C63 ALS and frontotemporal lobar degeneration (FTLD): dysfunctional family or distant relatives?
Strong MJ
Department of Clinical Neurological Sciences, The University of Western Ontario, London, Ontario, Canada
E‐mail address for correspondence: [email protected]
Once considered to be a discrete neurodegenerative disorder restricted to the motor system, ALS is increasingly recognized to be a syndrome in which multiple neuronal systems can be involved. Paramount among this has been the recognition that ALS may be associated with a frontotemporal lobar degeneration. The clinical spectrum of such dysfunction can include behavioural impairments (ALS with behavioural impairment: ALSbi), cognitive dysfunction in which impairments in verbal fluency and list generation may be the earliest evidence of dysfunction (ALS with cognitive impairment: ALSci), a more florid frontotemporal dementia meeting the Neary criteria (ALS‐FTD) or a more widespread dementia (ALS with dementia: ALS‐D). It remains unknown whether these are discrete clinical presentations, or part of a continuum or spectrum. Depending on the nature of the neuropsychological studies, the incidence among the ALS population of such deficits may range from 30% to 50% or more, with the vast majority exhibiting only subtle deficits.
The neuropathological and molecular basis of this process is consistent with a frontotemporal lobar degeneration (FTLD), leading to the concept that there is significant overlap between the FTLDs and ALS on a biological basis. The neuropathological hallmark includes superficial linear spongiosus, both a microglial and astrocytic proliferative response within the frontotemporal neocortex, and the presence of ubiquitinated intraneuronal aggregates within the dentate fascia. In common with many of the FTLDs, FTLD in ALS is a tauopathy as evidenced by the presence of intraneuronal and glial tau aggregates, tau immunoreactive neuritic processes and argyrophilic grains throughout the affected regions. Although these features are shared with many of the tau‐based FTLDs, the molecular signature of FTLD in ALS is unique with normal expression levels of 3R and 4R transcripts, increased 3R and 4R insoluble tau protein, and hyper‐phosphorylation of tau protein with unique phosphoepitopes.
The clinical and biological implications of FTLD in ALS are considerable. Clinically, patients with FTLD and ALS are less likely to participate in interventional therapies such as non‐invasive ventilation and are thus in a poorer prognostic subgroup. Biologically, this observation dispels the notion of ALS as a single disease entity and confirms the clinical hypothesis that ALS is syndromic with the potential for biological overlap between ALS and the FTLDs. Within the rubric of the FTLDs, a distinctive molecular signature for ALSci exists. The recognition of FTLD concurrently with ALS will have design and interpretive implications for therapeutic trials in ALS.
Acknowledgement: This work was supported by the ALS Society of Canada, the ALS Association (ALSA) and the McFeat family fund.
C64 AN FMRI INVESTIGATION OF THE NEURAL BASIS OF EMOTIONAL LABILITY IN MOTOR NEURON DISEASE (MND)
Newsom‐Davis IC1, Simmons A2, Bryant V1, Leigh PN3 & Goldstein LH1
1Department of Psychology, Institute of Psychiatry, London, 2Centre for Neuroimaging Sciences, Institute of Psychiatry, London, and 3Department of Neurology, Institute of Psychiatry, London, UK
E‐mail address for correspondence: [email protected]
Background: Emotional lability (EL) is seen in ∼20% of cases of MND although its neural basis has not previously been studied. The association of EL with pseudobulbar symptoms in MND had led to the assumption that loss of control of laughter/crying resulted from degeneration of corticobulbar pathways disrupting the execution of motor programmes for emotional expression. However, recent evidence for extra‐motor prefrontal cortex (PFC) involvement in a proportion of non‐demented MND patients, affecting associated inhibitory executive functions, combined with findings that such cognitive dysfunction may be more common in patients with bulbar symptoms, raises the possibility that, in MND, EL represents the loss of inhibition of emotional expression as a result of degeneration of PFC regions mediating emotional control.
Objectives: To explore the neural basis of the control of emotional expression, and to attempt to distinguish between these alternative aetiological hypotheses for EL in MND.
Methods: A functional magnetic resonance imaging (fMRI) paradigm was designed to evaluate the inhibition of emotional expression in response to amusing compared to neutral film stimuli. After careful testing in off‐line trials and an fMRI pilot, it was then administered to emotionally labile MND patients (MND‐EL, n = 7), non‐labile MND patients (MND‐NEL, n = 7), and healthy controls (n = 8) during fMRI scanning.
Results: Significant increases in brain activation were recorded for MND‐EL patients compared to the other two groups during the emotion inhibition task. The largest and most significant cluster was observed in the left medial frontal gyrus (Brodmann Area (BA) 9/10), with further smaller areas of increased activation affecting the superior and middle temporal gyri (BA 21/22), predominantly on the left.
Discussion and conclusions: Our findings suggest that EL in MND is not associated with PFC dysfunction, but instead implicates recruitment of left hemisphere medial PFC regions in the control of emotional expression. While the excess activation in BA 9/10 seen in the MND‐EL group may represent attempts to suppress a labile reaction caused by dysfunction lower down in the neural circuit mediating emotional expression, ongoing studies may clarify whether the identification of regions of cortical cell loss can further the understanding of cerebral abnormalities underlying EL in MND.
C65 MAGNETIC RESONANCE (MR) DIFFUSION TENSOR IMAGING (DTI) AND SPECTROSCOPIC IMAGING (MRSI) DETECT WIDESPREAD FRONTAL LOBE INVOLVEMENT IN ALS
Ulug A1, Watts R2, Mao X1, Kloosterman A2, Shungu D1, Chan S1, Battista V3, Hays A3 & Mitsumoto H3
1Cornell University, New York, USA, 2Univ of Canterbury, Christchurch, New Zealand, and 3Columbia University, New York, USA
E‐mail address for correspondence: [email protected]
Background: ALS is a disease that affects mainly motor neurons. Various MR imaging methods were used in the past to visualize the disease involvement in motor cortex and corticospinal tract. It has been known from pathology, PET studies, and volumetric analysis that other regions of the brain, particularly the frontal lobe, are affected in ALS.
Objective: To determine the extent of brain alterations in ALS using MR DTI and MRSI.
Methods: We studied 27 consecutive clinically non‐demented ALS patients and 12 age‐matched controls. The subjects were imaged with a clinical 1.5 T MR scanner and quadrature head coil. A single‐shot EPI diffusion tensor sequence is used to collect imaging data from 30 slices covering the entire brain. The slice thickness was 5 mm, FOV 22 cm; the imaging matrix was 128×128. We collected diffusion‐weighted images from 26 gradient directions, and six images without diffusion weighting. A total of 32 images per slice were acquired. Using all the images, we calculated the components of the diffusion tensor for every pixel. Maps of average diffusion constant (Dav) and diffusion anisotropy (FA) were then calculated. Using SPM (Statistical Parametric Mapping package) and MATLAB, we warped the diffusion tensor images from each subject into an image template. Using a t‐test, we then computed the regions that were either increased in Dav or decreased in FA in patients in comparison to controls. We then overlaid these regions onto either axial Dav or FA maps or 3D white matter volume rendered from the subject group. MRSI was also recorded on the same 1.5 T MR scanner with a highly optimized and almost fully automated multislice MRSI pulse sequence, in 27 min using a 240‐mm field of view, a TR of 2300 ms, 32×32 circularly applied phase‐encoding steps, and one excitation per phase‐encoding step. N‐acetylaspartate concentration was measured in multiple voxel localized within the anterior frontal cortex and the visual cortex in the second topmost of four slices recorded. Each voxel had a nominal size of 0.83 cc, allowing multiple uncontaminated spectral voxels.
Results: Our methods successfully visualized abnormal MR DTI variables in motor cortex and pyramidal tracts in ALS patients. In addition, we were able to show statistically significant (p<0.001 compared to controls) extensive frontal lobe regions that are involved by the disease process in the group of patients we studied. N‐acetylaspartate concentration in the frontal cortex of ALS patients was 6.6±1.6 on the right (controls 8.2±2.0, p = 0.009), 6.4±2.1 on the left (controls 8.2±2.1, p = 0.022), and the mean of both cortices in ALS was also significantly reduced (p = 0.007). There were no differences in N‐acetylaspartate concentrations in visual cortex between ALS and controls.
Discussion and conclusion: MR DTI visualized areas in extensive frontal lobe that are involved in ALS in addition to motor cortex and corticospinal tracts. These changes also involve frontal cortical neurons by measuring N‐acetylaspartate concentration. To the best of our knowledge, this is the first time that widespread ALS involvement in the frontal lobe can be visualized using both MR DTI and MRSI imaging studies.
Acknowledgement: This study was supported in part by a grant from National Institute of Neurological Disorders and Stroke (HM/DS, R01‐NS41672), MDA Wings Over Wall Street, and ALSA (AU).
C66 COGNITIVE IMPAIRMENT IN PRIMARY LATERAL SCLEROSIS
Grace GM1, Orange JB2, Murphy M2, Lee T‐Y2, Rowe A1, Findlater K1 & Strong MJ2
1London Health Sciences Centre, London, and 2University of Western Ontario, London, Canada
E‐mail address for correspondence: [email protected]
Background: Primary lateral sclerosis (PLS) is a rare upper motor neuron disease with adult onset. To date, there has been limited systematic investigation of the neuropsychological features of the disease, and no investigation into its emotional/behavioural features.
Objectives: The goal of the current study was to complete a prospective investigation of the possible cognitive and emotional/behavioural effects of PLS in a relatively large series of patients (n = 18).
Methods: Five major domains of neuropsychological functioning were assessed: executive skills; attention/concentration; visual‐perceptual/constructional skills; memory; and emotional/behavioural functioning. Tests were chosen to minimize the requirements for speech and manual motor skills. All scores were converted into T‐scores (mean of 50, SD of 10) based on normative samples, corrected when possible for age and education. For the purposes of this study, a T‐score less than 40 (less than 1 SD below the mean) was considered an abnormal performance. A patient's overall performance was considered impaired if he/she scored in the abnormal range on two or more measures.
Results: Results indicated a considerable amount of heterogeneity with some patients showing no impairment and others showing significant deficits. Overall, 11 out of 18, or 61% of patients were considered to be cognitively impaired. The areas of cognition most affected were as follows: oral word fluency (50% of subjects impaired); spatial working memory (40% impaired); verbal list learning (33% impaired); and auditory verbal working memory (29% impaired). There was no relationship between cognitive functioning and various disease parameters including disease duration, current site of disease, site of onset, and respiratory variables. Only three patients endorsed significant symptoms of depression. Results of behavioural inventories administered to patients' caregivers indicated abnormal behavioural symptoms (to be described) in a majority of patients.
Discussion and conclusions: 1) Patients with PLS are heterogenous with respect to cognitive impairment and behavioural symptoms; 2) However, the majority have at least mild cognitive impairment, and many have abnormal behavioural symptoms; 3) Deficits are most prominent in the areas of executive functioning, working memory, and learning efficiency; 4) Though not in the range of frontotemporal dementia, behavioural symptoms are common; 5) The findings are consistent with frontal circuitry dysfunction; and 6) The cognitive profile of PLS patients is very similar to that of sporadic ALS. These results suggest that cognitive impairment in PLS and ALS both result from dysfunction of similar neuroanatomical regions.
Acknowledgement: This research was supported by ALSA.
C67 COGNITIVE VULNERABILITY IN SUBGROUPS OF MND
Wicks P, Abrahams S, Papps B, Leigh PN & Goldstein LH
Institute of Psychiatry, London, UK
E‐mail address for correspondence: [email protected]
Background: Traditionally intellect was thought to be preserved intact among patients with MND. However, it is now accepted that MND is associated with frontotemporal dementia (FTD) in 3–5% of sporadic ALS cases, and ∼15% of familial ALS cases. In addition, a larger group of patients displays mild cognitive deficits, and these can be detected only by detailed neuropsychological assessment. However, few studies have investigated cognitive change in rarer subgroups of MND to investigate the possibility of differential cerebral vulnerability.
Objectives: To identify the profile of cognitive, behavioural and emotional change in three subgroups of MND patients: sporadic ALS, familial ALS, progressive muscular atrophy (PMA), and a group of matched healthy controls. As a higher proportion of familial ALS cases are associated with FTD it was predicted that they would show higher levels of cognitive and behavioural change. By contrast, as PMA patients lack upper motor neuron (UMN) involvement it was predicted they would perform as well as healthy controls.
Methods: Forty‐one sporadic ALS patients, 15 familial ALS patients, 10 PMA patients, and 35 healthy controls matched for age and IQ were recruited. They underwent a range of neuropsychological tests evaluating executive functions, memory, language, and visuospatial perception. Patients and carers completed behavioural self‐report questionnaires on aspects of dysexecutive function, behavioural change and emotional lability. Overall group differences were assessed by one‐way ANOVAs with post‐hoc Bonferroni analyses to identify deficits in MND subgroups relative to controls.
Results: While familial ALS and PMA patients had a longer disease duration, all patients had a similar level of functional disability. Relative to controls, familial ALS patients demonstrated deficits on tests of sentence completion, judgement of line orientation, and higher levels of self‐rated executive dysfunction following disease onset. In addition, there was an overall between‐groups trend for verbal fluency, accounted for by poorer performance by familial ALS patients relative to controls. Sporadic ALS patients had deficits on tests of confrontation naming and higher levels of emotional lability. PMA patients performed in a manner comparable to the control group.
Conclusions: Results support the hypothesis that familial ALS patients may be more susceptible to cognitive and behavioural change, suggesting a different pattern of cerebral vulnerability from sporadic ALS and PMA patients.