Sporadic amyotrophic lateral sclerosis with circumscribed temporal atrophy: A report of an autopsy case without dementia and with ubiquitinated intraneuronal inclusions

This report concerns an autopsy case of amyotrophic lateral sclerosis (ALS) with circumscribed temporal atrophy. The patient was a Japanese woman without hereditary burden who was 71‐year‐old at the time of death. She developed dysarthria and gait disturbance at age 69, followed by dysphagia. A neurological examination about 1 year 11 months after the onset of the disease revealed absence of character change and of dementia. Neuroradiological examination disclosed circumscribed atrophy of the anterior part of the right temporal lobe. The patient died of respiratory failure 2 years after the disease onset. No respirator administration was performed throughout the clinical course. Macroscopically, neuropathological examination showed circumscribed atrophy of the right first temporal gyrus. Histologically, there was neuronal loss in the cerebral cortex, including the first temporal gyrus, the parahippocampal gyrus, subiculum, amygdala, substantia nigra, brain stem motor nuclei, and anterior horns of the spinal cord, in addition to loss of Betz cells, obvious degeneration of the pyramidal tracts, and the presence of Bunina bodies. Ubiquitin‐immunoreactive intraneuronal inclusions were present in the hippocampal dentate granular cells, frontotemporal cortical layer II neurons, and motor neurons in the brain stem and spinal cord. Based on these clinicopathological findings and a review of the literature, we concluded that our case was atypical ALS without dementia, showing temporal lobe atrophy macroscopically, in addition to pathological hallmarks compatible with ALS with dementia. We also note the possibility that there is a forme fruste of ALS with dementia showing no overt dementia clinically.     

Is motor neuron disease‐inclusion dementia a forme fruste of amyotrophic lateral sclerosis with dementia? An autopsy case further supporting the disease concept

We report the autopsy findings of a 62‐year‐old man who exhibited progressive FTD 10 years before the appearance of muscle weakness and wasting, and who died approximately 11 years after onset of the symptoms. Degeneration and atrophy of the frontal and temporal lobes, which contained ubiquitin‐positive neuronal inclusions and dystrophic neurites, were evident. Circumscribed degeneration affecting the hippocampal CA1‐subiculum border zone was also a feature. Moreover, degeneration was present in both the upper and lower motor neuron systems, the latter being more severely affected. A few lower motor neurons were found to contain the cytoplasmic inclusions characteristic of ALS (i.e. Bunina bodies and ubiquitin‐positive skeins). Also of interest was the presence of pallidonigroluysian atrophy, which appeared to be responsible for the chorea‐like involuntary movements that developed in this patient approximately 2 months before death. The clinical and pathological features of our patient further support the idea that motor neuron disease‐inclusion dementia (MND‐ID), which has been classified as a pathological subgroup of FTD, is a forme fruste of ALS with dementia. In other words, if patients with MND‐ID live long enough, they may develop ALS.     

Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis

K. Soma, Y.‐J. Fu, K. Wakabayashi, O. Onodera, A. Kakita and H. Takahashi (2012) Neuropathology and Applied Neurobiology 38, 54–60 Co‐occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis Aims: Phosphorylated TDP‐43 (pTDP‐43) is the pathological protein responsible for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Recently, it has been reported that accumulation of pTDP‐43 can occur in the brains of patients with argyrophilic grain disease (AGD), in which phosphorylated 4‐repeat tau is the pathological protein. To elucidate the association of ALS with AGD, we examined the brains from 37 consecutively autopsied patients with sporadic ALS (age range 45–84 years, mean 71.5 ± 9.0 years). Methods: Sections from the frontotemporal lobe were stained with the Gallyas‐Braak method and also immunostained with antibodies against phosphorylated tau, 4‐repeat tau and pTDP‐43. Results: Fourteen (38%) of the 37 ALS patients were found to have AGD. With regard to staging, 5 of these 14 cases were rated as I, 4 as II and 5 as III. pTDP‐43 immunohistochemistry revealed the presence of positive neuronal and glial cytoplasmic inclusions in the affected medial temporal lobe in many cases (93% and 64%, respectively). On the other hand, pTDP‐43‐positive small structures corresponding to argyrophilic grains were observed only in one case. A significant correlation was found between AGD and the Braak stage for neurofibrillary pathology (stage range 0–V, mean 2.1). However, there were no significant correlations between AGD and any other clinicopathological features, including dementia. Conclusions: The present findings suggest that co‐occurrence of AGD in ALS is not uncommon, and in fact comparable with that in a number of diseases belonging to the tauopathies or α‐synucleinopathies.     

Primary lateral sclerosis: Upper‐motor‐predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration – immunohistochemical and biochemical analyses of TDP‐43

Primary lateral sclerosis (PLS) is clinically defined as a disorder selectively affecting the upper motor neuron (UMN) system. However, recently it has also been considered that PLS is heterogeneous in its clinical presentation. To elucidate the association of PLS, or disorders mimicking PLS, with 43‐kDa TAR DNA‐binding protein (TDP‐43) abnormality, we examined two adult patients with motor neuron disease, which clinically was limited almost entirely to the UMN system, and was followed by progressive frontotemporal atrophy. In the present study, the distribution and severity, and biochemical profile of phosphorylated TDP‐43 (pTDP‐43) in the brains and spinal cords were examined immunohistochemically and biochemically. Pathologically, in both cases, frontotemporal lobar degeneration with ubiquitin inclusions (FTLD‐U) was evident, with the most severe degeneration in the motor cortex. An important feature in both cases was the presence of Bunina bodies and/or ubiquitin inclusions, albeit very rarely, in the well preserved lower motor neurons. The amygdala and neostriatum were also affected. pTDP‐43 immunohistochemistry revealed the presence of many positively stained neuronal cytoplamic inclusions (NCIs) and dystrophic neurites/neuropil threads in the affected frontotemporal cortex and subcortical gray matter. By contrast, such pTDP‐43 lesions, including NCIs, were observed in only a few lower motor neurons. pTDP‐43 immunoblotting revealed that fragments of ～25‐kDa were present in the cortices, but not in the spinal cord in both cases. Genetically, neither of the patients had any mutation in the TDP‐43 gene. In conclusion, we consider that although PLS may be a clinically significant disease entity, at autopsy, the majority of such clinical cases would present as upper‐motor‐predominant amyotrophic lateral sclerosis with FTLD‐TDP.     

Possible concurrence of TDP‐43, tau and other proteins in amyotrophic lateral sclerosis/frontotemporal lobar degeneration

Transactivation response DNA‐binding protein 43 kDa (TDP‐43) has been regarded as a major component of ubiquitin‐positive/tau‐negative inclusions of motor neurons and the frontotemporal cortices in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Neurofibrillary tangles (NFT), an example of tau‐positive inclusions, are biochemically and morphologically distinguished from TDP‐43‐positive inclusions, and are one of the pathological core features of Alzheimer disease (AD). Although ALS/FTLD and AD are distinct clinical entities, they can coexist in an individual patient. Whether concurrence of ALS/FTLD‐TDP‐43 and AD‐tau is incidental is still controversial, because aging is a common risk factor for ALS/FTLD and AD development. Indeed, it remains unclear whether the pathogenesis of ALS/FTLD is a direct causal link to tau accumulation. Recent studies suggested that AD pathogenesis could cause the accumulation of TDP‐43, while abnormal TDP‐43 accumulation could also lead to abnormal tau expression. Overlapping presence of TDP‐43 and tau, when observed in a brain during autopsy, should attract attention, and should initiate the search for the pathological substrate for this abnormal protein accumulation. In addition to tau, other proteins including α‐synuclein and amyloid β should be also taken into account as candidates for an interaction with TDP‐43. Awareness of a possible comorbidity between TDP‐43, tau and other proteins in patients with ALS/FTLD will be useful for our understanding of the influence of these proteins on the disease development and its clinical manifestation.     

An autopsied case of sporadic adult‐onset amyotrophic lateral sclerosis with FUS‐positive basophilic inclusions

Basophilic inclusions (BIs), which are characterized by their staining properties of being weakly argyrophilic, reactive with Nissl staining, and immunohistochemically negative for tau and transactive response (TAR) DNA‐binding protein 43 (TDP‐43), have been identified in patients with juvenile‐onset amyotrophic lateral sclerosis (ALS) and adult‐onset atypical ALS with ophthalmoplegia, autonomic dysfunction, cerebellar ataxia, or a frontal lobe syndrome. Mutations in the fused in sarcoma gene (FUS) have been reported in cases of familial and sporadic ALS, and FUS immunoreactivity has been demonstrated in basophilic inclusion body disease (BIBD), neuronal intermediate filament inclusion disease (NIFID), and atypical frontotemporal lobar degeneration with ubiquitin‐positive and tau‐negative inclusions (aFTLD‐U). In the present study, we immunohistochemically and ultrastructurally studied an autopsy case of sporadic adult‐onset ALS with numerous BIs. The patient presented with the classical clinical course of ALS since 75 years of age and died at age 79. Postmortem examination revealed that both Betz cells in the motor cortex and motor neurons in the spinal cord were affected. The substantia nigra was spared. Notably, BIs were frequently observed in the motor neurons of the anterior horns, the inferior olivary nuclei, and the basal nuclei of Meynert. BIs were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP‐43, and neurofilament. Ultrastructurally, BIs consisted of filamentous or granular structures associated with degenerated organelles with no limiting membrane. There were no Bunina bodies, skein‐like inclusions, or Lewy‐like inclusions. All exons and exon/intron boundaries of the FUS gene were sequenced but no mutations were identified.     

Rapidly progressive aphasia and motor neuron disease: a clinical, radiological, and pathological study of an autopsy case with circumscribed lobar atrophy

This report concerns an autopsy case of rapidly progressive aphasia and motor neuron disease. The patient was a Japanese woman who was 75 years old at the time of death. The family history did not reveal hereditary burden. She developed language disturbances and difficulty in swallowing at age 74. Neurological examination 1 month after the disease onset revealed motor aphasia without dementia and bulbar sign, followed by muscle weakness of the four extremities. Neuroradiological examination revealed progressive atrophy of the anterior part of the left temporal lobe. She died of respiratory difficulty 10 months after the disease onset. Macroscopically, neuropathological examination showed circumscribed atrophy of the left perisylvian region and, histologically, neuronal loss in the cerebral cortex, including the primary motor area, substantia nigra, brain stem motor nuclei, and anterior horns of the spinal cord, in addition to obvious degeneration of the pyramidal tracts and presence of Bunina bodies. Ubiquitin-immunoreactive neuronal inclusions were present in the hippocampal dentate granular cells and frontotemporal cortical layer II neurons. Based on these clinicopathological findings and a review of the literature, we concluded that our case is the first reported case of amyotrophic lateral sclerosis with dementia that clinically showed rapidly progressive aphasia. Received: 1 March 1999 / Revised, accepted: 11 May 1999     

An autopsied case of unclassifiable sporadic four‐repeat tauopathy presenting with parkinsonism and speech disturbances

A 48‐year‐old Japanese woman experienced slow‐onset parkinsonism and speech disturbances. Neurological examinations revealed rigidity in the trunk and extremities, bradykinesia and postural instability, although cognitive impairments and psychiatric symptoms were not apparent in the early disease stage. Neuroimaging revealed progressive bilateral frontotemporal lobe atrophy with cerebral blood flow hypoperfusion. No apparent signs of lower motor neuron involvement were observed, such as fasciculation or electromyogram findings. She eventually reached the akinetic mutism state, and gastrostomy and tracheotomy were performed at 4 years after onset. A clinical diagnosis of progressive supranuclear palsy was made prior to her death, which occurred 6 years after onset. Post mortem examinations revealed that the brain weighed 1200 g and showed atrophy of the frontotemporal lobe and brainstem. Severe neuron loss and gliosis were observed in the frontotemporal lobe. The superior and middle frontal gyri were the most severely affected and showed spongiform changes in the superficial layer. The globus pallidus, subthalamic nucleus, cerebellar dentate nucleus, substantia nigra and inferior olivary nucleus also showed neuronal loss with gliosis. Using hyperphosphorylated tau (AT‐8) immunostaining, pretangle‐like neurons, numerous short threads and glial tau pathology were extensively observed. Using Gallyas?Braak silver staining, thin and short threads were also extensively observed, but considerably fewer than those observed by AT‐8 immunostaining. Neither astrocytic plaques nor tuft‐shaped astrocytes were observed. Examination by immunoelectron microscopy showed straight fibrils approximately 15 nm in diameter in the neuronal cytoplasmic inclusions in the cerebral cortex and in the fibrillary structures in the cerebral white matter. Western blot analysis of sarkosyl‐insoluble tau revealed predominantly four‐repeat tau and a banding pattern similar to that seen in progressive supranuclear palsy. No pathogenic mutations were found during the gene analysis of microtubule‐associated protein tau. After completing our comprehensive investigation, we diagnosed this patient with unclassifiable four‐repeat tauopathy.     

Amyotrophic lateral sclerosis with dementia showing clinical parkinsonism and severe degeneration of the substantia nigra: Report of an autopsy case

An autopsy case of amyotrophic lateral sclerosis with dementia (ALS‐D) showing clinically overt parkinsonism and severe degeneration of the substantia nigra is reported. The patient was a 78‐year‐old man who died after a 2‐year clinical course characterized by parkinsonism that was responsive to Levodopa (L‐DOPA) treatment. Motor neuron symptoms and dementia were not apparent ante‐mortem. The autopsy demonstrated the severe degeneration of the substantia nigra without α‐synucleinopathy‐related changes. Finely granular mineralization of necrotic neurons was a unique finding in the substantia nigra. The mild loss of spinal anterior horn cells, the appearance of several Bunina bodies and the degeneration of the hippocampal subiculum and temporal cortex were also noted. A small number of ubiquitinated intra‐cytoplasmic inclusions were found in neurons of the dentate fascia of the hippocampus and the temporal and frontal cortices. Although the degeneration of the substantia nigra is a common finding in ALS‐D, patients seldom develop clinically overt parkinsonism. This case indicates that patients with ALS‐D rarely present with predominantly parkinsonian clinical features and these symptoms and signs can be improved by L‐DOPA treatment.     

A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Patients presenting with left-sided FTLD syndromes sometimes develop a new preoccupation with art, greater attention to visual stimuli, and increased visual creativity. We describe the case of a 53-year-old, right-handed man with a history of bipolar disorder who presented with language and behavior impairments characteristic of FTLD, then developed motor symptoms consistent with a second diagnosis of amyotrophic lateral sclerosis. Though the patient had never created visual art before, he developed a compulsion for painting beginning at the earliest stages of his disease, and continued producing art daily until he could no longer lift a paintbrush because of his motor deficits. Upon autopsy, he was found to have ubiquitin and TDP43-positive inclusions with MND pathology. This case study details the patient's longitudinal neuropsychological, emotional, behavioral, and motor symptoms, along with structural imaging, neurologic, and neuropathologic findings. Multiple examples of the patient's art are depicted throughout all stages of his illness, and the possible cognitive, behavioral, and neurologic correlates of his new-onset visual artistry are discussed.     

Forme fruste or incipient form of widespread‐type amyotrophic lateral sclerosis,or motor neuron disease with pallido‐nigro‐luysian atrophy? An autopsy case report

We describe a 52‐year‐old man with body weight loss and bulbar palsy, who exhibited muscle atrophy and weakness with fasciculation especially in the respiratory muscles 4 years prior to death, necessitating respiratory support for 4 years, but who was able to walk until the end‐stage. He had no significant family history. Neuropathological examination revealed severe loss of motor neurons in the spinal cord and brainstem, and ubiquitin‐positive skein‐like inclusions and Bunina bodies in the remaining neurons. In addition, prominent degeneration of the anterolateral funiculus and severe loss of neurons in the intermediate zone of the spinal cord were evident, without marked alteration of the corticospinal tracts. Degeneration of the subthalamic nucleus, increased iron deposition in the substantia nigra, and axonal swelling, residual nodules and acidophilic granules in the spinal ganglia were found. The patient's condition was considered to have been a forme fruste or incipient form of widespread‐type amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) with pallido‐nigro‐luysian atrophy (PNLA). The neuropathological features of the present case appear to be important for understanding the nature of widespread‐type ALS and MND with PNLA.     

Coexistence of Huntington’s disease and familial amyotrophic lateral sclerosis: case presentation

We present the clinical, molecular genetic and neuropathological findings of an 81-year-old man with concurrent Huntington’s disease (HD) and familial amyotrophic lateral sclerosis (FALS). His mother had been diagnosed clinically as having ALS. There was no known family history of HD, but a maternal uncle had died in a chronic care psychiatric hospital. The diagnosis of HD in the patient was suspected at age 66, after 8 years of personality change, hallucinations, agitation, cognitive decline and choreoathetosis. No symptoms of motor neuron disease were noticed at that time, but progressive weakness developed later. Postmortem examination revealed cerebral atrophy, marked atrophy of basal ganglia (grade 3), and atrophy of brain stem and spinal cord. The neostriatum displayed massive neuronal loss and gliosis. The neocortex showed changes characterisitic of Alzheimer’s disease. Pathological lesions also included loss of neurons and gliosis in the anterior horns, Clarke’s columns and the hypoglossal nuclei; degeneration of the lateral corticospinal tracts, dorsal spinocerebellar tracts and fasciculus gracilis; and rare Bunina bodies and ubiquitin-positive filamentous skeins in motor-neuron perikarya. Molecular analysis demonstrated chromosome 4p16.3 expansion of trinucleotide repeats characteristic of HD. Analysis of Cu,Zn superoxide dismutase gene and heavy neurofilament subunit gene failed to demonstrate mutations. The concurrence of HD and FALS in our patient and three previously reported cases did not appear to be associated with cosegregation in other family members. Received: 4 December 1995 / Revised: 19 February 1996 / Accepted: 26 February 1996     

“Forme fruste” of amyotrophic lateral sclerosis with dementia: A report of five autopsy cases without dementia and with ubiquitinated intraneuronal inclusions

We clinicopathologically investigated five autopsy cases of ALS without dementia and with ubiquitinated intraneuronal inclusions. The age at onset of symptoms ranged from 52 to 81 years and the duration of the disease was from 10 months to 3 years, 3 months. All five patients initially developed lower motor neuron signs, including bulbar signs, and upper motor neuron signs were found in the middle to late clinical stages, but dementia was not observed in all five cases. Thus, the clinical diagnoses of all five patients were ALS without dementia. Neuropathological examination of all five cases revealed not only obvious degeneration of upper motor neurons with neuronal loss of Betz cells, but also lower motor neuron involvement associated with Bunina bodies. In addition, ubiquitin‐immunoreactive intraneuronal inclusions in the hippocampal dentate granular cells and degeneration of the substantia nigra were observed in all five cases. Furthermore, neuronal loss with astrocytosis in the dorsomedial portion of the anterior first temporal gyrus was observed in all three cases in which this structure was examined. Neuronal loss with astrocytosis in the subiculum was found in four cases. Neuronal loss of the parahippocampal gyrus was observed in three of the five autopsy cases, and amygdala involvement was encountered in three of four cases in which this structure was investigated. Based on these clinicopathological findings and a review of the published literature, we concluded that our five cases were ALS without dementia, but with pathological hallmarks compatible with ALS with dementia. We also concluded that there is a “forme fruste” of ALS with dementia showing no overt dementia clinically.     

Sporadic amyotrophic lateral sclerosis of long duration mimicking spinal progressive muscular atrophy exists: Additional autopsy case with a clinical course of 19 years

This report concerns an autopsy case of sporadic amyotrophic lateral sclerosis (ALS) clinically diagnosed as having spinal progressive muscular atrophy (SPMA). The patient was a Japanese woman without hereditary burden. She developed muscle weakness in the distal part of the right upper extremity at age 52, followed by muscle weakness in the left upper extremity and lower extremities at age 54 and 64, respectively. At age 66 she could not walk, even with assistance. Fasciculation and atrophy of the tongue appeared at age 68, followed by dysphagia and dysarthria at age 70. She died of respiratory disturbance at age 71. During the clinical course, neurological examination revealed neither Babinski sign nor hyperreflexia. No respirator administration was performed throughout the clinical course. Neuropathological examination disclosed not only neuronal loss with gliosis in the hypoglossal nucleus and anterior horns of the spinal cord, but also loss of Betz cells and degeneration of the pyramidal tract. Based on these clinicopathological findings and a literature review of sporadic autopsy cases of ALS with long clinical course (10 years or more), including four cases without pyramidal signs, we believe that sporadic ALS of long clinical course mimicking SPMA exists.     

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: A spectrum of TDP‐43 proteinopathies

It is now established that pathological transactive response DNA‐binding protein with a Mr of 43 kD (TDP‐43) on sodium dodecyl sulfate‐polyacrylamide gel electrophoresis is the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin‐positive inclusions (now known as FTLD‐TDP). In fact, the discovery of pathological TDP‐43 solidified the idea that these disorders are multi‐system diseases and this led to the concept of a TDP‐43 proteinopathy as a spectrum of disorders comprised of different clinical and pathological entities extending from ALS to ALS with cognitive impairment/dementia and FTLD‐TDP without or with motor neuron disease (FTLD‐MND). These align along a broad disease continuum sharing similar pathogenetic mechanisms linked to pathological TDP‐43. We here review salient findings in the development of a concept of TDP‐43 proteinopathy as a novel group of neurodegenerative diseases similar in concept to α‐synucleinopathies and tauopathies.     

Coexistence of mixed phenotype Creutzfeldt‐Jakob disease,Lewy body disease and argyrophilic grain disease plus histological features of possible Alzheimer's disease: A multi‐protein disorder in an autopsy case

We report hereby an autopsy case of sporadic mixed phenotype CJD without hereditary burden and a long‐term clinical course. An 80‐year old man was diagnosed with mild cognitive impairment 27 months before death, caused by bronchopneumonia and severe respiratory impairment. During this time, the patient developed gradual mental deterioration, some sleeping problems and myoclonus. Other clinical manifestations were progressive gait problems, language deterioration, presence of primitive reflexes and irritability. In keeping with those symptoms, a rapidly evolving dementia was clinically suspected. Cerebrospinal fluid test for 14‐3‐3 protein was negative. However, an abnormal EEG and MRI at end‐stage of disease were finally consistent with CJD. Post‐mortem examination revealed a massive cortical neuronal loss with associated reactive astrocytosis, also evident in the white matter. Diffuse spongiform changes involving some basal ganglia, especially medial thalamus, some troncoencephalic nuclei, mainly inferior olivary nucleus and the molecular layer of the cerebellum were seen. Immunorreactive deposits for anti‐prion protein antibody were present at different areas of the CNS. Additionally, Lewy bodies were observed at the brainstem and amygdala. Furthermore, argirophilic grains together with oligodendroglial coiled bodies and pre‐tangle inclusions in the neurons from the limbic system containing hyperphosphorylated 4R tau were noted. To the best of our knowledge, this is the first case of CJD combined with Lewy body disease and argirophilic grain disease. Furthermore, we believe this case is an extremely rare combination of MM2‐cortical‐type and MM2‐thalamic‐type sporadic CJD (sCJD), which explains the broad spectrum of MM2‐type sCJD findings and symptoms. Moreover, histological features of possible Alzheimer's disease were also reported.     

Relationship between ALS and the degree of cognitive impairment, markers of neurodegeneration and predictors for poor outcome. A prospective study

Introduction:  Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease affecting motor neurons and may be associated with impaired cognition. Reliable prognostic factors for ALS patients are still missing.
Methods:  We prospectively included 67 patients, 42 women and 25 men, with clinically defined ALS. The disease severity was assessed and the patients underwent SPECT, lumbar puncture with determination of tau, hyperphosporylated tau (p-tau) and beta-amyloid and a detailed neuropsychological assessment using a standardized test battery. In patients who died, a detailed neuropathologic evaluation was performed.
Results:  The mean survival duration was 26.8 months. The delay between the first signs and confirmation of the diagnosis was 12.75 months. Cognitive impairment did not have an impact on the evolution of the disease. There was no correlation between neuropsychological and SPECT findings. Higher age at onset, more pronounced handicap and elevated beta-amyloid in the CSF were associated with shorter survival times. In brain tissue from nine of the deceased patients with ALS and dementia, all showed signs of comorbidity, six had hallmarks of frontotemporal lobar degeneration (FTLD) and three showed Alzheimer disease pathology. Brain tissues form 11 deceased ALS patients who did not show signs of dementia, had only changes compatible with a diagnosis of motor neuron disease.
Conclusion:  In our prospective study, age, disease severity and CSF beta-amyloid levels taken together were a risk factor suggesting shorter survival times. Dementia is relatively frequent in ALS and may be a consequence of either FTLD or result from co-existing Alzheimer disease.     

A long surviving case of amyotrophic lateral sclerosis with atrophy of the frontal lobe: a comparison with the Mitsuyama type

A female patient with amyotrophic lateral sclerosis (ALS) showing psychiatric symptoms during her last 2 years of life is reported. Although pseudobulbar signs were seen at the onset of ALS and no respirator was used, the period from onset to death was rather long (9 years). The spinal lesions showed features common to ordinary ALS, while the marked atrophy with destructive changes throughout the frontal lobe seemed to be considerably more severe than that seen with either ordinary ALS or the Mitsuyama type of ALS. Since the clinical manifestations and histological characteristics are apparently different from those of the Mitsuyama type, our case may be a new nosological variant of ALS with psychiatric manifestations.