Masanobu Sakamoto

Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration.

A 52-year-old woman had a newly recognized disorder of familial hypoceruloplasminemia, blepharospasm, retinal degeneration, and high-density areas in CT of the basal ganglia and liver scan. Immunofixation electrophoresis disclosed apoceruloplasmin deficiency. Kinetic, x-ray analysis, and histochemical study showed accumulation of iron in liver and brain, but not of copper. Intestinal copper absorption was reduced, but liver uptake was increased. Ceruloplasmin is involved in iron metabolism, and the findings suggest that hypoceruloplasminemia due to lack of apoceruloplasmin was causally linked to the iron deposition in basal ganglia and other organs, leading to blepharospasm and retinal degeneration.

Alterations in binding site density of dopamine transporter in the striatum, orbitofrontal cortex, and amygdala in early Parkinson's disease : Compartment analysis for β-CFT binding with positron emission tomography

We investigated changes in the kinetics in the binding of the dopamine transporter probe 2‐β‐carbomethoxy‐3β‐(4‐[11C]fluorophenyl)tropane (β‐CFT) in living brain by compartmental analysis, using positron emission tomography in unmedicated patients with Parkinsons disease (PD) (Hoehn and Yahr stages I–II). With dynamic positron emission tomographic data from 90‐minute acquisitions and metabolite‐corrected arterial input functions, binding potentials (k3/k4) were calculated by using estimated rate constants (K1 − k4). In this analysis, the magnitude of the distribution volume (K1/k2) measured in the cerebellum, in which specific binding is negligible, was used as a constrained value for fitting in binding regions. Statistics showed that k3/k4 values in the striatum, the orbitofrontal cortex, and the amygdala were significantly lower in PD patients than in normal controls, whereas there were no differences in K1/k2 ratios and structural volumes between the groups. Correlation analysis showed that the putaminal and orbitofrontal binding levels were correlated positively with motor and mentation scores, respectively, of the Unified Parkinsons Disease Rating Scale. These results indicated that not only the striatal but also the orbitofrontal and amygdalar presynaptic dopaminergic functions were altered in early PD. The reductions in these mesocortical/mesolimbic functions might contribute to the mental and behavioral impairment observed in PD. Ann Neurol 1999;45:601–610

Neuroinflammation in the living brain of Parkinson's disease.

Evidence shows that neuronal injury accompanies neuroinflammatory reactions in the brain, and well as in Parkinsons disease (PD) animal models, in which the loss of dopamine neurons is associated with the activation of microglia in the substantia nigra. Activated microglia can be illustrated in vivo using Positron emission tomography and [(11)C](R)-PK11195. However, this tracer cannot distinguish between the two aspects of microglial function (protective and inflammatory). To solve this problem, we can use a dopamine transporter marker, [(11)C]CFT, which binds to the dopamine transporter. The binding of the tracer reflects the viability of the presynaptic dopaminergic neurons, as reported in a multicenter trial using single photon emission tomography (SPECT) with [(123I)]beta-CIT, a SPECT version of [(11)C]CFT. In early drug-naïve PD patients, these two tracers showed a unique pattern of binding, [(11)C](R)-PK11195 binding potential in the midbrain was correlated inversely with [(11)C]CFT binding in the putamen, and midbrain [(11)C](R)-PK11195 binding was found to be positively correlated with the motor severity of parkinsonism. These results indicate that early introduction of a neuroprotective drug to suppress microglial activation is favorable in PD and that [(11)C](R)-PK11195 can be used to monitor the progression of the disease. As the disease progressed, the [(11)C]CFT binding was further decreased, and the microglial activation spread over the entire brain. This paper briefly summarizes the neuroinflammation induced by microglia in PD and describes an in vivo aspect of the neuroinflammation in the PD brain by focusing on the covarying changes in microglial activation and neuronal damage.

Cerebellar ataxia associated with heteroallelic ceruloplasmin gene mutation

Background: Aceruloplasminemia, an autosomal recessive disorder that affects human iron metabolism, is caused by mutation of the ceruloplasmin gene. Heterozygous individuals with a partial ceruloplasmin deficiency may have normal iron metabolism and no clinical symptoms. Methods: The authors clinically characterized three Japanese patients from two families who had cerebellar ataxia with hypoceruloplasminemia from the fourth decade of life. Genetic analysis, restriction fragment length polymorphism analysis, and a pathologic study were performed. Results: All three patients presented with cerebellar dysfunction that included relatively nondisabling gait ataxia and dysarthria, as well as hyperreflexia. Brain and abdomen MRI showed cerebellar atrophy and no low-signal intensities in the basal ganglia, thalamus, and liver. Direct mutational analysis excluded SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, SCA-8, SCA-12, and DRPLA. The patients partially lacked serum ceruloplasmin, and the protein concentrations and ferroxidase activities ranged from 36% to 41% of the control values; moreover, they were heterozygous for a nonsense mutation of the ceruloplasmin gene (Trp858ter). Serum iron concentration and transferrin saturation were normal. At autopsy, pathologic and biochemical examinations showed marked loss of Purkinje cells, a large iron deposition in the cerebellum, and small depositions in the basal ganglia, thalamus, and liver. Conclusion: Cerebellar ataxia reflects the site of iron deposition. Being heterozygous for mutation of the ceruloplasmin gene may result in cerebellar ataxia.

Presynaptic and postsynaptic dopaminergic binding densities in the nigrostriatal and mesocortical systems in early Parkinson's disease: a double-tracer positron emission tomography study.

To investigate changes in the relation between presynaptic and postsynaptic dopaminergic functions in vivo in both nigrostriatal and mesocortical systems in Parkinsons disease (PD), 10 drug‐naive early PD patients were studied twice using positron emission tomography with [11C]CFT (dopamine transporter probe) followed by [11C]SCH 23390 (D1 receptor probe). Regional binding potentials (k3/k4) of [11C]CFT and [11C]SCH 23390 in the striatum (nigrostriatal system) and the orbitofrontal cortex (mesocortical system) were estimated by compartment analyses. Levels of [11C]CFT k3/k4 in the two projection areas were shown to be significantly lower in PD, whereas [11C]SCH 23390 levels remained unchanged. Regression analysis showed that estimates of CFT k3/k4 were positively correlated with those of SCH 23390 k3/k4 in the striatum in normal control, whereas the two binding estimates were less positively correlated in the caudate and inversely correlated in the putamen in PD. No significant correlation was observed in the orbitofrontal cortex in both groups. These results indicated that dopamine transporters and D1 receptors change in parallel in the normal striatal synapses, but the association becomes asymmetrical because of reduction in presynaptic and relative elevation in postsynaptic markers in PD. Alterations in synaptic parallel regulation in the nigrostriatal system might reflect early pathophysiology in the parkinsonian brain.

Effect of Simple Motor Performance on Regional Dopamine Release in the Striatum in Parkinson Disease Patients and Healthy Subjects: A Positron Emission Tomography Study

To investigate changes in dopamine release in the striatum during motor exercise in human subjects with and without striatal dopamine denervation, eight healthy subjects and eight patients with Parkinson disease (PD) were measured during unilateral foot extension/flexion movement using positron emission tomography with [11C]raclopride. Five subjects in each group were later scanned in the resting condition. Estimation of binding potential (k3/k4) of [11C]raclopride was based on Logan plot method. Significant reductions in [11C]raclopride k3/k4 were found in the dorsal putamen contralateral to the exercise side in the healthy group and ipsilaterally in the PD group. Spearman rank correlation analysis showed that [11C]raclopride k3/k4 correlated inversely with the decrease in performance (velocity and motion range) in the dorsal putamen contralaterally in the healthy group and ipsilaterally in the PD group. These results suggest that simple but laborious motor exercise (motor stimulation) generates significant dopamine release in the dorsal striatum contralateral to the motor execution in humans. Lack of the crossed pattern and ipsilateral increase in dopamine release in the dorsal striatum during the unilateral limb movement may reflect the pathophysiology for hypokinetic and insufficient coordinating movement in PD.

Prominent psychiatric symptoms and glucose hypometabolism in a family with a SNCA duplication.

The genomic duplication of the α-synuclein gene ( SNCA ) has been shown to cause familial parkinsonism.1,2 Although patients with SNCA duplication often exhibit similar features to those with idiopathic Parkinson disease (PD), we and others previously reported that patients with SNCA duplication may develop the phenotype of PD dementia (PDD).3,4 We identified a new family with SNCA duplication who developed parkinsonism, visual hallucination, and cognitive fluctuation, which are the characteristic phenotypes in patients with dementia with Lewy bodies (DLB). A PET study of this family revealed a pattern of cerebral glucose hypometabolism similarly described in patients with DLB.5 ### Case reports. #### Patient 1. The proband had symptoms of generalized anxiety disorder including palpitation, restlessness, sensation of dyspnea, and excessive worry 5 years prior to his first visit to our hospital with complaint of gait disturbance at age 47 years. On neurologic examination, poor facial expression, rigidity, and bradykinesia in his right extremities were noted. His cognitive function was apparently normal. At age 49, his bradykinesia has progressed and shuffling gait, impaired postural balance, and postural tremor were present. These symptoms were improved by treatment with l-dopa and cabergoline. At age 50, he developed visual hallucinations and delirium followed by obvious deficits in attention and verbal fluency, and prosopagnosia was occasionally noted. These psychiatric symptoms including his hallucinations were apparently unrelated to l-dopa therapy. He also exhibited fluctuating cognitive decline, as shown by his Mini-Mental State Examination (MMSE) score of 24 and Raven Colored Progressive Matrices score of 27. #### Patient 2. The mother of the proband …

Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier

A clinical association between Gaucher disease and parkinsonism has been demonstrated. We herein report a Japanese patient with type 3 Gaucher disease who was compound heterozygous for F213I and L444P mutations in the glucocerebrosidase gene while his father was heterozygous for the L444P mutation. They both presented with parkinsonism characterized by a predominance of akinetic-rigid signs and a favorable response to anti-Parkinson therapies. We investigated the dopaminergic neuronal function using positron emission tomography (PET) with radioligands, [(11)C] CFT and [(11)C] raclopride. PET studies of both patients demonstrated the [(11)C] CFT uptake to be severely decreased in the putamen and the caudate nucleus, however, the [(11)C] raclopride uptake was normal in the basal ganglia. Although the majority of Gaucher disease patients with parkinsonism tend to be refractory to anti-Parkinson therapies. The clinical features and the findings of the PET studies suggest that patients with parkinsonism associated with the mutation in the glucocerebrosidase gene, even in heterozygosis, may be related to the presynaptic dopaminergic neuronal dysfunction reported in Parkinsons disease. A PET study to evaluate the dopaminergic neuronal function in Gaucher disease would provide both a better understanding of the effects of anti-Parkinson therapies and a help to improve our ability to make an early diagnosis of parkinsonism associated with Gaucher disease.

Frontal lobe dysfunction associated with glucose hypometabolism in aceruloplasminemia

Sirs: Aceruloplasminemia is characterized by progressive neurodegeneration in association with iron accumulation [7]. Neurological symptoms, including ataxia, involuntary movement, and dementia, usually appear after the fourth decade. We clinically characterized two Japanese patients with cognitive dysfunction who had different truncation mutations in their ceruloplasmin genes. We used positron emission tomography (PET) with 18F-fluorodeoxyglucose to measure brain glucose metabolism by an autoradiographic method [6]. A 59-year-old man had suffered from bradykinesia, gait ataxia, and diabetes mellitus (DM) for two years. Serum ceruloplasmin was absent because of mutation of the ceruloplasmin gene, a 1-base (G) deletion (nt 2482). He presented with a 2-year history of mental slowing, and increasing apathy. There was no previous personal history of psychiatric illness. He was fully oriented as to time and place. Neurological examination showed positive jaw and prominent snout reflexes. Mental examination showed him to be inert with a bland affect. Spatial abilities were intact. His digit span was six forward, and four backward. He could repeat a seven-item name and address immediately after its oral presentation and could recall 6 of 7 items after a 5-minute delay. A Wechsler Adult Intelligence Scale (WAIS) showed verbal IQ of 78, performance IQ of 72, and full scale IQ of 75. His Mini Mental State Examination (MMSE) score was 23. In the Nelson modification of the Wisconsin card sorting test [9], he achieved two sorting categories only. Twenty per cent of errors were perseverative. The second patient was a 56year-old man who had had blepharospasm and DM for five years and had suffered scanning speech and forgetfulness from age 54. His mutation was a 5-base insertion at amino acid 410 in the ceruloplasmin gene. He became apathetic and lacking in motivation from age 54. He carried out tasks impulsively without checking, and was unconcerned by failures. He did not initiate conversation. His digit span was four digits forward and two backward. He could not recall any items of a name and address after a 5minute delay. His full-scale IQ was 72; verbal IQ 74 and performance IQ 70 on the WAIS. The MMSE score was 19. On the card sorting test he could complete only one sorting category, and 80 % of errors were perseverative. The mental manifestations in common in our patients were alteration of personality characterized by inertia and loss of volition but relative preservation of memory function. Cognitive deficits occurred in the domains of attention, abstraction, planning, and problem solving, whereas the primary tools of language, perception, and spatial functions were preserved. These aceruloplasminemia patients might have had frontal type neuropsychological deficits from the early stage. Visual inspection showed striking decreases in the cerebral metabolic rate of glucose in the cortices of both frontal lobes (Fig. 1A and B) as well as basal ganglia and cerebellar cortices. Relative glucose hypometabolism has been found only in the caudate nuclei in the very early stage of aceruloplasminemia [2]. Loss of several subcortical afferents from the basal ganglia to the frontal cortex may be responsible for this frontal cortical hypometabolism. However, PET studies of patients with Huntington’s and Wilson’s diseases, in which prominent lesions of the striatum are present, have not detected consistent frontal hypometabolism [1, 3–5]. Glucose utilization in our patients was somewhat more affected in the polar heteromodal cortices (Brodmann’s areas 9–10, 32, and 45–47) than in the motor and premotor areas closely connected with the basal ganglia. The heteromodal cortex derives most of its input from distant cortical territories [8, 10]. In advanced cases of aceruloplasminemia PET has shown a marked decrease in glucose consumption in the entire cerebral cortices [6]. Metabolic activity in the heteromodal cortex therefore may be less dependent on subcortical connections. Metabolic alteration in the frontal lobe may appear early in the course of the disease.

Increased anaerobic glycolysis in mitochondrial trifunctional protein-deficient brain.

Deficiency of mitochondrial trifunctional protein (TP), beta-oxidation enzyme, is characterized by recurrent rhabdomyolysis in adult patients. Positron emission tomography was used to measure brain oxygen (CMRO(2)) and glucose (CMRGlc) metabolisms in an adult patient with TP deficiency who had a homozygous G1331A transition of the beta-subunit gene. The molar ratio of oxygen to glucose consumption showed diffuse reduction; CMRO(2) was markedly decreased, whereas CMRGlc increased. Oxidative metabolism may be impaired and anaerobic glycolysis stimulated in the brain of this patient with TP deficiency.