Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.

Clinical diagnosis and management of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a genotypically and phenotypically heterogeneous disease, as reflected in the variability in age and site of onset, extent of extramotor involvement, and survival. Cognitive involvement is also common, and corroborates the connection between ALS and frontotemporal lobar degeneration. In this article, Robberecht and Swinnen review phenotypic heterogeneity in ALS and discuss some of its implications for understanding ALS pathogenesis and development of therapeutic interventions. Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3–5 years after onset—a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.

The phenotypic variability of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS; motor neuron disease) is a relentlessly progressive disorder. After half a century of trials, only one drug with modest disease-modifying potency--riluzole--has been developed. The diagnosis of this disorder is still clinical and there is a pronounced delay between the onset of symptoms and diagnosis, possibly beyond the therapeutic window. Bedside quantification of the involvement of the corticospinal tract and extramotor areas is inadequate and functional rating scales, forced vital capacity, and patient survival have been the measures of therapeutic response so far. Potential biomarkers that are sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being identified from analysis of the blood and cerebrospinal fluid, as well as from neuroimaging and neurophysiology studies. In combination, these biomarkers might be sensitive to early therapeutic effects and would reduce our reliance on animal models, which have uncertain relevance to sporadic ALS in human beings. Such biomarkers might also resolve complexities of phenotypic heterogeneity in clinical trials. In this Review, we discuss the development of biomarkers in ALS and consider potential future directions for research.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70293-X.pdf

Biomarkers in amyotrophic lateral sclerosis.

Mutation in the CHMP2B gene has been implicated in frontotemporal dementia. The authors screened CHMP2B in patients with ALS and several cohorts of control samples. They identified mutations (Q206H; I29V) in two patients with non-SOD1 ALS. Neuropathology of the Q206H case showed lower motor neuron predominant disease with ubiquitylated inclusions in motor neurons. Antibodies to p62 (sequestosome 1) showed novel oligodendroglial inclusions in the motor cortex.

https://n.neurology.org/content/neurology/67/6/1074.full.pdf

ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B)

Objective: Examining the unresolved relationship between the lower motor neuron disorder progressive muscular atrophy (PMA) and ALS is important in clinical practice because of emerging therapies. Methods: Spinal and brainstem tissues donated from patients with ALS/motor neuron disorder (n = 81) were examined. Using retrospective case note review, the authors assigned patients into three categories: PMA (12), PMA progressing to ALS (6), and ALS ab initio (63). Conventional stains for long tract degeneration and immunocytochemistry for ubiquitin and the macrophage marker CD68 were examined. Results: Rapid progression and typical ubiquitinated inclusions in lower motor neurons were present in 77 (95%) of the cases. Immunocytochemistry for CD68 was a more sensitive marker of long tract pathology in comparison with conventional stains. Half of the cases with PMA showed corticospinal tract degeneration by CD68. Conclusion: Patients with PMA frequently have undetected long tract pathology and most have ubiquitinated inclusions typical of ALS. A patient presenting with PMA with rapid clinical evolution likely has the pathology and pathophysiology of ALS whether or not upper motor neuron signs evolve.

M. Knopp

Papers

Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS.