Signs Of Motor Neuron Disease Research Articles

Anti-IgLON5 Disease: A New Bulbar-Onset Motor Neuron Mimic Syndrome.

ObjectiveTo expand the spectrum of anti-IgLON5 disease by adding 5 novel anti-IgLON5–seropositive cases with bulbar motor neuron disease-like phenotype.MethodsWe characterized the clinical course, brain MRI and laboratory findings, and therapy response in these 5 patients.ResultsPatients were severely affected by bulbar impairment and its respiratory consequences. Sleep-related breathing disorders and parasomnias were common. All patients showed clinical or electrophysiologic signs of motor neuron disease without fulfilling the diagnostic criteria for amyotrophic lateral sclerosis. One patient regained autonomy in swallowing and eating, possibly related to immunotherapy.ConclusionIgLON5 disease is an important differential diagnosis to evaluate in patients with bulbar motor neuron disease-like phenotype and sleep disorders. There is need for a deeper understanding of the underlying pathobiology to determine whether IgLON5 disease is an immunotherapy-responsive condition.

Verbal semantics and the left dorsolateral anterior temporal lobe: a longitudinal case of bilateral temporal degeneration

ABSTRACT Background Semantic variant primary progressive aphasia (svPPA), a clinical syndrome characterized by loss of semantic knowledge, is associated with neurodegeneration that starts in the anterior temporal lobe (ATL) and gradually spreads towards posterior temporal and medial frontal areas. At the earliest stages, atrophy may be predominantly lateralized to either the left or right ATL, leading to different clinical profiles with the greatest impairment of word comprehension or visual/social semantics, respectively. Methods & Procedures We report the in-depth longitudinal investigation of cognitive and neuroanatomical features of JB, an unusual case of ATL neurodegeneration with relative sparing of left lateral ATL regions. Outcomes & Results Over the course of 9 years, neurodegeneration progressed to involve bilateral temporo-lateral and frontal regions, resulting in a relatively symmetric and diffuse frontotemporal atrophy pattern. In parallel, JB developed greater behavioral, cognitive, and language impairments, as well as signs of motor neuron disease at her last evaluation. Episodic memory and socio-emotional processing deficits arose, likely secondary to semantic verbal deficits, while visuospatial processing, executive function, and non-semantic language abilities remained largely unaffected throughout the course of the disease. Conclusions The details of this rare case of early medial more than lateral ATL degeneration are consistent with a bilateral organization of the semantic system and, crucially, with a functional dissociation between medial paralimbic and lateral neocortical temporal regions. Cases of frontotemporal dementia (FTD) such as JB, who initially do not meet current clinical criteria for svPPA and instead present with some features of behavioral variant FTD, highlight the need for specific criteria for the right temporal variant of FTD that we propose could be called semantic variant FTD.

Potential multisystem degeneration in Asidan patients

ObjectiveTo evaluate a potential multisystem involvement of neurodegeneration in Asidan, in addition to cerebellar ataxia and signs of motor neuron disease. MethodsWe compared the new Asidan patients and those identified in previous studies with Parkinson's disease (PD, n=21), and progressive supranuclear palsy (PSP, n=13) patients using 123I-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy (Asidan, DAT: n=10; MIBG: n=15). ResultsBoth the PD and PSP groups served as positive controls for DAT decline. The PD and PSP groups served as a positive and negative control, respectively, of MIBG decline in the early phase H/M ratio. Of the Asidan patients, 60.0% showed DAT decline without evident parkinsonian features and 6.7% showed impaired MIBG in only the delayed phase H/M ratio. Combined with a normal range of the early phase H/M ratio, this phenotype was newly named Declined DAT Without Evident Parkinsonism (DWEP). InterpretationThe results of present study including DWEP suggest a wider spectrum of neurodegeneration for extrapyramidal and autonomic systems in Asidan patients than expected, involving cerebellar, motor system and cognitive functioning.

Globular glial-like inclusions in a patient with advanced Alzheimer’s disease

disturbances and memory problems. During disease evolution, apraxia and agnosia completed the clinical picture. He was globally apathetic and presented only occasionally sprouts of aggressiveness, but no prominent behavioural alterations. There were no parkinsonism and no signs of MND. He had no family history of a neurological disorder. He died due to cardiac failure. Unfixed brain weight was 1,305 g. On gross examination, frontal and temporally accentuated brain atrophy with marked ventricular enlargement and severe atrophy of amygdala and hippocampus were observed. Basal ganglia appeared atrophic showing flattening of the head of caudate nucleus (similar to patient 2 of Ahmed’s description). Substantia nigra and locus coeruleus were unremarkable. Histologically, prominent neuronal loss, astrogliosis and microglial proliferation were observed in frontal and temporal cortices, in amygdala, hippocampus and entoand transentorhinal regions. Abundant mature, diffuse and primitive βA4-amyloid plaques (DAKO, Glostrup, Denmark, clone 6F/3D) were detected (Fig. 1a). These were distributed in all cortical areas, basal ganglia, brainstem nuclei and cerebellar cortex, corresponding to a phase 5 according to Thal et al. [6] and to an age-related plaque score C according to CERAD criteria [4]. There was mild, occipitally accentuated leptomeningeal amyloid angiopathy. Furthermore, abundant hyperphosphorylated tau (Thermo-Scientific, clone AT8) immunoreactive neuropil threads, tangles and dystrophic neurites surrounding senile plaques were observed in frontal, temporal (Fig. 1b) and parietal cortex, with no involvement of primary visual cortex. Extensive tau pathology was also detected in insula, cingulum, hippocampus and parahippocampal gyrus, basal ganglia, basal nucleus of Meynert and some brainstem nuclei. In hippocampus, abundant ghost-tangles, neuronal granulovacuolar degeneration and Hirano bodies were also We read with interest the article by Ahmed and colleagues [1] entitled “Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies.” The authors present clinical, neuropathological and biochemical features of two patients, one with frontotemporal dementia (FTD) and the other with motor neuron disease (MND), both sharing the presence of characteristic globular glial 4-repeat tau positive inclusions (oligodendroglial and astrocytic) with different topographical distribution. Previously, Kovacs et al. [3] described in detail seven cases showing FTLD phenotype and abundant white matter globular glial inclusions. Both authors suggest grouping previous terms such as MSTD or FTD-P-MND/PSP-CST, in one encompassing term, as this pathology seems to represent a separate entity among tauopathies. We present the post-mortem neuropathologic study of an 82-year-old man, diagnosed with possible Alzheimer’s disease at the age of 73 years due to progressive word finding

Wheels within wheels: multifocal autoimmune myelitis in a woman with Huntington’s disease

Hungtington’s disease (HD) is an autosomal dominant inherited genetic/neurodegenerative disorder. Early clinical manifestation varies widely, including cognitive and behavioural abnormalities. In later stages, the full clinical picture of HD is not limited to choreiform movements, but may comprise various other symptoms and eventually imitate other neurologic disorders, e.g., rigidity in juvenile HD and even signs of motor neuron disease [1, 2]. Besides clinical examination and family history, if available, diagnosis consists of CAG repeats in the huntingtin gene, with CAG [ 39 certainly predicting HD. Despite current research efforts, the only available consensus surrogate marker for age of onset and disease progression, though limited in sensitivity, is the number of CAG repeats [3, 4]. A 47-year-old female patient was transferred to us from the psychiatric clinic for further clarification of dyskinesia and walking inability. She had previously been treated in an outpatient clinic after being found in her apartment in a cachectic and disoriented state unable to walk. She had been divorced for about 10 years and ever since without social contacts, accounting for the scarce medical and family history. After exclusion of apparent somatic deficits she had been referred to the psychiatric clinic suspecting a psychotic disorder, which was excluded, and she was referred to us. On admission she demonstrated a reduced cognitive performance, responding inadequately, and was unable to summarise her symptoms in an organised chronological order. On neurological examination she had mild distal choreiform hyperkinesias in the upper limbs and mild dysarthria, which in combination with behavioural abnormalities supported clinically manifest Huntington’s disease (HD). No further clinical HD signs were evident. Furthermore, she had severe spastic paraparesis [2/5 for the hip flexors on the Medical Research Council (MRC) scale] with brisk reflexes of the lower limbs and positive leftsided Babinski sign. No paresis or reflex abnormalities were present in the upper limbs. On genetic testing, 44 CAG repeats on one huntingtin allele and 17 on the other were detected. Total motor score on Unified Huntington’s Disease Rating Scale was 16 (range 0–124). As to the spastic paraparesis, external cranial MRI scans a week prior to admission had not revealed any abnormalities in terms of neuroinflammation, generalised or focal cortical/subcortical atrophy, or any neoplastic changes or neurovascular events. In addition, we performed electrophysiology (motor evoked potentials) showing prolonged central latencies (M. peroneus), cerebrospinal fluid (CSF) sampling demonstrating oligoclonal bands (OCB), and spinal MRI showing several increased T2-weighted signals in the cervical (C3/ 4, C6/7; Fig. 1a, b) and thoracic spine (Th2, Th4; Fig. 1c) with a gadolinium-enhancing lesion (C6/7; Fig. 1d). Further serological and CSF analyses excluded infectious, paraneoplastic or other autoimmune entities as neuromyelitis optica spectrum diseases (antibodies against A. Haghikia and B.F. Decard contributed equally to this case presentation.

Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72

Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.

Clinical appraisal of chronic traumatic encephalopathy

There are currently no consensus-based clinical diagnostic criteria for chronic traumatic encephalopathy (CTE). This review provides an update on recent literature pertaining to clinically relevant procedures that--presently or in the future--may be useful for the in-vivo detection, characterization, and/or prediction of CTE. Preliminary evidence about the clinical manifestations of CTE has been accumulating via post-mortem medical record review and interviews of friends or family members of individuals with neuropathologically documented CTE. This evidence suggests that CTE is manifested clinically by changes in cognition (especially memory and executive functioning, with dementia later in the disease course), mood (especially, depression, apathy, and suicidality), personality and behavior (especially poor impulse control and behavioral disinhibition), and movement (including parkinsonism and signs of motor neuron disease). At the present time, evidence regarding CTE has not been confirmed in a prospective study of a cohort at risk for CTE. On the basis of recent research in the fields of dementia and traumatic brain injury, several in-vivo procedures (including neurological examination, neuropsychological assessment, neuroimaging techniques, and blood and cerebrospinal fluid biomarkers) each have the potential to contribute unique information about the manifestations of CTE, including clinical and preclinical stages. More research is needed to develop a set of consensus diagnostic criteria that provide a reliable and valid indicator of neuropathologically verified CTE. Until such criteria are developed, the clinical assessment of CTE should be informed by modern research that is of relevance to traumatic brain injury and neurodegenerative diseases.

Parkinsonism and motor neuron diseases: Twenty‐seven patients with diverse overlap syndromes

It has long been recognized that signs of motor neuron disease (MND) may accompany clinical evidence of parkinsonism in different neurodegenerative conditions. By using the Columbia University Division of Movement Disorders database, we reviewed data from 5,500 cases of parkinsonism and recorded the presence of upper motor neuron (UMN) dysfunction, lower motor neuron (LMN) dysfunction, or both. Among the 27 patients so identified, we counted those with autonomic dysfunction, cerebellar dysfunction, or dementia. Among the 27 cases, seven had UMN signs and LMN signs as well as parkinsonism and were diagnosed with amyotrophic lateral sclerosis (ALS)-parkinsonism (Brait-Fahn disease). Three of the seven had dementia that was not deemed to be frontotemporal dementia (FTD). Six other patients had no LMN signs but had UMN signs and parkinsonism and were classified as having primary lateral sclerosis (PLS)-parkinsonism. Four patients had both UMN and LMN signs with parkinsonism as well as the characteristic dementia of FTD; they were diagnosed with FTD-parkinsonism-ALS. Seven patients had MND, parkinsonism, and autonomic or cerebellar dysfunction, a combination compatible with multiple system atrophy (MSA). Three patients had syndromes compatible with hereditary spastic paraplegia (HSP). In sum, we found that MND occurs in association with diverse parkinsonian syndromes; some are heritable, others sporadic and causes are uncertain. Having MND may be a risk factor for parkinsonism. A prospective study may elucidate this possibility.

TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea.

TDP-43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP-43-immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS.

P2-184: Identification of a novel chromosomal locus in a Belgian FTLD-MND family

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative brain disorder with a prevalence similar to that of Alzheimer's disease in the population below age 65 years. In some patients FTLD symptoms are accompanied by signs of motor neuron disease (MND). A positive family history is observed in up to 50% of FTLD patients indicating a significant contribution of genetics to the etiology of FTLD. A high degree of genetic heterogeneity has been observed with different mutations in the genes encoding the microtubule-associated protein (MAPT), progranulin (PGRN), charged multivesicular body protein 2B (CHMP2B) and valosin containing protein (VCP). Further, two loci on chromosome 9 at 9q21-q22 and 9p13–21 were implicated in FTLD with MND (FTLD-MND). In Belgian familial FTLD patients 65% remained unexplained by mutations in known FTLD genes. Of one patient diagnosed with FTLD-MND, we collected DNA of relatives and performed a genome-wide scan. We identified and finemapped a novel chromosomal locus that was not previously linked to FTLD and/or MND. Haplotype analysis identified a risk haplotype of 23 cM that co-segregated with disease. Further reduction of the candidate region and mutation analyses of positional and functional candidate genes are ongoing. Identification of the mutation in the underlying disease gene will significantly contribute to the understanding of neurodegenerative disease mechanisms in FTLD.

Frontotemporal dementia: evidence for impairment of ascending serotoninergic but not noradrenergic innervation. Immunocytochemical and quantitative study using a graph method.

A graph method was employed to analyze the spatial neuronal patterns of nuclear grays of the pontine tegmentum with ascending aminergic projections to the forebrain in 12 cases of frontotemporal dementia (FTD). The nuclear grays examined were the nucleus centralis superior (NCS), a part of the nucleus raphae dorsalis (NRD), and the locus coeruleus (LC). The results were compared with 30 cases of Alzheimer's disease (AD) and 35 non-demented controls. In addition to the graph evaluations, neuronal cytoplasmic inclusion bodies were stained by silver impregnation and ubiquitin (Ub) and tau immunohistochemistry. The FTD cases showed a significant, 40%, decline in number of neurons in the NCS and NRD, while the LC was spared. The magnitude of neuronal loss matched that of AD where, by contrast, the LC was also severely changed. Amyloid deposition and Alzheimer neurofibrillary tangles occurred in the aminergic nuclei almost exclusively in AD and, to a minor extent, in some aged controls. No cytoplasmic inclusion bodies were found in the aminergic nuclei of the FTD cases. However, 6 cases had Ub-positive but tau-negative neuronal inclusions in the hippocampal dentate fascia and in layer 2 of the prefrontal isocortex, and 3 showed clinical and histological signs of motor neuron disease. Our results suggest that the serotoninergic raphe nuclei with ascending projections to the forebrain, but not the LC, become directly or indirectly involved in frontotemporal dementia both with and without motor neuron disease.

Frontotemporal dementia with ubiquitinated inclusions: A case study of the regional distribution of hippocampal pathology

In motor neuron disease (MND) cases associated with dementia, neurons often contain ubiquitin-positive, taunegative cytoplasmic inclusions that are numerous in the granule cell neurons of the hippocampal complex. Dot or threadlike ubiquitinated neurites are also observed in the surrounding neuropil and in other frontotemporal regions. Cases of frontotemporal dementia (FTD) with identical appearing ubiquitinated deposits have been described in FTD cases lacking signs of MND. The underlying pathobiology of these cases remains obscure. We describe a case from a familial FTD kindred and use immunohistochemistry to evaluate the hippocampal ubiquitin-positive cytoplasmic granule cell inclusions in relationship to the threads and dots that surround them. Ubiquitin-positive threads were more numerous in the overlying molecular layer of the dentate gyrus (DG) compared with the underlying polymorphic layer, suggesting that threads are formed primarily in the dendrites of the affected granule cells. In contrast, dot-like inclusions were uniformly distributed. Using antibodies to synapticterminal specific proteins, we observed loss of perforant pathway synapses in the outer molecular layer of the DG. The numbers of thread-and dot-like inclusions were no greater in the region of synaptic loss than in the layer that lacked detectable synaptic loss. Similarly, ubiquitinated aggregates were more numerous in rostral sections, and they tended to cluster, whereas synapse loss was uniform. These findings expand upon previous data by suggesting that formation of these ubiquitinated aggregates relate to an inherent susceptibility in the granule cell neuron, rather than solely to a deafferentation effect. This study contributes to our understanding of what might be a common pathological process underlying FTD and MND cases with ubiquitinated inclusions.

Werdnig‐Hoffmann disease and chronic distal spinal muscular atrophy with apparent autosomal dominant inheritance

We report on a family in which both Werdnig-Hoffmann disease (severe infantile-onset spinal muscular atrophy) and chronic distal spinal muscular atrophy occurred, with apparent autosomal dominant inheritance. The female proband clinically had Werdnig-Hoffmann disease and died at 10 months. In their second decade of life, the proband's father and his 2 brothers developed bilateral progressive atrophy and weakness of the hands and mild weakness in the distal parts of the legs. Their mother had no symptoms or signs of motor neuron disease but electromyography revealed distal denervation of the limbs. While the family studies suggest autosomal dominant inheritance, it is possible that the proband's condition was influenced by a maternally derived allelic or modifying trait.