Late Cortical Cerebellar Atrophy Research Articles

Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis.

Neurologists have a difficult time identifying sporadic cerebellar ataxia. Multiple system atrophy of the cerebellar type (MSA-C), spontaneous late cortical cerebellar atrophy, and prolonged alcohol use are a few possible causes. In a group of people with sporadic cerebellar ataxia that was not MSA-C, an autosomal-dominant spinocerebellar ataxia (SCA) mutation was recently discovered. Chinese single-hospital cohort will be used in this study to genetic screen for SCA-related genes. One hundred forty individuals with CA were monitored over 8 years. Thirty-one individuals had familial CA, 109 patients had sporadic CA, 73 had MSA-C, and 36 had non-MSA-C sporadic CA. In 28 of the 31 non-MSA-C sporadic patients who requested the test, we carried out gene analysis, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA31, and dentatorubro-pallidoluysian atrophy (DRPLA). The control group consisted of family members of the patients. In 57% of the instances with spontaneous CA that were not MSA-C, gene abnormalities were discovered. The most frequent exception among individuals with sporadic CA was SCA6 (36%), followed by monsters in SCA1, 2, 3, 8, and DRPLA. In contrast, 75% of the patients with familial CA had gene abnormalities, the most frequent of which was SCA6 abnormality. The age of 69 vs 59 was higher, and the CAG repeat length was a minor age of 23 vs 25 in the former instances compared to the last one among individuals with SCA6 anomalies that were sporadic as opposed to familial cases. In sporadic CA, autosomal-dominant mutations in SCA genes, notably in SCA6, are common. Although the cause of the increased incidence of SCA6 mutations is unknown, it may be related to a greater age of onset and varied penetrance of SCA6 mutations.

Cortical Cerebellar Atrophy and Idiopathic Cerebellar Ataxia: Nomenclature and Diagnostic Approach

Marie et al. (1922) first proposed a disease entity "late cortical cerebellar atrophy (LCCA)", which is characterized neuropathologically by pure cerebello-olivary degeneration. LCCA was originally described as sporadic, late-onset, pure cerebellar ataxia of unknown etiology; however, it has occasionally been used to denote familial or secondary ataxias, particularly alcoholic cerebellar degeneration. Sporadic ataxia is classified mainly into LCCA or CCA and olivo-ponto-cerebellar atrophy (OPCA) in Japan. OPCA, now multiple system atrophy with predominant cerebellar ataxia, has characteristic brain imaging features and is clearly diagnosed based on the consensus criteria. On the other hand, there is no specific biomarker for LCCA/CCA, and neuropathological examination is required for a definitive diagnosis. Therefore, the clinical diagnosis of LCCA/CCA depends on the exclusion of other diseases manifesting as cerebellar ataxia. However the differential diagnosis for LCCA/CCA is not necessarily made carefully. As a result, the LCCA/CCA category in Japan is a "waste basket," including OPCA, hereditary ataxias, and secondary ataxias, which are unidentified yet. To refine the LCCA/CCA category, we proposed the clinically-defined term "idiopathic cerebellar ataxia (IDCA)" and established its diagnostic criteria. By nationwide screening, we have identified 51 patients with probable IDCA according to the criteria so far. Here we review the clinical characteristics of IDCA patients.

Genetic Screening for Spinocerebellar Ataxia Genes in a Japanese Single-Hospital Cohort.

Objective Diagnosis of sporadic cerebellar ataxia is a challenge for neurologists. A wide range of potential causes exist, including chronic alcohol use, multiple system atrophy of cerebellar type (MSA-C), and sporadic late cortical cerebellar atrophy. Recently, an autosomal-dominant spinocerebellar ataxia (SCA) mutation was identified in a cohort of patients with non-MSA-C sporadic cerebellar ataxia. The aim of this study is to genetically screen genes involved in SCA in a Japanese single-hospital cohort. Methods Over an 8-year period, 140 patients with cerebellar ataxia were observed. There were 109 patients with sporadic cerebellar ataxia (no family history for at least four generations, 73 patients with MSA-C, and 36 patients with non-MSA-C sporadic cerebellar ataxia) and 31 patients with familial cerebellar ataxia. We performed gene analysis comprising SCA1, 2, 3, 6, 7, 8, 12, 17, 31, and dentatorubro-pallidoluysian atrophy (DRPLA) in 28 of 31 non-MSA-C sporadic patients who requested the test. Familial patients served as a control.Results Gene abnormalities were found in 57% of non-MSA-C sporadic cerebellar ataxia cases. Among patients with sporadic cerebellar ataxia, abnormalities in SCA6 were the most common (36%), followed by abnormalities in SCA1 (7.1%), SCA2 (3.6%), SCA3 (3.6%), SCA8 (3.6%), and DRPLA (3.6%). In contrast, gene abnormalities were found in 75% of familial cerebellar ataxia cases, with abnormalities in SCA6 being the most common (29%). For sporadic versus familial cases for those with SCA6 abnormalities, the age of onset was older (69 years vs. 59 years, respectively), and CAG repeat length was shorter (23 vs. 25, respectively) in the former than in the latter (not statistically significant).Conclusion Autosomal-dominant mutations in SCA genes, particularly in SCA6, are not rare in sporadic cerebellar ataxia. The reason for the frequency of mutations in SCA6 remains unclear; however, the reason may reflect a higher age at onset and variable penetrance of SCA6 mutations.

Hypocupremia: a possible association with late cortical cerebellar atrophy.

BackgroundWe report a patient, diagnosed with late cortical cerebellar atrophy, who had persistent low serum copper levels.Case reportA 48-year-old male developed progressive difficulty with balance, frequent falls, and dysarthric speech, which worsened over a short time span. He had an extensive ataxia work-up, which was unremarkable except for persistent low serum copper levels despite adequate supplementation. Magnetic resonance imaging of the brain showed marked cerebellar atrophy. The patient experienced progressive worsening of symptoms, which did not improve with either oral or parenteral copper supplementation.DiscussionTo our knowledge, ours is the first case report of late cortical cerebellar atrophy in the setting of low serum copper levels. The current report should trigger further research in mechanisms leading to copper deficiency and its possible role in cerebellar disease.

Hypocupremia: A Possible Association with Late Cortical Cerebellar Atrophy

<strong>Background:</strong> We report a patient, diagnosed with late cortical cerebellar atrophy, who had persistent low serum copper levels. <strong>Case report:</strong> A 48-year-old male developed progressive difficulty with balance, frequent falls, and dysarthric speech, which worsened over a short time span. He had an extensive ataxia work-up, which was unremarkable except for persistent low serum copper levels despite adequate supplementation. Magnetic resonance imaging of the brain showed marked cerebellar atrophy. The patient experienced progressive worsening of symptoms, which did not improve with either oral or parenteral copper supplementation. <strong>Discussion:</strong> To our knowledge, ours is the first case report of late cortical cerebellar atrophy in the setting of low serum copper levels. The current report should trigger further research in mechanisms leading to copper deficiency and its possible role in cerebellar disease.

Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan

16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD-SCA) characterized by late-onset pure cerebellar ataxia and -16C>T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C-T substitution of the puratrophin-1 gene. By further analysis of the patients with the haplotype block, we observed a single-founder effect for 16q-ADCA, even in patients who are supposed to be sporadic late cortical cerebellar atrophy (LCCA). We also observed slippage mutations of microsatellite markers, GATA01 and 17 msm, in the pedigrees. We compared the clinical course of 16q-ADCA in heterozygotes and homozygotes with the haplotype block and observed no apparent gene dosage effect. 16q-ADCA accounts for 27% of AD-SCAs and is the most frequent AD-SCA in South Kyushu, Japan.

Distribution of cerebello‐olivary degeneration in idiopathic late cortical cerebellar atrophy: Clinicopathological study of four autopsy cases

Late cortical cerebellar atrophy (LCCA) is a neurodegenerative disease which presents with slowly progressive cerebellar ataxia as a prominent symptom and is characterized neuropathologically by a limited main lesion to the cerebellar cortex and inferior olivary nucleus. To elucidate the features of lesions in the cerebellar cortex and inferior olivary nucleus, four autopsy cases suffering from idiopathic LCCA without other cortical cerebellar atrophies, such as alcoholic cerebellar degeneration, phenytoin intoxication, or hereditary cerebellar atrophy including spinocerebellar ataxia type 6, were examined. All affected patients had identical distinct features of cerebellar cortical lesions. In all four cases, the most obvious pathological finding throughout the cerebellum was loss of Purkinje cells, but the rarefaction of granular cell layers was observed only where loss of Purkinje cells was very severe, and thinning of the molecular layer was seen only where the rarefaction of granular cell layers was moderate to severe. Two patients presented with vermis dominant cerebellar cortical lesions, but the other two patients showed hemispheric dominant pathological changes. Neuronal loss of the inferior olivary nucleus was observed in the three autopsy cases. Two of the three cases had a prominent lesion in the dorsal part of the inferior olive and the cerebellar cortical lesion disclosed the vermis dominance, but the other patient, showing prominent neuronal loss in the ventral olivary nucleus, had a cerebellar hemisphere dominant lesion. The patient without neuronal loss in the inferior olivary nucleus had suffered from a shorter period of disease than the others and the rarefaction of granular cell layers and narrowing of the molecular layer of the cerebellar cortex were mild. Therefore, it is obvious that there are two types of cerebellar cortex lesions in idiopathic LCCA; one is vermis dominant and the other is cerebellar hemispheric dominant. The lesion of the inferior olivary nucleus occurs as a secondary degeneration after rarefaction of the granular cell layer and thinning of the molecular layer of the cerebellar cortex progresses. Furthermore, the distribution of the degeneration in the inferior olivary nucleus depends on the distribution of the cerebellar cortex lesions.

Diffusivity and diffusion anisotropy of cerebellar peduncles in cases of spinocerebellar degenerative disease

Purpose: This study accessed the feasibility of using tractography-based analysis to evaluate the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of three cerebellar peduncles in subtypes of spinocerebellar degenerative disease. Materials and methods: We examined 7 cases of dentatorubro-pallidoluysian atrophy (DRPLA), 4 cases of multiple system atrophy, cerebellar type (MSA-C), 4 cases of late cerebellar cortical atrophy (LCCA) and 8 controls. Diffusion tensor images were obtained, and tractographies of cerebellar peduncles were generated. ADC and FA along the cerebellar peduncles and volume of cerebellar peduncle were measured, and analyses of variance were made among the control and each spinocerebellar degenerative disease groups. Results: There were statistically significant decrease in FA and volume and increase in ADC values between DRPLA cases and controls in all three cerebellar peduncles. On the other hand, MSA-C cases mainly showed statistically significant decreased FA and volume and increased ADC values in the middle cerebellar peduncle. LCCA cases did not show prominent difference in the three cerebellar peduncles. Conclusion: The values of diffusivity and diffusion anisotropy of cerebellar peduncles evaluated by tractography based measurements seem to reflect characteristics of the different types of spinocerebellar degenerative diseases. Tractography-based measurements may be a feasible tool for differential diagnosis of spinocerebellar degenerative disease.

Vecuronium in a patient with late cerebellar cortical atrophy

Little information is available regarding the sensitivity to neuromuscular blocking drugs in patients with spinocerebellar degeneration and associated diseases. We report the response to vecuronium in a patient with late cerebellar cortical atrophy, a nonhereditary type of cerebellar ataxia. Onset time and time to 25% recovery of T1/T0 after vecuronium 0.1 mg · kg −1 under sevoflurane anesthesia were 156 seconds and 43 minutes, respectively. Recovery index was 27 minutes. We believe this is the first report describing a response to neuromuscular blocking drugs in this disease.

Accumulation of NACP/α-synuclein in Lewy body disease and multiple system atrophy

OBJECTIVESNACP/α-synuclein is an aetiological gene product in familial Parkinson's disease. To clarify the pathological role of NACP/α-synuclein in sporadic Parkinson's disease and other related disorders including diffuse Lewy body disease...

Distribution of cerebellar cortical lesions in multiple system atrophy: a topographic neuropathological study of three autopsy cases in Japan.

We investigated neuropathologically the distribution of the cerebellar cortical lesions in three Japanese autopsy cases of multiple system atrophy (MSA) using hemisphere specimens. The lesions were classified as mild, moderate or severe. The distribution of cerebellar cortical lesions in all three cases were uniform: the cerebellar cortical lesions were more conspicuous in the vermis than in the hemisphere. These neuropathological findings differ from the established theory that cerebellar lesions of MSA are more pronounced in the hemisphere than in the vermis. The degree of cerebellar cortical lesions in our cases increased in relation to the duration of the disease. Our pathological data may contribute to the morphological differential diagnosis in various neurodegenerative disorders including late cortical cerebellar atrophy. Our neuropathological findings may also make a contribution to the neuroradiological progress in the differential diagnosis of spinocerebellar disease.

Vertical oculomotor disorders in progressive supranuclear palsy and spino-cerebellar degeneration

We performed neuro-otological investigation of vertical oculomotor disorders in 35 patients with degenerative disease [progressive supranuclear palsy (PSP) and spino-cerebellar degeneration], and obtained the following results: 1) In the patients with PSP, in addition to vertical oculogyric disorder both saccade and pursuit eye movements were disturbed, and the disturbance of saccade movement was greater. Even the patients without an oculogyric disorder were all found to have decreased saccade velocity, suggesting that this disorder may occur earliest in PSP. 2) In olivo-ponto-cerebellar atrophy (OPCA), saccade movement was less disturbed than that in PSP. In contrast, pursuit movement was disturbed more frequently. 3) In late cortical cerebellar atrophy (LCCA), vertical ocular movement was hardly disturbed compared with OPCA. 4) Concerning dentate nuclear degeneration, we cannot reach a conclusion because of the few cases studied, but a variety of oculomotor disorders were seen; both saccade and pursuit movements were disturbed, but saccade movement was less disturbed than in PSP. 5) In visual suppression tests, enhancement in the light area was frequently seen in the patients with PSP and OPCA, but none with LCCA showed such change. In addition, enhancement of the light area under visual suppression was significantly correlated with vertical oculomotor disorder.

晩発性皮質性小脳萎縮症の眼球運動と病理

An autopsy case of late cortical cerebellar atrophy (LCCA) is reported. A 58-yearold male without family history developed dysarthria and gait disturbance. Neurological examination revealed scanning speech, bradylaria and gradually progressive cerebellar ataxia of the trunk and all limbs. Clinical test for his eye movement showed both saccadic dysmetria and loss of smoothness in pursuit eye movement, but no nystagmus. His deep tendon reflexes remained normal except for decrease in ankle tendon reflex. There were no mental deterioration, nor dysautonomia. He died of sepsis at the age of 73. The duration of his illness was approximately 15 years. Neuro-otological findings were as follows; 1) On eye tracking test, horizontal pursuit eye movements were disturbed, but the severity of this disturbance was initially very mild and deferiorated slowly. 2) Rapid eye movement system such as saccade was normal. 3) No apparent gaze nor spontaneous nystagmus was revealed. 4) Optokinetic nystagmus were normally evoked in number, and the maximal slow phase velocity was almost normal range.On neuropathological examination, mild cerebellar atrophy of both the vermis and cerebellar hemispheres were shown macroscopically. There was severe deciduation of Purkinje cells in both the cerebellar vermis and hemispheres in microscopic examination. However, neurons of the inferior olivary nuclei were almost normal in number, although, slightly decreased in size. The molecular layer and cerebellar white matter showed no abnormalities. Neurons among the granular layer, the dentate nuclei, pontine nuclei and various nuclei of the brain stem showed a normal appearance.In conclusion, the characteristics of abnormal eye movement in cases that have been pathologically diagnosed as LCCA are disturbance of smooth eye movement system and normally evoked optokinetic nystagmus. We thought the neuropathological findings confirmed these results from a neuro-otological perspective.

Striatal 18F-Dopa uptake and brain glucose metabolism by PET in patients with syndrome of progressive ataxia

Striatal 18F-Dopa uptake and brain glucose metabolism were studied by PET with 6- l-[ 18F]fluorodopa and [ 18F]fluorodeoxyglucose in 11 patients with syndrome of progressive ataxia. Five of the 11 patients were diagnosed as having cerebellar cortical degeneration (CCD), including 3 with late cerebellar cortical atrophy and 2 with Holmes type hereditary ataxia while 6 demonstrated olivopontocerebellar atrophy (OPCA). The caudate and putaminal 18F-Dopa uptake ratios to the occipital cortex in CCD showed no significant difference from those in the controls. On the other hand, those with OPCA decreased as compared to the controls. In addition, the cerebellar glucose metabolism in CCD decreased as compared to the controls, while that in the brainstem showed no significant decrease from the controls. The glucose metabolic rates both in the cerebellar hemisphere and in the brainstem in the OPCA patients decreased compared to the controls. The cerebral cortical, striatal and thalamic glucose metabolisms were normal in both the CCD and OPCA in groups. The appearance of a decreased glucose metabolism in the cerebellum is considered to be relevant in the genesis of cerebellar ataxia, even though their underlying diseases were different from each other. The differences in the glucose metabolism of the brainstem and in the nigrostriatal presynaptic dopaminergic function between CCD and OPCA as assessed by PET may be caused by differences in the pathophysiological mechanism between CCD and OPCA, and those differences appear to be useful when making a differential diagnosis of CCD and OPCA.

Reduced cerebellar blood flow and oxygen metabolism in spinocerebellar degeneration: a combined PET and MRI study.

Fourteen patients with spinocerebellar degeneration (SCD) were subjected to MRI and PET studies. The quantitative MRI data revealed significant cerebellar and pontine atrophy in the patients with olivopontocerebellar atrophy (OPCA), and cerebellar atrophy in the patients with late cerebellar cortical atrophy (LCCA). We failed to demonstrate significant differences in the pons between LCCA patients and normal controls. PET measurements revealed decreases in cerebral oxygen metabolic rate (CMRO2) in the cerebellar hemisphere and vermis in both groups of patients. The markedly decreased cerebral blood flow (CBF) and CMRO2 in the pons were found only in the patients with OPCA. PET data corrected for the tissue shrinkage on the basis of MRI morphometry indicated a net reduction in cerebellar CMRO2 and CBF. The present study has demonstrated that a combination of functional and anatomical data offers further evidence in favour of the current acceptable classification of SCD based on clinicopathological grounds. Our data further suggest that the amount of atrophy in the cerebellum could not fully account for the decreased metabolic rates observed in PET studies.

Micturitional disturbance in late cortical cerebellar atrophy

Micturitional disturbance in late cortical cerebellar atrophy

晩発性小脳皮質萎縮症例の神経耳科学的検討

A 65 year-old male patient had been treated for Late cortical cerebellar atrophy (LCCA) for 7 years. His neuro-otological findings and a review of the literature on LCCA are presented in this paper.In 1985, this patient was found to have down-beat nystagmus and gaze nystagmus. Electronystagmography (ENG) showed a very abnormal pattern. His eye tracking test (ETT) showed saccadic pursuit, no optokinetic nystagmus and no visual suppression. The neuro-otological findings suggested a cerebellar lesion, although he had no neurological abnormality.In 1986, trunkal ataxia and speech disturbance appeared. MRI showed atrophy of the vermis. These findings led us to the clinical diagnosis of LCCA.It was interesting that the neuro-otological findings preceded the neurological signs. Probably the oculomotor system and the equilibrium system of this patient with LCCA are degenerating separately.

A significant reduction of putative transmitter amino acids in cerebrospinal fluid of patients with Parkinson's disease and spinocerebellar degeneration

We evaluated the concentrations of the putative transmitter amino acids in the cerebrospinal fluid, and found a significant reduction of glutamate, aspartate, γ-aminobutyric acid (GABA), and glycine concentrations in parkinsonian patients. There was no difference in amino acid concentrations between parkinsonian patients receiving l-DOPA and those not receiving l-DOPA. A similar decrease of glutamate and aspartate concentrations was found in patients with spinocerebellar degeneration. Concentrations of asparagine, glycine and taurine were also significantly decreased in patients with late cortical cerebellar atrophy.

REM Sleep without Muscle Atonia (Stage 1‐REM) and Its Relation to Delirious Behavior during Sleep in Patients with Degenerative Diseases Involving the Brain Stem

Nocturnal sleep was examined in 12 patients with degenerative diseases involving the brain stem and in 2 patients with late cerebellar cortical atrophy (LCCA). A peculiar sleep state, characterized by the concomitant appearance of a low-voltage mixed frequency EEG, rapid eye movements (REMs) and tonic EMG in mental muscles, repeatedly appeared during nocturnal sleep in all of the 12 patients with degenerative diseases involving the brain stem and it was called stage 1-REM after Tachibana et al. In 8 of the 12 patients, delirious or oneiric behavior appeared during, or soon after, the episodes of stage 1-REM. Inner experiences reported by one of the subjects well corresponded to his behavior during the episode of stage 1-REM. Stage 1-REM was not observed during nocturnal sleep of the patients with LCCA. These results indicate that a degenerative lesion in the brain stem induced stage 1-REM and delirious behavior during nocturnal sleep through abolishing muscle atonia of REM sleep and causing dissociation of the functional components characterizing REM sleep.

Hair trace elements in cerebellar degeneration: low copper levels in late cortical cerebellar atrophy

The levels of ten elements in the hair of 7 patients with olivopontocerebellar atrophy (OPCA), 10 patients with late cortical cerebellar atrophy (LCCA) and 1489 healthy persons were determined by inductively coupled plasma emission spectrometry. The phosphorus, zinc, selenium, calcium, magnesium, iron, manganese, aluminium and mercury concentrations did not show any statistically significant difference among the three groups. The copper concentration was significantly lower in the patients with LCCA than in the patients with OPCA, and in the healthy controls. The possibility that LCCA is associated with a mild degree of copper deficiency is considered.