Role Of Behavioural Changes and Cognitive Impairment In Mortality For ALS Patients

A recent report from researchers following a study demonstrated that patients with Amyotrophic Lateral Sclerosis (ALS) who develop Frontotemporal Syndrome (FTS), have their lives cut short in spite of being equipped with a breathing mask. Going by facts, nearly 50 percent of patients with ALS and deficiency in behavioural and cognitive abilities due to FTS, do not respond to the ventilation mask known as the non-invasive ventilation (NIV).

There has been increasing evidence that patients diagnosed with ALS also exhibited signs of FTS such as behavioural, cognitive or language dysfunctions. The frequency of FTS features in ALS vary in the literature but, as of now, it is accepted that some symptoms of FTS can be detected in up to 50 percent of ALS patients.

It is estimated that 30 percent of ALS patients will exhibit signs of frontal lobe decline, which impacts on behavioural and cognitive tendencies. The patients with FTS may first show characteristics of either FTS or ALS with the rest of the symptoms manifesting as the disease progresses.

About ALS

ALS is a progressive nervous system disease that causes damage to the nerve cells and results in disability. ALS is often called Lou Gehrig’s disease, after the famous baseball player who was diagnosed with it sometime back. It is a form of motor neuron disease whereby the nerve cells break down and die in a gradual process.
As it stands, medical research has not been able to ascertain why ALS occurs. In some cases, the disease is inherited, that is Familial ALS and on the other hand Sporadic ALS occurs randomly in the population.

ALS has mainly been viewed as a neurological disorder that affects the motor system. It now recognized as a multisystem neurodegenerative disease attributed to the fact that other regions rather than motor areas of the brain undergo degeneration.

The ALS features of the disorder eventually render patients unable to stand, walk or use their hands and legs. It is known to commence with muscle twitching and weakness in the limbs and slurred speech. With time, it affects control of the muscles necessary for movement, speaking, eating, swallowing and breathing. Patients eventually lose the ability to breathe on their own and will require support on NIV for survival.
Unfortunately, there exists no cure for ALS, and the disease in its fatality has resulted in the death of many.

About FTS

FTS is a form of Frontotemporal Dementia that is characterized as a syndrome of progressive changes in behaviour and language due to loss of function of neurons in the frontal and temporal lobes.
The symptoms of FTS in ALS are observed in the changes in behaviour, personality and thinking. They include: weakness in the muscles, increased clumsiness in fine hand movements, weak and stiff legs, shortness of breath, shrinkage and twitching of muscles, swallowing complications, muscle cramps, slurred speech, spasticity, exaggerated reflexes of limbs and emotional outbursts.

The Link Between ALS and FTS

Going by studies, scientists have acknowledged significant association between FTS and ALS. In most cases, FTS has insignificant impact on the regions of the nervous system that regulate movement. It has been established that a large number of patients maintain their physical strength and quite active until the late stages of the disease.

Both FTS and ALS are heterogeneous at the clinical, neuropathological and genetic levels and, even though they are seen distinct progressive disorders, there is increasing evidence of the fact that they share some clinical, neuropathological and genetic features. This implies that they are similar in neurodegenerative pathways and they may be part of a well-known spectrum.

The patients of ALS with FTS may be seen to have the same behavioural and language changes. These changes go hand in hand with destruction of motor neurons that manifest as weakness in the muscles with stiffness, difficulty making fine movements, atrophy of the muscles and fine muscle twitches alongside cramps. The changes in muscle can affect the limbs, face, tongue and mouth dependent the extent of damage to the nervous in a given patient. Patients with diagnosis of ALS with FTS usually experience a rapid decline in both physical and cognitive abilities.

In a small percentage of patients with FTS, the disease also comprises the nerve cells responsible for controlling voluntary movement that are known as motor neurons. In this case, the syndrome is called FTS with ALS. The symptoms observed are dependent on which regions of the nervous system have been affected. All ALS patients FTS will undergo a gradual and consistent decline in functioning of the nervous system.

According to neuroimaging studies in patients with ALS and FTS there exists atrophy of the frontal and temporal lobes. As per nuclear medicine studies, some of which measure glucose utilization by the brain which normally measures cerebral blood flow, they indicate decrease in glucose use and blood flow in the frontal and temporal lobes.

The first reports of disorders that in terms of cognitive and behavioural symptoms resemble FTS and in terms of motor symptoms resemble ALS were established over a century ago. Over the years, more specifically in the last two decades, evidence has emerged that FTS signs can be seen in patients primarily diagnosed with ALS. This suggests clinical overlap among ALS and FTS.

FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options.

Conducting the Study

It investigated how FTS of ALS is associated with poor survival and was published in the Neurology journal. A distinct linkage between FTS and survival has been hindered by limiting the examination of non-motor symptoms to cognitive impairment and not including the following: behavioural changes, small sample size, assessment of FTS with non-disease specific tools and lack of consideration of NIV initiation.

The researchers conducting the study stated the primary aim of it as examining if FTS is an independent risk factor for poor survival in ALS patients. Additionally, there was intention to investigate the impact of FTS on NIV initiation and duration in ALS patients.
The researchers mobilized and monitored 110 patients of whom 47 has FTS. They assessed the effect of FTS on survival and the commencement and duration of NIV in comparison to patients who did not have FTS. They determined behavioural changes took place if the ALS patient scored more than 22 points on the ALS-Frontotemporal-Dementia Questionnaire. To add on, they existed if they scored three or more points on two or more items of the Neuropsychiatric Inventory.

Cognitive impairment was defined as below the fifth percentile on two or more tests looking into executive function, memory or language. The survival was assessed from the beginning of the symptoms and time from NIV start until death. Classic ALS was defined as ALS without FTS. They went on and assessed age at onset, site of onset, time to diagnosis, disease duration, duration to NIV initiation, and presence of C90rf72 repeat expansion. Kaplan-Meier analyses from symptom onset to death and time from NIV initiation to death were conducted.

Analysis from the Study

It showed that ALS patients with FTS had a significantly shorter survival independent of prognostic factors such as older age at onset, bulbar onset, short time to diagnosis, and the presence of the C9orf72 repeat expansion which causes neurodegeneration, even after initiation of NIV. This observation demonstrated that FTS is associated with shorter survival regardless of whether the patient starts NIV or not.c

The team also noticed that ALS patients with behavioural changes, but not cognitive changes, less often initiated NIV but it was not possible in this study to investigate definitively what behavioural changes, such as apathy or impulsivity, could bring about the difference.

Conclusions Based on the Study

There is need to conduct studies in future with larger groups of ALS patients. These will be necessary in order to confirm the association between FTS and poor survival outcome in ALS. This has been observed to remain present even after the introduction of NIV.
In this respect, more patient cases need to be screened and more functional studies need to be performed in order to give clarity into the correlations between genetic variations and the clinical manifestation of FTS and ALS. More research is required to gain insight into the pathways which are impacted on by the pathogenic mutations.

Researchers have established that the frontal and temporal lobes of the brain show atrophy. These lobes including the motor regions of the cerebral cortex, show loss of neurons and gliosis, that is, scar tissue in the brain and majority of the remaining neurons are shrunken, shaped anomalously and composed of toxic protein known as inclusions.
Nearly two decades ago, the inclusions were found to consist of a protein called ubiquitin. The evidence of ubiquitin positive inclusions in the extra motor cortex was shown in both pure ALS patients and ALS patients with FTS.

Recent studies have demonstrated that pathological investigations and genetic screening have contributed immensely in explaining the pathology and genetic variability associated with FTS and ALS. To the most important recent discoveries belong TAR DNA binding protein, that is, TDP-43 and its implication in these disorders. There is also degeneration of motor neurons in the brain stem and spinal cord.

The linkage of FTS and ALS to the protein TDP-43 may be an important discovery in the medical field. TDP-43 can be attributed how the cell’s molecular code is decoded and used to make proteins that are responsible for multiple cell functions.

There have been speculations that TDP-43 as a DNA and RNA processing factor and its genetic variability could be responsible for toxic gain of function triggering a disrupted RNA metabolism. Most of the mutations in TDP-43 appear in a region of the protein which could describe the translocation and accumulation in the cytoplasm of the mutated protein.

On a different note, families with mutations in the gene coding for TDP-43 gene have been seen to develop ALS, but so far, such patients have not been seen to show signs of FTS. However, given that there are families who have some members with ALS combined with FTS, researchers have exerted efforts to discover genes that may explain the development of this combination of symptoms.

The Future of ALS and FTS

The understanding of the relationship between ALS and FTS is subject to further scientific studies. It has been noted that most reported cases of ALS are not hereditary. There is absence of clear genetic abnormality that is closely associated with the development of ALS and FTS.
As it is, there exists no cure for motor neuron diseases. Riluzole, the first drug approved for use in the treatment of ALS, has exhibited success in slowing the progression of ALS. Other therapies can aid in relieving the symptoms of muscle cramping and spasticity in the disease.

Physical therapy comprising of stretching exercises and less intense exercise can help relieve muscle symptoms. The design of machines such as ramps, braces, walkers, and wheelchairs have enabled patients to use less energy and enhanced their mobility. In addition, speech therapy can allow the patient to come up with strategies to speak more clearly.

Seeking insight on the clinical, pathological and genetic features characterizing FTS and ALS will provide clarity into overlaps among these two disorders and the underlying mechanisms that lead to the onset and development of the disorders. Scientists are hopeful that advancements in the knowledge of the biology of ALS and FTS will aid in developing novel and highly effective diagnostic and treatment options.

It is vital that caregivers consider long-term ALS with FTS management issues and come up with ways to cope with medical, financial and emotional challenges. Having teams of specialist who are well versed in ALS and FTS and approaches to treatment will increase the survival chances of the patients. Some medical specialists who may facilitate the process include: speech therapists, occupational and physical therapists, neuropsychologists, home-care nurses and genetic counsellors.