Amyotrophic Lateral Sclerosis

The word amyotrophic is derived from Greek, and means “without nourishment to muscles”, lateral means to the sides and sclerosis means hardened (“What is ALS?,” n.d.). First described by Jean-Martin Charcot in the 1800s, Amyotrophic Lateral Sclerosis (ALS) is a progressive degenerative motor neuron disease. Motor neurons are very important cells, and extremely unique since they can be very long with some motor neurons having a length of over a meter (“Disease Mechanisms,” n.d.). About 5-10% of the cases of ALS are inherited, which is known as familial ALS or fALS, and it is known as autosomal dominant in these patients (“Amyotrophic lateral sclerosis”, 2019; “ALS - amyotrophic lateral sclerosis,” n.d.). In the 1950s, there was an extraordinarily high rate of ALS diagnosis in Guam. There were about fifty cases of ALS in a group of 25,500 people, five of which were classified as familial cases. This was an indication to researchers that there may have been an unknown underlying cause. A few years later the researchers defined it as familial ALS with dominant inheritance (Mathis, Goizet, Soulages, & Vallat, 2018). In the other cases of this disease, known as sporadic ALS (sALS), the cause is unknown (“Amyotrophic lateral sclerosis (ALS)”, 2019). In the United States it is often referred to as Lou Gehrig’s disease, from the famous New York Yankee baseball player who had this disease in the 1940s. This specific type of motor neuron disease is the most common form of motor neuron disease in adults (“Amyotrophic lateral sclerosis”, 2015). Motor neurons are the neurons that control movements such as walking, talking, breathing, swallowing and others. These nerve cells expand from the brain to the spinal cord and then to muscles throughout the body that control voluntary muscle movement. When the motor neurons die, the brain can no longer initiate and control muscle movement due to lack of contact (“What is ALS?,” n.d.). This disease causes the motor neurons to slowly degenerate and, eventually, become hardened and die. Without neuronal stimulation to the muscles, the muscles begin to atrophy. ALS affects the motor neurons, cerebral cortex, brainstem and spinal cord (“ALS - amyotrophic lateral sclerosis,” n.d.)

How predictive are temporal lobe changes of underlying TDP-43 pathology in the ALS-FTD continuum?

Detection of underling proteinopathies is becoming increasingly important across neurodegenerative conditions due to upcoming disease intervention trials. In this review, we explored how temporal lobe changes in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) can potentially predict underlying TDP-43 pathology subtypes in FTD. To date, emphasis has been given to frontal lobe changes in the study of the cognitive and behavioural impairments in both syndromes but an increasing number of pathological, imaging and neuropsychological studies suggest how temporal lobe changes could critically affect the cognition and behaviour of these conditions. In this current article, we reviewed pathological, imaging as well as clinical/neuropsychological findings of temporal involvement in the ALS-FTD continuum, how they relate to temporal lobe changes and the underlying TDP-43 pathology in FTD. Findings across studies show that TDP-43 pathology occurs and coincides in many structures in ALS and FTD, but especially in the temporal lobes. In particular, anterior and medial temporal lobes atrophy is consistently found in ALS and FTD. In addition, memory and language impairment as well as emotional and Theory of Mind (ToM) processing deficits that are characteristics of the two diseases are highly correlated to temporal lobe dysfunction. We conclude by showing that temporal lobe changes due to TDP-43 type B might be particular predictive of TDP-43 type B pathology in behavioural variant FTD (bvFTD), which clearly needs to be investigated further in the future

Widespread Structural and Functional Connectivity Changes in Amyotrophic Lateral Sclerosis: Insights from Advanced Neuroimaging Research

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease principally affecting motor neurons. Besides motor symptoms, a subset of patients develop cognitive disturbances or even frontotemporal dementia (FTD), indicating that ALS may also involve extramotor brain regions. Both neuropathological and neuroimaging findings have provided further insight on the widespread effect of the neurodegeneration on brain connectivity and the underlying neurobiology of motor neurons degeneration. However, associated effects on motor and extramotor brain networks are largely unknown. Particularly, neuropathological findings suggest that ALS not only affects the frontotemporal network but rather is part of a wide clinicopathological spectrum of brain disorders known as TAR-DNA binding protein 43 (TDP-43) proteinopathies. This paper reviews the current state of knowledge concerning the neuropsychological and neuropathological sequelae of TDP-43 proteinopathies, with special focus on the neuroimaging findings associated with cognitive change in ALS

Apraxia and motor dysfunction in corticobasal syndrome

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.   Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.   Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.   Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy

Cerebral Hemodynamic Disturbances in Motor Neuron Disease

An association between motor neuron disease (MND) and dementia was first realized in the late 1800s, yet substantiating research and a description of dementia as part of the clinical syndrome would not appear until the 1990s. In the last two decades, medical imaging has investigated cerebral blood flow changes in the motor and nonmotor cortex to correlate with motor dysfunction and clinical dementia, respectively. The aim of this thesis is to describe early cerebral hemodynamic disturbances with the goal to determine a marker for cognitive decline in MND. Chapter 2 describes the relationship between changes in cerebral hemodynamics and cognition in primary lateral sclerosis (PLS) patients compared to normal controls. Neuropsychological testing revealed subtle frontotemporal changes characterized by executive dysfunction that were associated with global increases in mean transit time (MTT) in grey and white matter, and increased cerebral blood volume (CBV) in the frontotemporal grey matter. Chapter 3 presents a longitudinal clinical study of early cerebral hemodynamic changes in amyotrophic lateral sclerosis (ALS) patients without evidence of cognitive impairment at study onset. This Chapter characterized the relationship between duration of disease and MTT in the cortical grey matter. MTT was found to be the most sensitive indicator of early cerebral hemodynamic change accompanying disease progression in ALS. Furthermore, these findings corroborate the trend of increased MTT in the absence of cognitive impairment found in PLS patients in Chapter 2, and may further indicate that hemodynamic changes may occur before the onset of cognitive impairment. in The aim of Chapter 4 was to elucidate a biological mechanism for increased MTT described in the previous Chapters 2 and 3. A rabbit model of global hypotension was used to demonstrate that MTT is an indicator of cerebral perfusion pressure (CPP). A spectrum of cognitive dysfunction has now been described in MND. The use of sensitive neuropsychological testing has enabled us to identify patients with mild changes in cognitive function from those who are cognitively intact. With the help of this stratification, we were able to show that changes in MTT was associated with disease progression and cognitive impairment. The experimental data presented in this thesis suggest that vascular factors may contribute to cognitive dysfunction in MND

Tackling clinical heterogeneity across the Amyotrophic Lateral Sclerosis-Frontotemporal Dementia spectrum using a transdiagnostic approach

The disease syndromes of amyotrophic lateral sclerosis and frontotemporal dementia display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke’s Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant frontotemporal dementia (n = 58) and amyotrophic lateral sclerosis-frontotemporal dementia (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippocampus, amygdala, thalamus, and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-amyotrophic lateral sclerosis patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the amyotrophic lateral sclerosis-frontotemporal dementia and behavioural variant frontotemporal dementia groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76-90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in amyotrophic lateral sclerosis-frontotemporal dementia relative to pure-amyotrophic lateral sclerosis. In contrast, pure-amyotrophic lateral sclerosis displayed significantly greater parietal atrophy. Both behavioural variant frontotemporal dementia and amyotrophic lateral sclerosis-frontotemporal dementia were characterised by volume decrease in the frontal lobes relative to pure-amyotrophic lateral sclerosis. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in amyotrophic lateral sclerosis-frontotemporal dementia compared to pure-amyotrophic lateral sclerosis, and greater left motor cortex and insula atrophy relative to behavioural variant frontotemporal dementia. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum, with key structures including the motor cortex and insula, Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum