Whilst the diagnostic use of El Escorial Criteria has been shown to correlate well with neuropathological features in ALS (Chaudhuri et al. 1995), diagnosis can only be absolutely certain on necroscopy. The major pathological features of ALS are degeneration of the corticospinal tracts and extensive loss of lower motor neurons (LMNs) or anterior horn cells (Ghatak et al., 1986 Hughes, 1982 Leigh and Garofolo, 1995), degeneration and loss of Betz cells and other pyramidal cells in the primary motor cortex (Hammer et al., 1979 Maekawa et al., 2004 Udaka et al., 1986 and reactive gliosis in the motor cortex and spinal cord (Ekblom et al., 1994 Kawamata et al., 1992 Murayama et al., 1991 Schiffer et al., 1996
An established hallmark of ALS is the presence of various inclusion bodies in degenerating neurones and surrounding reactive astrocytes (Barbeito et al., 2004 Ubiquitinated inclusions are the most common and specific type of inclusion in ALS and are found in LMNs of the spinal cord and brainstem (Matsumoto et al., 1993 and in corticospinal UMNs (Sasaki and Maruyama, 1994 They are classified as ‘Lewy body-like inclusions’ (LBIs) and ‘Skein-like inclusions’ (SLIs) (He and Hays, 2004 Kawashima et al., 2000 The exact composition of such inclusions is not known, although proteins identified so far include (in varying amounts) ubiquitin (Leigh et al., 1991 Murayama et al., 1989 Cu/Zn superoxide dismutase 1 (SOD1) (Shibata et al., 1996; Shibata et al., 1994), peripherin (He and Hays, 2004 and Dorfin (a RING-finger type E3 ubiquitin ligase) (Niwa et al., 2002 Accumulations of intermediate filament proteins (mainly hyperphosphorylated neurofilament subunits and peripherin) are found in hyaline conglomerate inclusions (HCIs) and axonal ‘spheroids’ in spinal cord motor neurons (Corbo and Hays, 1992 Munoz et al., 1988 Sobue et al., 1990 and pyramidal cells of the motor cortex (Troost et al., 1992 in ALS post-mortem tissue.
Additionally, Bunina bodies (BBs), which are cystatin C-containing inclusions, are found in the cell bodies of motor neurons in ALS (Okamoto et al., 1993 Sasaki and Maruyama, 1994 although these are now thought to be less specific for ALS than the ubiquitinated and neurofilamentous inclusions, as they are similar to structures found in neurons of aged rats and humans (Kusaka, 1999 Another subtype of inclusion bodies found in MND are Crescent Shaped Inclusions (SCIs), often found in the upper layers of the cortex and dentate gyrus in MND-Dementia (al Sarraj et al. 2002). UIBs are thought to result from the breakdown of abnormal proteins caused by oxidative stress, implicated in the pathogenesis of ALS (Alves-Rodrigues et al. 1998). They are also found in transgenic mice expressing the G93A SOD1 mutation, a model of Familial ALS (Ince et al. 1998).Other neuropathological features seen in ALS include fragmentation of the Golgi apparatus (Fujita et al., 2000 Fujita et al., 2002 Gonatas et al., 1998 mitochondrial vacuolisation (Okamoto et al., 1990 and ultrastructural abnormalities of synaptic terminals (Sasaki and Iwata, 1996
Pathological features of ALS-FTD
In addition to the typical signs of neuronal degeneration in ALS (see above), neuropathological changes in ALS-FTD consist of cortical atrophy (including the frontal and temporal lobes (Nakano 2000), hippocampus and amygdala (Anderson et al. 1995;Wilhelmsen et al. 2004)), spongiform change in the neocortex (Wilson et al. 1996), and UIBs in the substantia nigra (al Sarraj et al. 2002). Furthermore, the presence of SCI-type UIBs in the neostriatum has been found to be a feature specific to ALS-FTD, not occurring in a variety of other neurodegenerative disorders including Pick’s disease, Parkinson’s, and Alzheimer’s disease (Kawashima et al. 2001 Alzheimer’s disease may also be excluded by the absence of neurofibrillary tangles (Horoupian et al. 1984). Whilst there is evidence of some change in the substantia nigra in ALS-FTD, neuronal loss is less pronounced than that found in Parkinson’s disease and occurs in the absence of other clinical signs of this disease such as resting tremor and bradykinesia (al Sarraj et al. 2002; Horoupian et al. 1984).
Extra-Motor pathology in ALS with cognitive impairment
In parallel with the progression of research in neuropsychology and neuroimaging, neuropathological studies have also identified extra-motor changes in ALS. As in neuroimaging, neuropathology studies demonstrate a relationship between the density and distribution of pathological changes and cognitive correlates observed in the living patient. Wilson et al compared 4 cognitively unimpaired ALS patients with 4 healthy controls and 4 cognitively impaired ALS patients as defined by poor performance on neuropsychological testing (Wilson et al. 2001). They found that whilst UIBS were found amongst all ALS patients in the dentate gyrus, frontal and parietal neocortices, anterior cingulate gyrus, and hippocampus, the density and distribution of these inclusions was higher in cognitively-impaired ALS patients than in the unimpaired group. In addition to these changes, cognitively impaired patients also had UIBs in the temporal, occipital and entorhinal cortices, posterior cingulate gyrus, caudate, and the putamen.
More pronounced contrasts were apparent comparing ALS patients with ALS-FTD patients. In a larger study comparing 19 ALS patients with 5 ALS-FTD patients (Kawashima et al. 2001 the authors looked in detail at the SCI subgroup of UIBs and found that whilst these were distributed heterogeneously, if at all, amongst the dentate gyrus, parahippocampal gyrus, amygdala, neostriatum, and anterior horn cells in ALS patients, they were numerous and almost uniformly present in patients with ALS-FTD. In particular, the number of SCIs in the second and third layers of the parahippocampal gyrus and amygdala was significantly higher in those with ALS-FTD than ALS. Considering 13 cases of ALS, a recent study by Maekawa et al quantified extra-motor neuronal loss in regions of the prefrontal cortex, specifically the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex, which had been implicated in neuropsychology and neuroimaging studies (Maekawa et al. 2004 Computerised morphometry revealed a 25% reduction in the pyramidal neuronal density in layer V of the pre-motor cortex, DLPFC, and anterior cingulate cortex (ACC) relative to 8 age-matched controls. This is particularly relevant in the context of findings from PET neuroimaging which identified decreased binding of the GABAergic ligand (11C)-Flumazenil in the prefrontal cortex (Lloyd et al. 2000; Turner et al. 2005a) and increased microglial activation (implicated in mechanisms of neuronal cell death) in the DLPFC (Turner et al. 2004). It is hoped that the validation of these imaging techniques in identifying in vivo neuropathological changes in ALS may one day be used in the diagnosis of specific ALS phenotypes (Turner et al. 2002).
MND Inclusion Body Dementia (MNDIBD)
Whilst ALS has traditionally been thought to affect only the motor neurones whilst sparing the central nervous system, the identification of Motor Neurone Disease Inclusion Body Dementia (MND-IBD) (Jackson et al. 1996) provides the antithesis; patients with MNDIBD initially display behavioural changes characteristic of FTD with language disturbances but do not display any signs of UMN or LMN involvement (Rossor et al. 2000). On neuropathological examination, ubiquitin-immunoreactive but tau-negative inclusions are found in the frontotemporal cortex, hippocampus, and dentate gyrus, identical to those described in non-motor areas in patients with ALS-FTD, but not in the corticospinal tract or motor system (Jackson et al. 1996). A recent study found that survival in MND-IBD was significantly longer (mean= 6 years) than ALS-FTD patients (mean= 2.9 years). The MND-IBD group also had a positive family history of any neurodegenerative or psychiatric disorder in 73% of cases, suggesting a strong component of heritability. Patients with ALS-FTD and MND-IBD differed from ALS patients by the presence of ubiquitinated cytoplasmic inclusions, dystrophic neurites, intranuclear inclusions in the dentate gyrus and/or superficial frontal cortex (Bigio et al. 2004).
Leigh, P.N., and O. Garofolo. 1995. The molecular pathology of motor neurone disease. In Motor neurone disease. M. Swash and P.N. Leigh, editors. Springer Verlag, London. 139-161.
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