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Stem Cell Therapy for Amyotrophic Lateral Sclerosis

Introduction Amyotrophic lateral sclerosis (ALS) is a terrifying diagnosis that strikes at the core of an individual’s function and productivity. The disease is characterized by progressive and selective degeneration of upper and lower motor neurons. This manifests as an insidious, inexorable decline in motor function, with progressively compromised strength, coordination, gait, swallowing, speech, and respiratory function. For nearly all those afflicted, this means first relying on…

Gene Therapy for Amyotrophic Lateral Sclerosis: Therapeutic Transgenes

Introduction As discussed in Chapter 4 , Molecular Mechanisms of Amyotrophic Lateral Sclerosis, amyotrophic lateral sclerosis (ALS) is a disease with a poorly understood etiology. There are a wide variety of abnormalities present, including mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress, astrogliosis and microgliosis, loss of innervation of neuromuscular junctions (NMJs), and death of motor neurons (MNs). However, the relative contribution of these factors to disease initiation…

Introduction to Gene and Stem-Cell Therapy

Introduction Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are devastating neurodegenerative diseases that are progressive and fatal. There is no cure and the current standard of care is merely palliative. For example, riluzole is the only FDA-approved treatment for ALS and extends life for 3–6 months. Due to the inability of conventional therapies to have an impact on these…

Genetics of Spinal Muscular Atrophy

Introduction Spinal muscular atrophy (SMA) refers to a group of disorders that affect the lower motor neuron, and a number of genes have been defined that cause SMA. The most common SMA is proximal SMA that maps to chromosome 5q. In contrast, the late-onset distal SMAs (DSMAs), which show considerable overlap with Charcot–Marie–Tooth disease phenotype, are mostly non-5q SMAs. For these disorders many genes have been…

An Introduction to the Natural History, Genetic Mapping, and Clinical Spectrum of Spinal Muscular Atrophy

Introduction: Epidemiology The neurodegenerative disease spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality worldwide. Incidence and prevalence estimates vary widely across populations sampled; studies have estimated the incidence of SMA at 7.8 in 100,000 births (Northeast Italy), 9.80 in 100,000 births (West-Thuringen, Germany), and 3.53 per 100,000 births (Cuba). The study in Cuba further analyzed incidence by self-reported race, and noted a…

Molecular Mechanisms of Amyotrophic Lateral Sclerosis

Introduction Amyotrophic lateral sclerosis (ALS) is recognized as the most common form of adult-onset motor neuron disease. This progressive, fatal neurodegenerative disorder occurs in approximately two persons per 100,000. Since the initial description of the symptoms and associated pathology in 1874, considerable insights into the genetic, molecular, and biochemical mechanisms of ALS have been gained. The pathological hallmark of ALS is the death of pyramidal motor…

Genetics of Amyotrophic Lateral Sclerosis

Introduction Studies of disease concordance rates among monozygotic and dizygotic twins suggest that 53–84% of amyotrophic lateral sclerosis (ALS) population risk is genetically determined. * * Refers to the proportion of disease risk that is genetically determined both within and across all individuals of a population, not the proportion of cases for which genetic risk factors are involved. Ten percent of patients exhibit a readily identifiable…

Natural History of Amyotrophic Lateral Sclerosis

History The term “amyotrophic lateral sclerosis” (ALS) was first proposed by Jean-Martin Charcot in 1874, deriving the name from his method of correlating clinical symptoms and signs with anatomical lesions found at autopsy. While working at the Salpetriere Hospital in France, Charcot and colleagues clinically followed patients with exclusively spastic weakness in addition to those with predominantly weakness and atrophy. Upon their death, Charcot then performed…

Molecular and Extracellular Cues in Motor Neuron Specification and Differentiation

Introduction Motor neurons (MN) are a diverse group of cells without which complex life would not be possible. MNs are responsible for integrating signals from the brain and the sensory systems to control voluntary and involuntary movements. Though MNs can be split into cranial and spinal subsets, this chapter will focus on spinal MNs, as they are a key target of disease and injury. As such,…

Key Select References

End of Chapter___Ref title Basic Principles of Mental Status Testing (Chapters 1–6) Ahmadian N., van Baarsen K., van Zandvoort M., Robe P.A.: The cerebellar cognitive affective syndrome—a meta-analysis. Cerebellum 2019; 18: pp. 941-950. Clark D.L., Boutros N.N., Mendez M.F.: The Brain and Behavior.4th ed.2018.Cambridge University PressNew York, NY Finney G.R., Minagar A., Heilman K.M.: Assessment of mental status. Neurol Clin 2016; 34: pp. 1-16. Genetti Gatfield…

Mental Status Scales

10 Select Mental Status Scales Pages SHORT (≤5 minutes) Clock Drawing Test Mini-Cog Six-Item Screener Short Portable Mental Status Questionnaire Short Test of Mental Status MODERATE (5–15 minutes) Mini-Mental State Examination Montreal Cognitive Assessment Rowland Universal Dementia Assessment Scale Saint Louis University Mental Status Examination LONG (15–30 minutes). Full scales not included here Addenbrooke’s Cognitive Examination-III (ACE-III) is available from The University of Sydney—Diagnostic Dementia Tests;…

Index of Mental Status Tasks

Arousal, Attention, and Other Fundamental Functions AROUSAL 1. Verbal and Physical Stimulation. If a patient is not awake or responding to the environment, the examiner loudly calls the patient’s name while tapping him/her and, if still unresponsive, the clinicians applies pressure to the sternum or a fingernail or pinches the Achilles tendon. 2. Responsiveness to Stimulation. The examiner notes the type of responsiveness to stimulation. Note…

Tele-Neurobehavior and Computerized Cognitive Tests

The application of telemedicine extends to the administration of the mental status examination via telephone or videoconferencing and the use of computers for cognitive testing. “Tele-neurobehavior” is defined here as the use of telecommunications to evaluate neurocognition and related behavior in patients who are at different sites than the examiner. The COVID-19 pandemic has accelerated the need for tele-neurobehavior, which was already developing at a rapid…

Overview of Neuropsychological Testing

The neuropsychological examination is the ultimate extension of the mental status examination (MSX). Neuropsychological testing involves the administration of standardized, validated, and reliable instruments to patients, usually under the supervision of a professional neuropsychologist. Referral for this testing is necessary in some patients who have undergone prior levels of MSX and require even more investigation. The mental status examiner must know when to refer for neuropsychological…

General Mental Status Scales, Rating Instruments, and Behavior Inventories

There are over 50 general mental status scales for assessing cognition, and a large number of inventories for behavioral assessment. This does not include the many available targeted mental status scales, which focus on a particular disorder or syndrome that is not dementia or general cognitive impairment. Chapter 15 discusses general characteristics and guidelines for choosing among these instruments. This chapter expands on those guidelines and…

Overview of Scales and Inventories

This chapter discusses scales and inventories for mental status assessment. Scales are instruments for measuring or grading mental status attributes, and inventories are questionnaires for surveying or cataloging mental status traits. Scales and inventories are useful for screening for the presence of cognitive impairment and not for making a diagnosis. Screening is a method for determining whether there is a potential problem that could indicate a…

The Neurological Behavioral Examination

This chapter is about the neurological behavioral examination. It greatly overlaps with the psychiatric interview, which is valuable in its own right. The neurological behavioral examination targets neuropsychiatric changes potentially associated with known neurological disorders or lesions. In fact, most “psychiatric behaviors” can result from neurological disorders or lesions, and a major objective of this chapter is to emphasize the need to assess for neurological disease…

Executive Operations and Abilities

Executive operations refer to cognitive processes that underlie goal-directed behavior, and executive attributes refer to decision-making abilities such as abstraction, judgment, and problem solving. They are what a chief executive of a company does: formulate a strategic plan toward a goal and implement it. This executive process involves steps, which can be broken down into the following: reflecting on different options and deciding on a goal,…

Calculations and Related Functions

The ability to appreciate quantities, understand numbers, and calculate is a cognitive domain in its own right. This domain has a left inferior parietal hub involving the horizontal portion of the intraparietal sulcus, an area that appears dedicated to processing symbolic numerical information. However, many other areas and their cognitive functions can affect calculation abilities. This chapter discusses the evaluation for acalculias and includes assessment of…

Praxis and Related Cortical Movement Abnormalities

Clinicians have applied the term “praxis,” and its disorder, “apraxia,” to a wide number of conditions involving impaired motor performance. A strict and specific use of the term “apraxia” (or “dyspraxia”), however, is limited to disturbances in learned skilled movements due to a cognitive defect in motor programming, such as errors in pantomiming brushing one’s teeth or gesturing “good-bye.” Patients with apraxia have normal basic motor…