Abstract
Background: Amyotrophic Lateral Sclerosis (ALS) is the most fatal and major diagnostic category of motor neuron diseases and is characterized by involvement of both the upper (central) motor neuron and lower (peripheral) motor neuron resulting in patient’s death three to five years from the time of diagnosis, mainly because of respiratory insufficiency. The traditional view of ALS as a pure motor disease with any extra-motor involvement being described only in frontal areas and characterized by mild executive dysfunction or behavioral changes according to the ALS-Frontotemporal Dementia (FTD) continuum, has been totally updated. ALS is now regarded as multi-systematic disease with change within and beyond the primary motor cortex, the corticospinal tract and frontal associative areas, which leads in an extended map of multiple affected areas in gray (cortical and subcortical) and white matter. By means of phenomenology, these changes are evident as fasciculations, muscle weakness and m ...
Background: Amyotrophic Lateral Sclerosis (ALS) is the most fatal and major diagnostic category of motor neuron diseases and is characterized by involvement of both the upper (central) motor neuron and lower (peripheral) motor neuron resulting in patient’s death three to five years from the time of diagnosis, mainly because of respiratory insufficiency. The traditional view of ALS as a pure motor disease with any extra-motor involvement being described only in frontal areas and characterized by mild executive dysfunction or behavioral changes according to the ALS-Frontotemporal Dementia (FTD) continuum, has been totally updated. ALS is now regarded as multi-systematic disease with change within and beyond the primary motor cortex, the corticospinal tract and frontal associative areas, which leads in an extended map of multiple affected areas in gray (cortical and subcortical) and white matter. By means of phenomenology, these changes are evident as fasciculations, muscle weakness and motor difficulty, but also include several cognitive impairments (both executive and non-executive), behavioral changes or emotional lability (pathological laughing and crying). Aim: The aim of the present thesis was the structural and functional investigation of motor and extra-motor involvement in ALS using advanced neuroimaging techniques and methods of clinical neurophysiology and neuropsychology. Methods: We included 75 patients with sporadic ALS (based on revised El Escorial criteria) without dementia. Patients’ data were entered in the database “AMATUM ALS” (Acquisition, Management, Analysis, Therapeutic Unique Monitoring for Amyotrophic Lateral Sclerosis Database). A comprehensive neuropsychological assessment was administered to all patients (cognitive domains: executive functions, attention & working memory, learning-memory, expressive language, visuospatial-constructive dexterities, symbolic reasoning) who were also evaluated for the presence of severe clinical depressive symptoms and emotional lability. Based on normative data for each neuropsychological measures and according to widely-used criteria for ALS-related cognitive impairment, all patients were categorized into two subgroups: a) ALS-motor (pure motor involvement without cognitive impairment) and b) ALS-plus (motor involvement and cognitive impairment). Twenty-five healthy controls with normal general mental status and 50 (out of 75) ALS patients were included in the neuroimaging scanning with high resolution sequences for further investigation of changes in gray matter [HR_3DT1w sequence, voxel-based morphometry (VBM) analysis] and white matter [30dir-DTI sequence, Tract-Based Spatial Statistics (TBSS), Diffusion Tensor Imaging (DTI) Tractography for specific white matter tracts]. Seventeen ALS patients (with available neuropsychological and neuroimaging data) were included in the neurophysiological evaluation with transcranial magnetic stimulation (TMS) for the investigation of functional integrity of pyramidal tract, corpus callosum and motor cortex. Results: 1. Neuropsychological profile: More than 65% of ALS Greek patients show cognitive impairment. Executive functions are mostly affected and 47% of patients show executive impairment (with or without other cognitive impairment). 20% of patients show pure memory impairment without executive or other cognitive impairment. Executive performance is associated with memory performance in the total ALS sample but accounts only for 9% of the variance in memory performance. 2. Neuroimaging profile of gray and white matter: ALS patients show diffuse changes in gray matter and white matter both in pure motor areas (motor cortex, sensorymotor part of cerebellum, corticospinal tract, body of the corpus callosum) and extra-motor areas (medial, orbital and dorsolateral frontal areas, temporal areas, occipital areas). ALS-motor patients show increased gray matter volume compared to healthy controls in right supplementary motor area. ALS-plus patients show more diffuse changes in motor and extra-motor regions compared to healthy controls. Compared to ALS-motor patients, ALS-plus patients show decreased gray matter volume in left precuneus. The combined use of advanced neuroimaging techniques and methods of post-processing analysis enable the identification of brain areas with both gray and white matter changes. 3. Structural integrity of motor cortex and corticospinal tract and motor disease severity: We found a) positive association between the degree of disease severity (ALSFRS-R) and gray matter volume in left precentral gyrus; b) negative association between ALSFRS-R and gray matter volume in left supplementary motor area; and c) negative association between ALSFRS-R and Daxial in left corticospinal tract.4. Structural integrity of motor cortex, corticospinal tract and callosal fibers and functional integrity of motor system based on TMS: The functional integrity of the corticospinal tract is related to gray matter structural changes, irrespective to corticospinal tract involvement. We found a) positive association between gray matter volume of right precentral gyrus and MEP / M ratio recorded from the right APB (decreased gray matter volumes is related to decreased MEP / M ratio); b) negative association between gray matter volume in right supplementary motor area and MEP / M ratio (increased gray matter volume is related to decreased MEP / M ratio). Using the Brainance DTI Suite that enables the tractography of both crossing and non-crossing corticospinal tract fibers, we found that interhemispheric inhibition (IHI) can be pathologically increased due to different involvement of crossing and non-crossing fibers. Specifically, we observed a) negative association between ΙΗΙ and FA in left corticospinal tract [decreased FA (worse microstructural integrity) is related to increased IHI]; b) positive association between IHI and Dradial in right corticospinal tract [increased Dradial (worse microstructural integrity) is related to increased IHI]; and c) negative association between silent perior (SP) and FA in left corticospinal tract (decreased FA is related to increased SP). 5. Degree of extra-motor structural white matter changes and memory impairment: After correcting for multiple comparisons, ALS patients showed increased Dradial in the left perforant pathway zone (PPZ) compared to HC and impaired microstructural integrity in fornix and uncinate fasciculus. For the first time, we support the contribution of left PPZ integrity in ALS patients verbal learning performance and the contribution of left PPZ and uncinate fasciculus in long-term verbal recall. 6. Degree of extra-motor structural gray matter changes and emotional lability [pseudobulbar affect (PBA)/pathological laughing and crying]: Compared to healthy controls, ALS patients with PBA show reduced gray matter volume in frontal (inferior orbitofrontal gyrus, rectus), temporal (superior temporal gyrus), occipital (cuneus, fusiform gyrus, lingual gyrus) lobes, in anterior cingulate gyrus and in cerebellum bilaterally. Compared to ALS patients without PBA, ALS patients with PBA show decreased gray matter volume in right precunues/posterior cingulate gyrus and middle temporal gyrus, in accordance with the contribution of right hemisphere in emotional processing and perception. 7. The prognostic role of structural (neuroimaging) and functional (neuropsychological) changes in disease progression rate: Verbal learning ability is a negative prognostic factor, with reduced verbal learning ability being related to faster progression rate. Reduced gray matter volume in bilateral basal ganglia (putamen) and left superior temporal gyrus is associated with faster progression rate. Finally, increased Daxial in the body of the corpus callosum is also related to faster disease progression rate.Conclusions: With a background of almost two centuries from the first descriptions of Bell and Aran and less than a half century from the description of Charcot and the introduction of the term Amyotrophic Lateral Sclerosis (ALS), the disease has definitively a multisystematic character, with great diversity regarding the range and severity of clinical and subclinical (motor and extra-motor) symptomatology and prognosis being difficult to be accurately determined based on statistical models. However, it is a disease that confirms the paradigm shift (according to Kuhn) which is the result of both linear and non-linear accumulation of new knowledge from the methods of classical neurophysiology and neuropsychology and advanced neuroimaging techniques.
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