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Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig’s disease, is a neurodegenerative disease that results muscle atrophy and weakness due to progressive loss of motor neurons. Although it was generally believed that ALS was not complicated with cognitive impairment until the late stages of the disease, cognitive and behavioural symptoms have been described for over a century. cognitive or behavioral dysfunction is present in 30-40% of individuals with ALS. It is estimated that 10% of ALS patients show signs of frontotemporal dementia (FTD). ALS and FTD are considered to be part of a common disease spectrum because of genetic, clinical, and pathological similarities. Since it is difficult to detect the presence of cognitive dysfunction in ALS due to physical dysfunction such as dysarthria, we have to conduct tests according to physical function in order to identify cognitive dysfunction. In this article, we review the disease concept of ALS, the characteristics, the clinical assessment, the approach, and the prognosis of frontotemporal dysfunction in patients with ALS. [ABSTRACT FROM AUTHOR]

A definite diagnosis of neurodegenerative diseases is required for neuropathological examination during an autopsy. Each neurodegenerative disease has specific vulnerable regions and affected systems (system degeneration), and is typified by an accumulation of abnormal protein with the formation of characteristic morphological aggregates in the nerve and glial cells, called proteinopathy. The most common neurodegenerative diseases are tauopathy, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD); α-synucleinopathy, including multiple system atrophy (MSA); and TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). PSP and CBD show characteristic tau-positive astrocytic inclusions known as tufted astrocytes and astrocytic plaques, respectively. PiD shows tau-positive neuronal inclusions termed Pick bodies. MSA is characterized by α-synuclein-positive oligodendroglial inclusions, called glial cytoplasmic inclusions. ALS- and FTLD-TDP show TDP-43-positive neuronal inclusions, such as skein-like and round inclusions. Huntington's disease shows polyglutamine-positive neuronal inclusions, and Creutzfeldt-Jakob disease shows diffuse deposition of granular prions in the neuropil. The atypical proteins in these diseases have abnormal conformational properties. A comprehensive comparison of the clinical findings and neuropathological observations, including neuroanatomy and images acquired during life, is important to improve the sensitivity of clinical diagnosis.

We describe a case of behavioral variant frontotemporal dementia (bvFTD) presenting with frequent laughter during conversations. A 72-year-old male patient visited our hospital because of aspontaneity and abnormal behaviors. His medical history revealed epilepsy attacks approximately five years prior, which improved following administration of antiepileptic drugs. At the age of 67 years, the patient began exhibiting aspontaneity and abnormal behaviors, such as leaving a teahouse without paying for his coffee. Neurological examinations indicated moderate dementia and bradykinesia while walking. The patient frequently laughed during conversations with his wife and doctor, creating the impression that he was euphoric. His laughter was neither explosive nor obsessive, and did not involve loss of consciousness or seizures. MRI of the head revealed symmetrical atrophy of the bilateral frontal lobes. SPECT demonstrated decreased cerebral blood flow in the bilateral frontal lobes, particularly in the outer and inner frontal convexities. Based on the patient's clinical history and imaging results, a diagnosis of bvFTD was established. Our literature review identified only one research paper discussing the frequency of laughter in frontotemporal dementia, which suggested that patients with bvFTD laugh less often. However, several reports indicated that patients with FTD exhibit euphoric behaviors more frequently compared to those with other forms of dementia. We hypothesize that euphoric patients with bvFTD may laugh more frequently during conversations, reflecting disorders of emotional expression and a loss of empathy.

A 55-year-old woman with extreme obesity presenting with limb weakness since 1 year was diagnosed with amyotrophic lateral sclerosis (ALS) based on clinical findings and needle electromyography. She had a habit of overeating, and her body mass index (BMI) was 38.2. MRI showed an enlargement of the right central cerebral sulcus, and N-isopropyl-p-[‍ 123 I]-iodoamphetamine single-photon emission computed tomography demonstrated reduced blood flow predominantly in the right frontal lobes, suggesting overlapping frontotemporal dementia (FTD). She maintained adequate dietary intake, and her BMI was stable at 38.2 until 3 months after diagnosis. However, over the next 2 months, her dietary intake decreased owing to pronounced bulbar palsy and BMI decreased to 34.5. At this point, forced vital capacity decreased from 69.3% to 39.0%, while forced expiratory volume in 1 second decreased from 75.3% to 47.7%. Consequently, noninvasive ventilation at night was initiated, followed by tracheostomy invasive ventilation at the emergency department after 2 months. We assume that the frontotemporal lobar degeneration pathology progressed to the frontal lobe and hypothalamus over time, which increased the patient's excessive appetite and body weight. Her obesity reduced the compliance of the thorax and increased the workload of the respiratory muscles, resulting in rapid respiratory deterioration. Additionally, the extensive neurodegeneration, extending to the area other than the primary motor cortex, might have played a pivotal role in rapid ALS progression. High-calorie nutritional management is generally recommended in patients with ALS. Although the prognosis of patients with ALS having BMI under 27 can be improved via high calorie intake and BMI maintenance, the nutritional management strategy for patients with ALS and high obesity (BMI ≥ 35) remains unclear. Through this case we emphasize that in patients with ALS and FTD excessive appetite and obesity can lead to rapid respiratory deterioration, and therefore, prudent calorie management is recommended.

A 57-year-old man with no family history of amyotrophic lateral sclerosis (ALS) or diabetes was diagnosed with ALS, and placed in long-term care where an artificial respirator with tracheotomy was used. He was fed through a gastric fistula tube. He gradually lost the ability to communicate, and computed tomography revealed advanced atrophy of the frontotemporal lobe. He was abruptly suffered from polyuria 11 years after the onset of ALS, and was diagnosed with hyperosmolar hyperglycemic state (HHS). It recurred six years later with severe ascites and worsening of pleural effusion. He passed away 18 years after the onset of ALS. Pathological examination revealed a reduced numbers of Betz cells in the motor cortex, anterior horn cells in the spinal cord, and hypoglossal neurons. The remaining lower motor neurons and cells in the hippocampal dentate gyrus were positive for phosphorylated TDP-43. These corresponded to Type B on harmonized classification system for frontotemporal lobar degeneration (FTLD)-TDP pathology (Mackenzie, et al. 2011). Furthermore, the lateral, anterior, and anterolateral funiculi of the spinal cord, globus pallidus, thalamus, and brainstem tegmentum showed atrophy. The findings were compatible with ALS pathology in totally locked-in state (TLS). Hyalinized islets of Langerhans were observed scattered throughout the pancreas. The patient's muscles were nearly completely replaced by white, firm fat tissue. We considered that the patient's diabetic conditions contributed to the accumulation of excess fat in internal and external fat tissue as a result of the long-term dependence on enteral nutrition. Moreover, a disturbance in glucose metabolism in skeletal muscles that resulted from severe atrophy could have been another cause.

Fused-in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Under normal conditions, FUS forms a high-molecular-weight complex with SFPQ in the nucleus. However, disease-associated mutations in the FUS gene disrupt formation of the complex, resulting in unregulated alternative splicing of tau, a disproportional increase in the 4-repeat (4R)-tau/3-repeat (3R)-tau ratio, and eventual neurodegeneration. Disruption of the FUS-SFPQ interaction leads to an increase in the 4R-tau/3R-tau ratio, which manifests as FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with ALS/FTLD, progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD), Alzheimer's disease (AD), or Pick's disease (PiD). Immunofluorescence imaging showed impaired intranuclear colocalization of FUS and SFPQ in the neurons in the ALS/FTLD, PSP, and CBD cases, but not in the AD and PiD cases. Furthermore, the ratio of 4R-tau/3R-tau was elevated in cases of ALS/FTLD and PSP but was largely unaffected in cases of AD. We concluded that impaired interactions between FUS and SFPQ and the subsequent increase in the 4R-tau/3R-tau ratio constitute a common pathogenesis pathway in FTLD spectrum diseases.

Arnold Pick described a focal cortical syndrome caused by focal temporal and/or frontal cortical atrophy, later reffered to as Pick's disease (PiD), a prototype of frontotemporal lobar degeneration (FTLD). In contrast to the current concept of PiD, the presence of Pick bodies (tau-positive inclusions) was not thought to be necessary for the diagnosis of PiD. Four out of the seven patients in his original paper had predominant left temporal atrophy and language related symptoms corresponding to semantic dementia. It is now known that most patients with semantic dementia have transactive response DNA-binding protein 43kDa (TDP-43) pathology rather than tau pathology. The original concept of PiD was substantially similar to the current concept of FTLD, which has heterogeneous molecular pathology including tau, TDP-43 and fused in sarcoma (FUS).

A 57-year-old man developed rapidly progressive dementia and a gait disturbance over 4 months. The patient had a slowly progressive executive dysfunction and speech problems for 4 years and was previously monitored in our outpatient clinic following a diagnosis of frontotemporal dementia. Diffusion-weighted MRI revealed high signal intensities in the right caudate nucleus and the bilateral cortices. Cerebrospinal fluid analysis showed increased levels of the 14-3-3 and total tau proteins. Periodic synchronous discharge was not evident on an electroencephalogram. Prion protein gene analysis identified a glutamate-to-lysine substitution at codon 219 (E219K) in the presence of the E200K mutation, leading to a genetic diagnosis of genetic Creutzfeldt-Jakob disease (CJD). The E219K polymorphism found on the allele of the E200K mutation may have influenced the characteristic clinical course of our patient that differed from that of typical E200K genetic CJD.

A 76-year-old woman showed a dramatic lowering of her tone of voice in October 2014, followed by muscle weakness of the left arm. The previous attending physician noticed remarkable left dominant frontotemporal lobe atrophy on cranial MRI. Her dysarthria, dysphagia and the muscle weakness of her extremities worsened, and a muscle biopsy revealed mitochondrial abnormality. The mitochondrial DNA from her muscle showed multiple deletions; the previous physician therefore diagnosed the patient with mitochondrial disease. The patient resembled amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). No other cases of ALS-FTD with mitochondrial disease have been reported in Japan. We therefore consider the present case to be valuable.