Comparison of clinical imaging and pathological findings of various brain lesions including cerebrovascular diseases and other systemic diseases.

Looking back at the cases of brain cutting conducted in Sumitomo Hospital over the past 32 years, cases where clinical brain imaging could be compared with pathological findings other than degenerative diseases are examined and carefully selected, and instructive examples of them are presented. Although there are some limitations, the comparison between clinical brain imaging and pathological finding is significant to the final diagnosis and understanding of the pathogenesis of brain lesions.

Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan.

BACKGROUND: We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. METHODS: DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. RESULTS: We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. CONCLUSIONS: Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.

Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis: a clinical-pathological case report.

BACKGROUND: The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. CASE PRESENTATION: A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. CONCLUSIONS: Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.

[A case of Parkinson's disease following restless genial sensation].

A 62-year-old woman experienced uncomfortable genial sensation in 2010. Her uncomfortable sensation was exacerbated during rest at night and improved by walking. She exhibited short-stepped gait with postural disturbance and was diagnosed as suffering from Parkinson's disease (PD) in 2013. Administration of clonazepam and pramipexisole improved her uncomfortable genial sensation. In persistent genital arousal disorder (PGAD)/restless genial syndrome (RGS), abnormal genital sensation occurred without sexual desire, which was relieved by clonazepam administration. PGAD/RGS often coexists with restless legs syndrome (RLS). PGAD/RGS and RLS share common characteristics. This is the first case report of PD following PGAD/RGS, suggesting similar underlying mechanisms between PGAD/RGS and RLS associated with PD.

[The medial temporal area and parietal lobe are involved in epileptic polyopia and palinopsia: A case report].

This report presents the case of an 83-year-old female with a tumor in the right temporal lobe. She experienced various epileptic visual auras including visual perseveration. Visual perseveration is classified into polyopia and palinopsia. Epileptic visual perseveration is a rare phenomenon, and the mechanism has not been fully explained. MRI revealed a tumor in the right temporal lobe with edema in the occipital white matter. To reveal mechanisms of epileptic polyopia and palinopsia, we recorded EEG and (123)I-IMP-SPECT when she experienced epileptic attacks. EEG showed epileptic discharges beginning at the occipital area, which spread to the temporal and parietal areas. During the EEG recording, the main symptom was an unformed hallucination. SPECT showed that blood flow increased in the right medial temporal and parietal lobes and, to a slightly lesser extent, in the right occipito-temporal area when the polyopia and palinopsia frequently appeared. Involvement of the multiple foci may have caused the different kinds of visual symptoms. The medial temporal and parietal areas were likely responsible for polyopia and palinopsia at least for this patient.

[A case of optic neuritis associated with lymphocytic hypophysitis revealed by pattern-reversal VEP].

Lymphocytic hypophysitis (LYH) is a rare neuroendocrine disorder characterized by autoimmune inflammation of the pituitary gland. Visual disturbance is one of the most common and serious symptoms of LYH. Most of the visual symptoms in LYH are secondary to compression of the optic chiasm and some reports have described direct inflammatory involvement of the optic pathways. We describe a 30-year-old man with a 9-day history of bilateral blurred vision. Ophthalmic examination demonstrated severely impaired vision without temporal hemianopsia. Hypothyroidism, hypocortisolism, and hypogonadism were detected in laboratory tests. Central diabetes insipidus was diagnosed by a hypertonic saline infusion test. MRI revealed thickening of the pituitary stalk and enlargement of the hypophysis, which was enhanced with gadolinium. High intensity of the posterior lobe was not recognized on T1-weighted images. These findings established a clinical diagnosis of lymphocytic panhypophysitis. Methylprednisolone pulse therapy was introduced and his visual acuity gradually recovered. The anterior pituitary function improved, but desmopressin was still required. Pattern-reversal visual evoked potentials (VEP) have been widely used to detect optic nerve lesions caused by multiple sclerosis and brain tumors. However, there have been no previous reports of their usefulness for LYH. The P100 latency in our case was slightly prolonged and the amplitude was markedly reduced. These findings are similar to ischemic optic neuropathy and other conditions in which axonal damage is prominent. The prolonged latency and low amplitude on VEP examination in this case showed rapid improvement in parallel with the recovery of visual acuity. Taken together, our case implies the usefulness of pattern-reversal VEP for the diagnosis of optic neuritis in LYH, especially for the evaluation of its pathogenic mechanisms.

Protein kinase C gamma, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin.

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disease caused by mutations in the gene encoding protein kinase C gamma (PKC gamma). We report an SCA14 family with a novel deletion of a termination-codon-containing region, resulting in a missense change and a C-terminal 13-amino-acid extension with increased kinase activity. Notably, one patient with a severe phenotype is the first homozygote for the mutation causing SCA14. We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (APTX), a DNA repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant PKC gamma, and phosphorylation inhibited its nuclear entry. The phosphorylated residue was Thr111, located adjacent to the nuclear localization signal, and disturbed interactions with importin alpha, a nuclear import adaptor. Decreased nuclear APTX increased oxidative stress-induced DNA damage and cell death. Phosphorylation-resistant APTX, kinase inhibitors, and antioxidants may be therapeutic options for SCA14.

Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease.

OBJECTIVES: Sleep attacks (SAs) in Parkinson's disease (PD) are rare, but clinically important because they significantly impair the daily lives of patients. Causes of SAs include long-term activation of dopaminergic (especially D3) receptors. Recent studies suggest that SAs in PD may be related to impairment of hypothalamic orexin neurons, similar to narcolepsy. Whether orexin is associated with long-term activation of dopaminergic receptors remains uncertain. PATIENTS AND METHODS: We measured levels of orexin in samples of spinal cerebrospinal fluid (CSF) from 25 patients with PD, including 9 with excessive daytime sleepiness and 4 with SAs. Furthermore, in the four patients with SAs, the selective dopamine D1/D2 agonist pergolide was substituted for the causative drugs with D3 stimulatory activity, and CSF-orexin levels were measured before and after switching treatment. RESULTS: In the 25 patients with PD, including the 4 patients with SAs, lower CSF-orexin levels were associated with a longer disease duration, which has been linked to a higher incidence of SAs. Switching treatment to pergolide significantly increased CSF-orexin levels and completely resolved SAs in the four patients with PD. CONCLUSION: Despite the small number of patients studied, our results suggest that orexin transmission is most likely involved in SAs in PD and that abrogation of D3 receptor stimulation may increase orexin and thereby inhibit SAs.

[Magnetic resonance imaging in multiple sclerosis].

Brain and spinal magnetic resonance imaging (MRI) play an important role in the diagnosis of multiple sclerosis (MS). McDonald criteria allow MRI evidence for dissemination in space and dissemination in time to be used to diagnose MS in patients who present with clinically isolated syndromes. Long spinal cord lesion on spinal MRI is a diagnostic finding of opticospinal MS with autoantibodies to the aquaporin-4 water channel. Magnetic resonance spectroscopy, diffusion tensor imaging and magnetization transfer ratio map may reveal chemical pathology and tract change in normal appearing white matter of MS.

Odor abnormalities caused by bilateral thalamic infarction.

Odor is the only sensation thought to be unrelated to the thalamus. However, accumulating evidence suggests that the dorsomedial nucleus (DM) of the thalamus is associated with odor. Although the thalamus is prone to ischemia, only a single patient with bilateral DM infarctions was reported to have odor abnormalities. We describe a second such patient with infarctions involving the left DM and the right ventral posterior nucleus and ventral lateral nucleus, nuclei adjacent to the DM, associated with transient edema. In contrast to the previous case, our patient had transient odor abnormality. These observations suggested that direct and/or indirect bilateral involvement of the DM might be associated with odor abnormalities in patients with thalamic infarction.

Thalamic hyperperfusion in verbal hallucination of Parkinsonian patients.

OBJECTIVE: We compared brain perfusion image using 3D-SSP analysis of (123)I-IMP SPECT between Parkinson's disease patients with auditory verbal hallucination and those without auditory hallucination. METHODS: Eighty-three cases with Parkinson's disease were studied. In 6 of these patients, auditory hallucination was noted. Among them, four cases had verbal hallucination and two other cases had elementary hallucination. Auditory hallucination was not found in the other 77 cases. RESULTS: Right thalamic perfusion was significantly increased in the verbal hallucination group compared to the group that lacked auditory hallucination. CONCLUSION: In Parkinson's disease, the right thalamic hyperactive state may be related to verbal hallucination.

Depression in Parkinson's disease. Diffusion tensor imaging study.

OBJECTIVES: The pathophysiology of depression and anxiety in Parkinson's disease remains obscure. We aimed to compare the fractional anisotropy (FA) values of Parkinson's disease (PD) patients with and without depression to investigate the nature of depression in PD. METHODS: Twenty-eight patients were divided into two groups: those with depression and those without. Diagnosis of depression was made using the DSM-IV criteria. Patients in the two groups were matched for Hoehn Yahr stage. RESULTS: There were significant reductions in FA values in the bilateral frontal ROIs possibly representing anterior cingulate bundles. CONCLUSIONS: The anterior cingulate bundles play an important role in depression in PD, and some aspects of depression in PD have pathological processes in common with de novo depression.

Trousseau syndrome due to pleural mesothelioma.

BACKGROUND: Thrombosis involving a brain infarction frequently occurs in patients with a malignant tumor. Although nearly all types of tumor have been reported in association with a hypercoagulable state, pleural mesothelioma-associated Trousseau syndrome is extremely rare. SUMMARY: A 69-year-old female was admitted to our hospital with cough, sputum, and breathing difficulties. She was diagnosed as having a mesothelioma from a percutaneous pleural biopsy. Although there were no risk factors for atherosclerosis, brain infarctions showed frequent relapses, even under anticoagulant therapy, and there was a marked hypercoagulable state. CONCLUSION: Attention should be paid to this syndrome when unexplained brain infarctions occur in patients with pleural mesothelioma.

Auditory event-related potentials in Parkinson's disease: prominent correlation with attention.

OBJECTIVE: Auditory P300 has been reported to be abnormal in demented patients with Parkinson's disease. However, it is still controversial which factors in Parkinson's disease influence P300 parameters. METHODS: Forty patients with Parkinson's disease were included. Patients were divided into two groups: patients with dementia (PDD) and without dementia (PDND). An 'odd-ball' paradigm was used for auditory event-related potentials. RESULTS: P300 latency was markedly delayed in PDD patients. Age and DRS1 (attention) were the most important factors influencing P300 latency. CONCLUSIONS: Although there have been reports of P300 in the past, its abnormalities reflect the deficit of attention in Parkinson's disease.

Sympathetic disturbances increase risk of sudden cardiac arrest in sporadic ALS.

BACKGROUND: ALS exclusively involves motor neurons, however, accumulating evidence suggests involvement of sympathetic neurons, as in other diseases including Parkinson's disease and multiple system atrophy. In these diseases increased risk of sudden cardiac arrest is established, while that in ALS remains uncertain. METHODS: The authors retrospectively studied 12 pathologically confirmed sporadic ALS patients who received no assisted ventilation. Among them, two patients died of sudden cardiac arrest. Changes in QTc interval and dispersion, indices of sympathetic activities obtainable by routine electrocardiograms, were evaluated at the early stage and the terminal stage. Pathologically, intermediolateral nucleus (IML) sympathetic neurons in the upper thoracic cord were examined. RESULTS: The QTc intervals and dispersion were significantly increased at the terminal stage compared with that at the early stage (p<0.01). The numbers of IML neurons were significantly lower in ALS patients than in controls (p=0.017), and had linear inverse correlation with the rate of increases in maximum QTc interval and QTc dispersion (p=0.01, r=-0.915 and p=0.02, r=-0.884). Notably, two patients with sudden cardiac arrest showed longer QTc interval, larger QTc dispersion, and lower number of IML neurons than most of others. CONCLUSIONS: Patients with ALS had reduced sympathetic activities at the terminal stage of disease, presumably due to neuronal loss in IML, which may increase risk of sudden cardiac arrest. Thus, prolonged QTc intervals and increased QTc dispersion may suggest an increased risk of sudden death in ALS, as in other neurodegenerative diseases.

Heterogeneous factors in dementia with Parkinson's disease: IMP-SPECT study.

BACKGROUND: Nature of the dementing process in Parkinson's disease, and particularly its relationship with Alzheimer's disease, diffuse Lewy body disease or frontal dementia remains controversial. OBJECTIVE: We hypothesize that origins of dementia in Parkinson's disease are heterogeneous, so we compared cortical regional cerebral blood flow (rCBF) between Parkinson's disease patients with and without dementia. PATIENTS: Forty consecutive patients with Hoehn-Yahr stage III or IV Parkinson's disease were used (13 patients had dementia (PDD group), and 27 patients had no dementia (PDND group)). RESULTS: There were significant rCBF reductions in the left parietal association cortex and left frontal association cortex in PDD. Multiple logistic regression analysis demonstrated that only rCBF of the left frontal association cortex was significant. PDD patients were divided into three groups according to rCBF patterns: frontal hypoperfusion group, Alzheimer's disease-like group, and diffuse Lewy body disease-like group. CONCLUSIONS: Controversial study results involving PDD patients may be mainly due to heterogeneity in dementing processes in Parkinson's disease.