Hence, NAA is used as a marker of neuronal integrity [11, 19]. Myoinositol (mI) is a sugar alcohol with a similar structure to glucose. Its function is unknown, but it is found predominantly in glial cells and is thought to be a marker for gliosis [16]. Previous work has suggested that MR spectroscopy is a useful technique in the differential diagnosis of dementia. Reduction in the spectral peak of NAA and increase in the peak for mI in occipital, parietal, temporal and frontal lobes have been shown consistently to discriminate Alzheimer’s disease (AD) sufferers from normal control subjects [4]. One previous study suggested that an increase in the mI levels and reduction in NAA in the frontal region differentiates FTD from early AD [2]. Recently, single-voxel MR spectroscopy in the posterior cingulate cortex showed a reduction in NAA and an increase in mI in both FTD and AD patients [8]. No previous study has looked at the pattern of spectroscopic abnormality in FTD in frontal, temporal and parietal lobes. In this study we carried out MR spectroscopy on a group of patients with FTD to assess whether this in vivo technique could demonstrate the neuronal loss and gliosis found in this condition. We hypothesized that changes in spectral peaks would be shown in frontal and temporal lobes and spare the parietal lobe. We aimed to evaluate the potential of this technique to demonstrate characteristic profiles of spectroscopic abnormality in individual patients.
Methods Ethics approval was given by the Newcastle and North Tyneside ethics committee and written consent was obtained.
Table 1 Neuropsychological data
Subject
Age (years)
Sex
■ Subjects and Neuropsychology Seven patients were recruited from the Newcastle Cognitive Neurology Clinic (mean age 60.6 years, range 56–65, 6 male, 6 right-hand dominant). Five had semantic dementia using standard diagnostic criteria [14]. All presented with difficulty in naming previously familiar people or objects. They were an average 7.2 years into the course of their illnesses and subjects 2 and 5 had developed behavioural features by the time of spectroscopy (aggression and ranting). Subject 2 developed prosopagnosia six years after presentation. All had typical changes on MR of left temporal atrophy (see Fig. 1 for structural scans). Two subjects had the frontal form of FTD (average 30 months into the course of the illness). Both presented with prominent behavioural features. (See supplementary material for full clinical details.) Neuropsychological assessment included Wechsler Adult Intelligence Scale (WAIS III), Wechsler memory scale (WMS III), Delis Kaplan tests of frontal and executive function and the graded naming tests [1, 9, 20] (Table 1). Neuropsychological assessment of the patients was undertaken within three months of MR spectroscopy. All the subjects had been symptomatic for longer than 2 years and showed more generalized deficits than at the time of diagnosis.All semantic dementia patients showed marked impairment in naming ability from early in the course of their disease. Earlier testing had revealed relative preservation of memory and other cognitive domains including frontal and executive tasks. All patients showed significant impairment on the Delis Kaplan tasks performed in this study. It was not possible to test subject 4 because of his cognitive deterioration. Results in brackets are from earlier assessments of naming based on the Addenbrookes Cognitive Assessment when other cognitive domains were intact. The 11 control subjects were either the spouses of FTD subjects or non-medical staff from the Royal Victoria Infirmary, Newcastle (mean age 60 years, range 50–69, 3 male, 10 right-hand dominant). ■ MR structural imaging and spectroscopy Structural sequences and spectra were acquired on a Philips Intera 1.5 Tesla scanner (Best, the Netherlands). See Fig. 1 for structural scans. Spectra were acquired from anterior cingulate, temporal (right and left) and right or left parietal regions of interest (ROI). The voxel size for each of these was: cingulate: 40 40 20 mm; parietal 40 30 20 mm; temporal 40 20 20 mm. All ROI contained both grey and white matter and were placed entirely within the lobe of interest only, whilst being large enough to obtain good-quality spectra
Diagnosis Duration of symptoms (years)
ACE Total (/100)
Naming (/10)
VIQ
PIQ
Vocab
Blocks
GMI
2 4 2 (1995 7/10, 1997 0/10) 1 9 9
63 78 50 –
75 84 69 –
3 4 1 –
8 8 7 –
53 73 53 –
52 63 54
71 86 54
1 2 3
9 4 2
51 – –
1 2 3 4
61 65 61 65
F M M M
Semantic 7 Semantic 6 Semantic 6 Semantic 11
63 69 62 –
5 6 7
56 59 57
M M M
Semantic 6 Frontal 3 Frontal 4
56 69 58
WAIS III
WMS III
ACE Addenbrookes Cognitive Assessment; WAIS III Wechsler adult intelligence scale III; VIQ verbal IQ (normal range: mean = 100, standard deviation = 15); PIQ performance IQ (normal range: mean = 100, standard deviation = 15); Vocab/Blocks subtests of WAIS III (normal range: mean = 10 standard deviation = 3); WMS III Wechsler memory scale III; GMI general memory index
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Fig. 1 Coronal MRI sections from seven FTD patients. The structural scans comprised 5 mm T2 weighted images in three planes for voxel positioning, as well as an axial 3D T1 weighted Gradient echo sequence (T1TFE sequence) with 1 mm slice thickness and 0.98 mm in plane resolution. Temporal sections show marked asymmetrical atrophy of the temporal lobe in the SD patients but not in the frontal lobe patients
Subject 1
Subject 2
Subject 3
Subject 4
Subject 5
Subject 6
Subject 7
reliably (Fig. 2). Spectra were collected using PRESS (point resolved spectroscopy) sequence (repetition time (TR) = 2000ms, echo time (TE) = 30ms, 128 averages, 1024 points, 1000 Hz bandwidth). Chemical shift selective water suppression was used. Automated shimming took approximately 5 minutes, and data acquisition time per spectrum also took approximately five minutes. Spectra without water suppression were also collected (same voxel location) with variable TE (TR = 10000ms, TE = 30, 45, 67.5, 101, 200, 500, 1500 ms).
■ Analysis Spectra were analysed using the jMRUI program [13]. The residual water peak was removed with HLSVD filtering, spectra were phased using a non water-suppressed spectrum, and spectral areas were determined by fitting Lorentizian lineshapes with the AMARES algorithm. The unsuppressed spectra were processed in jMRUI to calculate water peak area for each echo time. Then a bi-exponential was fitted to the peak area verses echo time curve. The fast decaying component was taken as the brain water, a measure used as an estimate of
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Temporal volume
Frontal volume
Parietal volume
Fig. 2 Sample volumes used for spectroscopy. Algorithm for spectroscopic volumes: The temporal lobe volume was 40x20x20 mm and placed parallel to and centred along the superior temporal sulcus. It was constrained not to extend superiorly any further than the superior temporal plane and the posterior superior extent was positioned where the planum temporale angle changes. The medial border was positioned adjacent to the temporal horn of the lateral ventricle. The algorithm was designed to focus on upper temporal lobe to avoid the temporal bone and to avoid the most severely atrophic areas in semantic dementia patients. The frontal lobe volume (40x40x20 mm) was centred on the cingulate cortex and placed in the midline (no roll/yaw) over the lower cingulate cortex to abut third ventricle. The tilt plane was altered to achieve best fit of volume for individual patients. In the parietal lobe, the volume (40x30x20 mm) abuts the lateral ventricle and there was free rotation in roll/yaw/tilt planes
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the quantity of brain tissue in the voxel, and the slow decaying component as the cerebrospinal fluid [3]. Ratios of metabolite to brain water were calculated. Results are expressed as ratios with creatine (Cr) which is found in grey and white matter but not CSF and is conventionally used as a control for brain volume differences and variable amounts of CSF in the samples [4]. Group means for NAA/Cr and mI/Cr in the temporal, frontal and parietal lobes of patients and controls were calculated and compared.We carried out independent samples t-tests to compare the mean data between the groups in the presence of specific hypotheses about the regional results. NAA to brain water ratios were also calculated in order to validate creatine as an internal reference. Individual analyses were carried out by calculating Z scores for individual patients’ peak heights in each region based on the control population.
Results Spectra were acquired in all areas except for subjects 4 and 5 (left temporal) and subject 5 (parietal). Fig. 3 shows spectra acquired on all subjects. The quality of the spectra was assessed by visual inspection by MF. Despite mild movement artifact seen on some of the structural scans, good quality spectra were obtained in 25/28 volumes of interest. The poor quality of the missing spectra could have been due either to movement artifact or to poor shimming resulting in poor magnetic homogeneity.
■ NAA/Creatine – marker of neuronal integrity Comparison of the FTD and normal control groups revealed that the NAA/Cr ratio was significantly lower in the temporal (t = 2.64, p < 0.05) and frontal (t = 2.91, p < 0.01) lobes of patients with FTD than in normal controls (Fig. 4). There was no significant difference between parietal lobes of patients and controls. The Cr/brain water ratio was not significantly different between controls and patients in frontal, temporal or parietal regions. Further analysis was performed to see if individual patients with FTD could be separated from age-matched norms. Two of the FTD patients had abnormal Z scores in both temporal lobes (subject 2: left temporal Z score –6.06; right temporal Z score –2.95, subject 3: left temporal Z score –3.26; right temporal Z score –2.15). The two frontal variant FTD subjects had low Z scores in the frontal region as did one of the semantic subjects (cingulate Z scores: subject 5 = –2.3, subject 6 = –5.53 and subject 7 = –2.56).
■ mI/Creatine – marker of gliosis No significant differences were found in mI/Creatine ratio between the temporal or parietal lobes of normal control and FTD patients (Fig. 5). In the frontal ROI, mI/Cr was significantly higher in the FTD patients than
normal controls (t = 2.43, p < 0.05, one-tailed). This was particularly marked in the frontal presentation patients and the difference was no longer significant when these two patients were removed from the group. The mI/NAA ratios were also calculated in an attempt to refine group differences. There were significant group differences between the FTD patients’ and normal control subjects’ frontal lobes (t = 2.78, p < 0.05) using this measure. Individual analysis of the mI/Cr ratio showed that one of the semantic dementia subjects had a Z score of 3.04 in the left temporal lobe (subject 3). Both of the frontal presentation patients had raised Z scores in the frontal region (subject 6: cingulate Z score 1.99, subject 7: cingulate Z score 3.48). One of them also had a raised Z score in the parietal lobe (subject 7: parietal Z score 3.84). This suggests parietal lobe involvement in his disease process, perhaps reflecting the fact that he is in the more advanced stages of FTD, with other cortical regions being affected. Alternatively, he may be suffering from a more widespread cortical degeneration with an unusually frontal presentation.
■ NAA/brain water NAA/brain water varied similarly to NAA/Cr. There were significant differences between the frontal and temporal lobes of patients when compared to the same regions in control subjects (t = 2.303, p < 0.05 and t = 2.194, p < 0.05 respectively). There were no significant differences between the patients’ and normal controls’ parietal regions.
Discussion This work was carried out on patients with relatively advanced dementia and behavioural problems. Despite this we were able to obtain spectra of good quality and demonstrate significant group differences. These results were largely independent of the atrophy seen on structural imaging. The effects of reduced brain volume and variable CSF content in the samples were controlled for by expression of results as a ratio with creatine and also by using regions for spectroscopy in the temporal lobe that were deliberately chosen to avoid the most severely atrophic areas [12, 15]. Creatine is validated as an internal reference in our group of patients by its stability between regions and across subject groups and the finding that NAA/Cr and NAA/brain water varied similarly between FTD subjects and normal controls. Brain water is used as an estimate of the volume of brain tissue within a voxel [3]. Thus our spectroscopic findings mirror the pattern of abnormality seen on structural imaging without being directly caused by the atrophy. The results show that spectroscopic changes reflect
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L Temporal
R Temporal
Frontal
Parietal
1
2
3
4
5
6
7
Fig. 3 All spectra acquired from patients and example spectrum from Subject 1’s cingulate region (NAA n-acetylaspartate; Cho Choline; Cre Creatine; mI myo-inositol). Spectra were acquired from all four areas (left/right temporal, frontal and parietal) in all patients except for subject 4 and 5. This was due to excessive movement during the procedure. Approximate duration of scanning for full spectroscopy was 60 minutes
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Fig. 4 Graph of NAA/Cr in cingulate, temporal and parietal regions in FTD subjects and normal controls
or density in the fronto-temporal regions. Changes in mI/Cr are more variable in the FTD group. This perhaps reflects the heterogeneity of neuropathology particularly with regard to gliosis found at post mortem examination [18]. Importantly, the pattern of spectroscopic findings demonstrated here is different to that found in previous studies of established Alzheimer’s disease which have shown reduced levels of NAA and increased mI in occipital, parietal, temporal and frontal lobes [4]. The pattern of spectroscopic abnormality is consistent with the neuropsychological findings. The semantic dementia patients had all previously shown a pure verbal-semantic deficit. At the time of testing, all the patients showed more widespread cognitive impairment: despite this, specific patterns of performance were still found. For example, the block design subtest of WAIS III (a visuospatial task) was normal in all of the semantic patients who could be tested, in contradistinction to verbal tasks, which were abnormal in all subjects. One aim of the study was to investigate the potential of MR spectroscopy as a diagnostic technique.Although there was a significant reduction at a group level in NAA/Cr in the frontal and temporal lobes of FTD patients, it was not demonstrated in all individuals despite their well-established disease. This urges one to be cautious in using this technique to make individual-subject inference. However, it is possible that spectroscopy at an earlier stage of disease might show larger differences between temporal, parietal and other brain areas.A further limitation to the clinical application of MR spectroscopy is that the collection of separate single voxel spectra from different brain areas is somewhat time-consuming (one hour for this study). Chemical shift imaging provides a means of obtaining spectra from throughout the brain in a single acquisition which might be preferable in the clinical setting. Further work is required to examine these possibilities.
Supplementary Information ■ Summaries for seven FTD subjects (5 SD, 2 frontal variant FTD)
Fig. 5 Graph of mI/Cr in cingulate, temporal and parietal regions in FTD subjects and normal controls
the disease pattern described in pathological studies of FTD. There is a reduction in NAA/Cr in the frontal and temporal lobes but not in the parietal lobes of FTD patients suggesting selectively reduced neuronal viability
1. This 61-year-old right-handed woman had a seven-year history of difficulty with naming. She had difficulties finding the names of relatives, but not with recognising their faces and also a difficulty naming animate and inanimate objects. She developed prosopagnosia six years into the course of her illness. Her husband reported that she had become more stubborn. Initial cognitive testing showed a severe problem with naming, but otherwise relative preservation of cognitive function. Her initial MRI showed focal lateral left temporal atrophy. Her diagnosis was of semantic dementia. 2. This 65-year-old left-handed man had a six-year history of cognitive problems. His problems initially involved naming people in films and then progressed to naming previously familiar people and objects. His conversation deteriorated due to difficulty with general knowledge and understanding of concepts. His wife reported that he had a tendency to “rant”. There was no suggestion
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of prosopagnosia revealed during initial clinical or neuropsychological assessments. Initial cognitive testing showed reduced verbal fluency and a marked naming difficulty. MRI showed marked lateral left temporal atrophy. The diagnosis was semantic dementia. 3. This 61-year-old right-handed man had a 6-year history of problems with naming. His speech output was normal apart from difficulty with finding names of animate and inanimate objects. There was no suggestion of prosopagnosia. Neuropsychological testing showed a marked naming problem and reduced verbal fluency. The diagnosis was semantic dementia. 4. This 65-year-old right-handed retired policeman had a 12-year history of difficulty naming people and places. There was no suggestion of prosopagnosia. Initial cognitive screening showed a striking naming deficit and impaired episodic verbal memory, but other cognitive domains were preserved. MRI revealed marked left temporal atrophy and mild right temporal atrophy. His diagnosis was semantic dementia. 5. This 56-year-old right-handed retired fisherman had a 5-year history of behavioural changes. He reported difficulty with finding words to say and developed marked difficulty with reading and writing. He developed a sweet tooth. He became withdrawn and occasionally aggressive. At a stage when his naming was significantly impaired, he was able to function as a fisherman remembering the whereabouts of over 700 lobster pots. There was no suggestion of prosopagnosia. Initial neuropsychological assessment showed striking impairments restricted to the verbal do-
main. His initial MRI showed left temporal lobe atrophy. He was diagnosed with the semantic variant of frontotemporal dementia. 6. This 59-year-old right-handed retired businessman presented with a three-year history of a marked change in personality. His wife reported a complete loss of motivation and interest in all activities. He had also displayed some inappropriate social behaviour. His speech was fluent and he had no problems with verbal comprehension or memory. There was no suggestion of prosopagnosia. Initial neuropsychological testing showed impaired verbal and executive function. MRI revealed a pattern of mesial frontal atrophy. The diagnosis is of a frontal form of FTD with an abulic presentation. 7. This 57-year-old right handed retired off-shore oilrig worker had a 2-year history of cognitive problems. His wife reported an early behavioural change in that he had become much less assertive and less able to converse. He had no insight into his behaviour abnormalities. He had recently developed problems remembering things and some difficulty naming. There was no suggestion of prosopagnosia. Initial cognitive testing showed striking problems in multiple domains. MRI showed atrophy affecting the frontal lobes and the lateral rather than the medial temporal lobes, especially in the left with some white matter signal change especially on the left. His initial diagnosis was of a frontal variant of FTD or Alzheimer’s disease. ■ Acknowledgements The work was funded by the Wellcome Trust.
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