Summary:
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 scvanning with high resolutiob 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 Statistica
(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.
Keywords:
Amyotrophic lateral sclerosis, Diffusion tensor imaging, Voxel-based morphometry, Transcranial magnetic stimulation, Neuropsychological assessment
