Tatsuhiro Terada

CLINICOPATHOLOGIC STUDY OF A SNCA GENE DUPLICATION PATIENT WITH PARKINSON DISEASE AND DEMENTIA

There is evidence that α-synuclein gene ( SNCA ) point mutations and gene multiplications play a pivotal role in the development of Lewy bodies (LBs) and Lewy neuritic (LN) pathology. Dysregulation of the production/degradation of the α-synuclein protein, a major component of LBs and LNs, is speculated to result in its accumulation and produce the neuropathological features of SNCA -related neurodegeneration.1 The identification of SNCA multiplications in families with parkinsonism suggests that SNCA gene dosage may play a role in the onset of Parkinson disease (PD).2 Most patients with SNCA triplication develop cognitive and autonomic dysfunction in early stage of the disease.3,4 However, three families with SNCA duplication have been reported with symptoms more reminiscent of typical PD.5,6 Interestingly, a recent study reported that one triplication (a Swedish-American pedigree) and one duplication pedigree have a common ancestor.7 As a common mechanism of multiplications, the area including the SNCA-MMRN1 locus could play a role in multiple copy numbers. Another multiplication family has been reported also to have the rearrangement change in the same region indicating the SNCA-MMRN1 locus may be fragile.2,5–7 With regard to clinical aspects, patients with SNCA duplication tend to have milder symptoms compared to those with triplication.5–7 The onset of disease in SNCA duplication patients occurs approximately 15 years later (50 years of age) than that of SNCA triplication families (35 years of age). These features suggest that differences in genetic copy numbers could influence the clinical features of PD. Recently, we identified two families of Japanese origin with SNCA duplications.8 One patient from Family B (named as B-1) developed severe parkinsonism and dementia. These findings indicate that SNCA duplication also causes PD with dementia (PDD). Three copies of the locus SNCA-MMRN1 were identified in the two duplication families. The length of …

Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin.

Ceruloplasmin plays an essential role in cellular iron efflux by oxidizing ferrous iron exported from ferroportin. Ferroportin is posttranslationally regulated through internalization triggered by hepcidin binding. Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis resulting from mutations in the ceruloplasmin gene. The present study investigated the biological effects of glycosylphosphatidylinositol (GPI)-linked ceruloplasmin on the hepcidin-mediated internalization of ferroportin. The prevention of hepcidin-mediated ferroportin internalization was observed in the glioma cells lines expressing endogenous ceruloplasmin as well as in the cells transfected with GPI-linked ceruloplasmin under low levels of hepcidin. A decrease in the extracellular ferrous iron by an iron chelator and incubation with purified ceruloplasmin in the culture medium prevented hepcidin-mediated ferroportin internalization, while the reconstitution of apo-ceruloplasmin was not able to prevent ferroportin internalization. The effect of ceruloplasmin on the ferroportin stability was impaired due to three distinct properties of the mutant ceruloplasmin: namely, a decreased ferroxidase activity, the mislocalization in the endoplasmic reticulum, and the failure of copper incorporation into apo-ceruloplasmin. Patients with aceruloplasminemia exhibited low serum hepcidin levels and a decreased ferroportin protein expression in the liver. The in vivo findings supported the notion that under low levels of hepcidin, mutant ceruloplasmin cannot stabilize ferroportin because of a loss-of-function in the ferroxidase activity, which has been reported to play an important role in the stability of ferroportin. The properties of mutant ceruloplasmin regarding the regulation of ferroportin may therefore provide a therapeutic strategy for aceruloplasminemia patients.

α-SYNUCLEIN ACCUMULATION IN SKIN NERVE FIBERS REVEALED BY SKIN BIOPSY IN PURE AUTONOMIC FAILURE

Pure autonomic failure (PAF), a rare clinical manifestation of Lewy body (LB) disorders, is characterized by fibrillary aggregates of α-synuclein in the cytoplasm of a select population of neurons and glia. It is a sporadic, idiopathic, neurodegenerative disorder with orthostatic hypotension as the cardinal symptom. Patients may also present with decreased sweating, urinary dysfunction, constipation, and sexual dysfunction. Postmortem studies1-3 have disclosed prominent LB pathology in sympathetic and parasympathetic nervous systems, as well as the substantia nigra and locus ceruleus. Here, we show for the first time α-synuclein accumulation in nerve fibers in the dermis of a patient with PAF. The patient is a 73-year-old man with a 13-year history of severe orthostatic hypotension with recurrent syncope, urinary dysfunction (hesitancy and prolongation), erectile failure, and decreased sweating with heat intolerance. Supine blood pressure was 163/84 mm Hg. After 1 minute of a 60° head-up tilt test, the patients blood pressure fell to 62/33 mm Hg and he fainted. The patients pulse was 60 beats/minute before tilting and 65 beats/minute after 1 minute of tilting, and his plasma noradrenaline was 40 and 36 pg/mL before and after tilting, respectively (normal: >100 pg/mL). The coefficient of variation of R-R intervals was 0.81% (normal: >1.5%). Denervation supersensitivity to noradrenaline was detected with infusion testing. A thermoregulatory sweat test revealed a patchy lack of sweating in the legs. The heart-to-mediastinum (H/M) ratio of 131I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy was reduced (early: 1.30, late: 1.25, normal: >1.85). After …

Functional brain imaging in glucocerebrosidase mutation carriers with and without Parkinsonism

Mutations in the glucocerebrosidase gene (GBA) increase the risk for Parkinsons disease and are also associated with an earlier onset of the disease and an akinetic parkinsonian phenotype. To investigate the underlying pathogenesis of this condition, we assessed cerebral metabolism using positron emission tomography (PET) in GBA mutation carriers with and without parkinsonism. [18F]‐fluorodeoxyglucose (FDG)‐PET using a three‐dimensional stereotactic surface projection analysis was used to measure the cerebral metabolic rates of glucose (CMRGlc) in a patient with parkinsonism and Gaucher disease (GD) and five subjects with a heterozygous GBA mutation, including three patients with parkinsonism and three asymptomatic carriers in comparison to 10 healthy controls in the same age range. Dopaminergic neuronal activity was investigated using [11C] CFT‐ and [11C] raclopride‐PET. All GBA mutation carriers displayed a significant CMRGlc decrease in the supplemental motor area (SMA). The carriers with parkinsonism showed additional hypometabolism in the parietooccipital cortices. The CFT and raclopride PET images in the asymptomatic carriers demonstrated the CFT binding to be within normal values in the putamen and a significant increase was observed in the caudate nucleus while raclopride binding in the striatum was in the normal range. An advanced parkinsonian carrier showed decreased CFT binding and increased raclopride binding in the striatum. The decreased CMRGlc in the SMA was characteristic of the GBA mutation carriers. The hypometabolism in the SMA may, therefore, be involved in the clinical characteristics of parkinsonism associated with GBA mutations when the carriers manifest parkinsonism.

Alterations in α4β2 nicotinic receptors in cognitive decline in Alzheimer’s aetiopathology

Nicotinic acetylcholine receptor subtype α4β2 is considered important in the regulation of attention and memory, and cholinergic degeneration is known as one pathophysiology of Alzheimers disease. Brain amyloid-β protein deposition is also a key pathological marker of Alzheimers disease. Recent amyloid-β imaging has shown many cognitively normal subjects with amyloid-β deposits, indicating a missing link between amyloid-β deposition and cognitive decline. To date, the relationship between the α4β2 nicotinic acetylcholine receptor and amyloid-β burden has not been elucidated in vivo. In this study we investigated the relation between α4β2 nicotinic acetylcholine receptor availability in the brain, cognitive functions and amyloid-β burden in 20 non-smoking patients with Alzheimers disease at an early stage and 25 age-matched non-smoking healthy elderly adults by measuring levels of α4β2 nicotinic acetylcholine receptor binding estimated from a simplified ratio method (BPRI) and Logan plot-based amyloid-β accumulation (BPND) using positron emission tomography with α4β2 nicotinic acetylcholine receptor tracer (18)F-2FA-85380 and (11)C-Pittsburgh compound B. The levels of tracer binding were compared with clinical measures for various brain functions (general cognition, episodic and spatial memory, execution, judgement, emotion) using regions of interest and statistical parametric mapping analyses. Between-group statistical parametric mapping analysis showed a significant reduction in (18)F-2FA-85380 BPRI in the cholinergic projection region in patients with Alzheimers disease with a variety of (11)C-Pittsburgh compound B accumulation. Spearman rank correlation analyses showed positive correlations of (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region with scores of the Frontal Assessment Battery (a test battery for executive functions and judgement) in the Alzheimers disease group (P < 0.05 corrected for multiple comparison), and also positive correlations of the prefrontal and superior parietal (18)F-2FA-85380 BPRI values with the Frontal Assessment Battery score in the normal group (P < 0.05 corrected for multiple comparison). These positive correlations indicated an in vivo α4β2 nicotinic acetylcholine receptor role in those specific functions that may be different from memory. Both region of interest-based and voxelwise regression analyses showed a negative correlation between frontal (11)C-Pittsburgh compound B BPND and (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region in patients with Alzheimers disease (P < 0.05 corrected for multiple comparison). These findings suggest that an impairment of the cholinergic α4β2 nicotinic acetylcholine receptor system with the greater amount of amyloid deposition in the system plays an important role in the pathophysiology of Alzheimers disease.

Frontal lobe-mediated behavioral changes in amyotrophic lateral sclerosis: are they independent of physical disabilities?

OBJECTIVE Several studies have indicated that frontal cognitive impairment is present in patients with amyotrophic lateral sclerosis (ALS). However, it remains to be elucidated whether the behavioral change is a direct consequence of ALS pathology or the measurements are confounded by the physical impairments. We examined frontal lobe-mediated behavioral dysfunction in daily living in patients with ALS by using the family- and self-rating forms of the Frontal Systems Behavior Scale (FrSBe) and assessed the relationship between the scores and motor impairments or ventilatory status. METHODS We examined 24 patients with sporadic ALS, who were aged 65.7 ± 10.5 years with mean disease duration of 2.3 ± 1.7 years, Mini-Mental State Examination score of ≥ 24, normal Self-rating Depression Scale, no need of assistance in daily life, normal respiratory function, and normal arterial blood gas analytes. We examined the relationship between FrSBe scores and ALS Functional Rating Scale (ALSFRS), respiratory function, and arterial blood gas analytes. RESULTS The scores of family- and self-rating FrSBe were significantly higher after onset of ALS than before onset, most notably in apathy. The family-rating FrSBe scores after onset were not correlated with ALSFRS, respiratory function, or arterial blood gas analytes. CONCLUSION The frontal-lobe-related behavioral dysfunction is present after the onset of ALS, but is independent of physical impairments.

Depiction of microglial activation in aging and dementia: Positron emission tomography with [11C]DPA713 versus [11C](R)PK11195

The presence of activated microglia in the brains of healthy elderly people is a matter of debate. We aimed to clarify the degree of microglial activation in aging and dementia as revealed by different tracers by comparing the binding potential (BPND) in various brain regions using a first-generation translocator protein (TSPO) tracer [11C](R)PK11195 and a second-generation tracer [11C]DPA713. The BPND levels, estimated using simplified reference tissue models, were compared among healthy young and elderly individuals and patients with Alzheimer’s disease (AD) and were correlated with clinical scores. An analysis of variance showed category-dependent elevation in levels of [11C]DPA713 BPND in all brain regions and showed a significant increase in the AD group, whereas no significant changes among groups were found when [11C](R)PK11195 BPND was used. Cognito-mnemonic scores were significantly correlated with [11C]DPA713 BPND levels in many brain regions, whereas [11C](R)PK11195 BPND failed to correlate with the scores. As mentioned elsewhere, the present results confirmed that the second-generation TSPO tracer [11C]DPA713 has a greater sensitivity to TSPO in both aging and neuronal degeneration than [11C](R)PK11195. Positron emission tomography with [11C]DPA713 is suitable for the delineation of in vivo microglial activation occurring globally over the cerebral cortex irrespective of aging and degeneration.

Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate.

Terada T, Tsuboi Y, Obi T, Doh‐ura K, Murayama S, Kitamoto T, Yamada T, Mizoguchi K. Less protease‐resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate.
Acta Neurol Scand: 2010: 121: 127–130.
© 2009 The Authors Journal compilation

Case of presymptomatic aceruloplasminemia treated with deferasirox.

Aceruloplasminemia is an autosomal recessive disease characterized by an abnormal iron metabolism. The absence of ferroxidase activity caused by mutation of ceruloplasmin leads to iron overload in the brain, liver and other organs. We report a 35‐year‐old man who was diagnosed with aceruloplasminemia without neurological manifestation despite the accumulation of iron in the brain and liver. To prevent the development of neurodegenerative disorder related to iron toxicity, iron depletion therapy was performed. Iron chelator deferasirox was effective in reducing serum ferritin level and to prevent the progression of the disease.

High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous disorder, characterized by the accumulation of iron in regions such as the basal ganglia. We enrolled 28 patients with childhood intellectual disability and young-onset parkinsonism (≤40 years at onset) and 4 patients with infantile neuroaxonal dystrophy. All had been clinically diagnosed, and the prevalence of genetic mutations linked to NBIA (PANK2 [exons 1-7], PLA2G6 [exons 2-17], C19orf12 [exons 1-3], WDR45 [exons 2-11], COASY [exons 1-9], FA2H [exons 1-7], and RAB39B [exons 1, 2]) was evaluated. We detected 7 female patients (25.0%, 7 of 28) with de novo heterozygote WDR45 mutations, which are known to be pathogenic for beta-propeller protein-associated neurodegeneration. All 7 patients had common clinical features. Pathogenic mutations in other NBIA genes were not found. We also screened 98 patients with early-onset parkinsonism without intellectual disability and 110 normal controls of Japanese origin for WDR45 mutations. None had WDR45 mutations. Our data suggest a high frequency of beta-propeller protein-associated neurodegeneration mutations in the Japanese population.