Conventional magnetic resonance imaging key features for distinguishing pathologically confirmed corticobasal degeneration from its mimics: a retrospective analysis of the J-VAC study.

PURPOSE: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. METHODS: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. RESULTS: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer's disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. CONCLUSION: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.

Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts.

BACKGROUND: Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively. MATERIALS AND METHODS: Eight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families. RESULTS: Seven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (<0.1%). CONCLUSION: Biallelic SNORD118 mutations were exclusively found in most unrelated families with LCC.

Low-titer anti-GAD-antibody-positive cerebellar ataxia.

The majority of cases of anti-glutamic acid decarboxylase (GAD)-antibody-positive cerebellar ataxia are reported to have high levels of anti-GAD antibody, and the diagnostic value of low titers of anti-GAD antibody in a patient with cerebellar ataxia is still unknown. The purpose of this study was to verify the characteristics of low-titer-anti-GAD-antibody-positive cerebellar ataxia patients and the diagnostic value of low titers of anti-GAD antibody in patients with cerebellar ataxia. The subjects were six patients positive for low-titer GAD antibody (<100 U/mL). We examined them with MRI, including voxel-based morphometry, and with single-photon emission computed tomography and monitored the GAD antibody index in the cerebrospinal fluid. The levels of antineuronal, antigliadin, anti-SS-A, antithyroid antibodies, and of vitamins E, B1, and B12 were determined. Thoracic and abdominal CT scans were performed to exclude a paraneoplastic origin. We treated three patients with immunotherapy. All cases showed cortical cerebellar atrophy. The GAD antibody index in three of the five patients reviewed was >1.0. Two of the six patients were thyroid antibody-positive, and one was both antinuclear- and anti-SS-A antibody-positive. After the administration of immunotherapy to three patients, two showed clear effectiveness, and one, transient effectiveness. Effectiveness was greatest in the two patients with familial occurrence of the disease. In cerebellar ataxia, regardless of family history or isolated illness, it is critical to measure the GAD antibody level, and, even with a low titer level, if the result is positive, immunotherapy should be considered.

Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

An autopsy case of lymphomatosis cerebri showing pathological changes of intravascular large B-cell lymphoma in visceral organs.

We describe the case of a 61-year-old man presenting with subacute encephalopathy. The clinical manifestations included progressive dementia and pyramidal and extrapyramidal tract signs. Brain CT scan and MRI showed diffuse bilateral white matter changes in the cerebral hemispheres, basal ganglia, thalamus and brainstem. No contrast-enhanced lesion was observed. Peripheral blood studies, CSF analysis, and brain and muscle biopsies were nonspecific and failed to reveal diagnostic evidence of any specific disease. The patient was diagnosed with and treated for a cerebral demyelinating disorder. Post mortem examination showed diffuse infiltration of lymphoma cells without mass lesions in the extensive cerebral white and gray matter with minimal intravascular patterns, particularly in the perivascular and periventricular spaces. These findings were consistent with lymphomatosis cerebri (LC). In other visceral organs such as the lungs, liver, kidneys and adrenal glands, blood vessels were plugged by numerous neoplastic cells which were morphologically and immunohistochemically similar to those observed in the CNS, consistent with intravascular malignant lymphoma (IVL). To our knowledge, this is the first autopsy report showing the coexistence of LC and IVL. This case suggests a possible link between LC and IVL.

Demyelinating Neuropathy Due to Intravascular Large B-cell Lymphoma.

We herein report the case of a 67-year-old man who presented with the acute onset of limb weakness. Brain magnetic resonance imaging revealed multiple abnormal-signal-intensity lesions. Steroids were administered, and the patient initially responded. Nerve conduction testing findings were consistent with demyelinating polyneuropathy. A sural nerve biopsy specimen revealed fascicles with extensive onion-bulb formation. Although skin and sural nerve biopsies showed no atypical cellular infiltration, the histopathological diagnosis of intravascular large B-cell lymphoma was obtained by a brain biopsy. The neuropathy in this patient may be attributed to a demyelinating process independent of ischemic damage by lymphoma.

An autopsied case of panencephalopathic-type Creutzfeldt-Jakob disease with mutation in the prion protein gene at codon 232 and type 1 prion protein.

In this study, we describe the clinicopathologic findings in a 68-year-old man with panencephalopathic-type CJD with a substitution from methionine to arginine at codon 232 (M232R) in the prion protein (PrP) gene and type 1 PrP. Initial symptoms of the patient were a rapidly progressive memory disturbance and disorientation. The patient showed myoclonus and periodic sharp-wave complexes on electroencephalogram in the early stages of disease. Diffusion-weighted MRI along with the presence of both neuron-specific enolase and 14-3-3 protein in the CSF showed similarities to classic-type sporadic CJD. The patient reached the akinetic mutism state 2 months following the onset of symptoms and died after 13 months. Neuropathologic examination revealed panencephalopathic-type CJD pathology including widespread neuron loss with severe hypertrophic astrocytosis and status spongiosus in the cerebral gray matter, particularly in the neocortex. Cerebral white matter and the cerebellum also showed severe involvement. Immunohistochemical staining for PrP showed diffuse gray matter staining, indicating synaptic-type PrP deposition without plaque-type. Two different clinical phenotypes of M232R CJD were recognized despite the presence of the same PrP genotype, and the present case is speculated to correspond to the rapid-type.

Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse nuclear staining and nuclear inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.

Inclusion-positive cell types in adult-onset intranuclear inclusion body disease: implications for clinical diagnosis.

The distribution of inclusions in adult-onset type intranuclear inclusion body disease (INIBD) has not been fully described. We analyzed the clinical and pathological changes of three autopsy cases of adult type INIBD and provide a detailed description of the distribution of inclusions in nervous system and visceral organs. Although patients showed cognitive decline and autonomic dysfunction, there were no specific symptoms related to general organs. The neuropathological changes responsible for cognitive decline and autonomic dysfunction were considered to be white matter changes in the cerebral hemispheres and inclusions in the autonomic nervous system, e.g., in the sympathetic ganglia and myenteric plexus. Alterations of spongiosis with both myelin and axon loss in the cerebral white matter seemed to be related to dysfunction of astrocytes with intranuclear inclusions. In visceral organs, the inclusions were much more widely distributed than previously appreciated and included renal mesangial cells, adrenal sustentacular cells, fibrocytes, Kupffer cells, pancreatic centroacinar and ductal epithelial cells. Since skeletal muscle cells, Schwann cells and smooth muscle cells were also inclusion positive, we propose that biopsy of muscle, peripheral nerve or rectum may prove useful for the clinical diagnosis of INIBD.

Corpus callosal involvement is correlated with cognitive impairment in multiple system atrophy.

OBJECTIVE: We examined the anatomical involvement related to cognitive impairment in patients with multiple system atrophy (MSA). METHODS: We examined 30 patients with probable MSA and 15 healthy controls. All MSA patients were assessed by the Unified MSA-Rating scale and Addenbrooke's Cognitive Examination-Revised (ACE-R). We classified 15 MSA patients with ACE-R scores > 88 as having normal cognition (MSA-NC) and 15 with scores ≤ 88 as having cognitive impairment (MSA-CI). All subjects underwent 3 T MRI scanning and were investigated using voxel-based morphometry and diffusion tensor imaging. RESULTS: Both the MSA-NC and MSA-CI patients exhibited cerebellar but not cerebral atrophy in voxel-based morphometry compared to controls. In contrast, tract-based spatial statistics revealed widespread and significantly decreased fractional anisotropy (FA) values, as well as increased mean diffusivity, radial diffusivity, and axial diffusivity in both the cerebrum and cerebellum in MSA-CI patients compared to controls. MSA-NC patients also exhibited similar involvement of the cerebellum but less extensive involvement of the cerebrum compared with the MSA-CI patients. In particular, FA values in MSA-CI patients were significantly decreased in the anterior part of the left corpus callosum compared with those in MSA-NC patients. The mean FA values in the left anterior part of the corpus callosum were significantly correlated with total ACE-R scores and subscores (memory, fluency, and language) in MSA patients. CONCLUSIONS: Decreased FA values in the anterior corpus callosum showed a significant correlation with cognitive impairment in MSA.

[Successful outcome of VP shunt operation in 3 cases of idiopathic normal pressure hydrocephalus with long duration of illness].

Three cases (70- and 83-year-old females and 77-year-old male) with cognitive impairment, gait disturbance and urinary incontinence for 8 to 15 years were diagnosed as idiopathic normal pressure hydrocephalus (iNPH) according to the iNPH guideline in Japan (2004). All were operated by ventriculo-peritoneal shunt and had a good outcome despite their long duration of illness. Two of the three cases had been earlier diagnosed as progressive supranuclear palsy (PSP). because they had vertical gaze palsy. Some iNPH patients with vertical gaze palsy clinically might be misdiagnosed as PSP.

Effects of turmeric on Alzheimer's disease with behavioral and psychological symptoms of dementia.

We describe here three patients with the Alzheimer's Disease (AD) whose behavioral symptoms were improved remarkably as a result of the turmeric treatment, which is the traditional Indian medicine. Their cognitive decline and Behavioral and Psychological Symptoms of Dementia (BPSD) were very severe. All three patients exhibited irritability, agitation, anxiety, and apathy, two patients suffer from urinary incontinence and wonderings. They were prescribed turmeric powder capsules and started recovering from these symptoms without any adverse reaction in the clinical symptom and laboratory data. After 12 weeks of the treatment, total score of the Neuro-Psychiatric Inventory-brief questionnaire decreased significantly in both acuity of symptoms and burden of caregivers. In one case, the Mini-Mental State Examination (MMSE) score was up five points, from 12/30 to 17/30. In the other two cases, no significant change was seen in the MMSE; however, they came to recognize their family within 1 year treatment. All cases have been taking turmeric for more than 1 year, re-exacerbation of BPSD was not seen. The present cases suggest a significant improvement of the behavioral symptoms in the AD with the turmeric treatment, leading to probable benefit of the use of turmeric in individuals with the AD with BPSD.

Differential age-dependent trophic responses of nodose, sensory, and sympathetic neurons to neurotrophins and GDNF: potencies for neurite extension in explant culture.

The age-dependent trophic responses of sympathetic, sensory, and nodose neurons to the neurotrophins NGF, BDNF, and NT-3 and to glial cell line-derived neurotrophic factor (GDNF) were examined by an explant culture system. Superior cervical ganglia (SCG), dorsal root ganglia (DRG), and nodose ganglia (NG) were removed from rat embryos (E18), neonatals (< or = 1 day old), young adults (3-6 months old), and aged adults (> 24 months old). The ganglia were cultured with and without each neurotrophic factor; the neurite extension and neurite density were then assessed. The SCG from rats of all ages were significantly influenced by NGF, NT-3, and GDNF; the effects of NT-3 and GDNF were reduced after maturation. The DRG from embryos and neonates were influenced by all neurotrophic factors; however, the effects of BDNF and NT-3 disappeared after maturation. The GDNF showed little effect on adult DRG and no effect on aged DRG. The effect of NGF was preserved over all ages of DRG. The NG from embryonic rats were significantly responsive to BDNF and GDNF; their effects decreased in the neonatal NG, but a minimum effect remained in the aged NG. These results indicate that age-dependent profiles of trophic effects differ extensively among the lineages of the peripheral nervous system and also among the individual neurotrophic factors.

Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer's disease.

The cellular distribution of malondialdehyde (MDA) was assessed immunohistochemically in brain specimens from young and normal elderly subjects as well as patients with Alzheimer's disease (AD). MDA was increased in the cytoplasm of neurons and astrocytes in both normal aging and AD, but was rarely detected in normal young subjects. By electron microscopic immunohistochemistry, neuronal MDA formed cap-like linear deposits associated with lipofuscin, while glial MDA deposits surrounded the vacuoles in a linear distribution. In the hippocampus, neuronal and glial MDA deposition was marked in the CA4 region but mild in CA1. By examination of serial sections stained with anti-MDA and antibodies against an advanced glycation end product, N(epsilon)-(carboxymethyl)lysine (CML), neuronal and glial MDA deposition was colocalized with CML in AD, but only neuronal MDA was colocalized with CML in normal aged brains. Glial MDA, although abundant in the aged brain, typically was not colocalized with CML. In AD cases, MDA was colocalized with tau protein in CA2 hippocampal neurons; such colocalization was rare in CA1. MDA also was stained in cores of senile plaques. Thus, while both MDA and CML accumulate under oxidative stress, CML accumulation is largely limited to neurons, in normal aging, while MDA also accumulates in glia. In AD, both MDA and CML are deposited in both astrocytes and neurons.