Chairs：MasahisaKatsuno
DepartmentofNeurology,NagoyaUniversity
GraduateSchoolofMedicine,Japan
NorikoNishikawa
NationalCenterofNeurologyand
Psychiatry,Japan
≪Objective≫
Neurodegenerative diseases are characterized by a progressive decline of the motor and/or cognitive function caused by a selective loss of neurons within the central nervous system. Pathological changes at molecular and cellular levels precede the clinical onset by several years, underscoring a pressing need for initiation of interventions before the emergence of neurological symptoms. Using exquisite biomarkers, recent studies revealed the preclinical and prodromal progression of pathophysiology, as well as compensatory brain responses in several neurodegenerative diseases. This session aims to discuss the recent advancement of biomarker studies on presymptomatic subjects and the perspective on a preventive trial of disease-modifying therapies for devastating neurological disorders.
S-18-1 Preclinical biomarkers of Alzheimer's disease
○ AkinoriNakamura
Department of Clinical and Experimental Neuroimaging, National Center for Geriatrics and Gerontology, Japan
【Curriculum Vitae】
ChiefofLaboratoryforCognitiveBrainSciences,
DepartmentofClinicalandExperimentalNeuroimaging,
NationalCenterforGeriatricsandGerontology,Obu,Japan 1985GraduatedfromFacultyofMedicine,KagoshimaUniversity,
thenstudiedclinicalneurology
1995Scientist,DepartmentofBiofunctionalResearch,National
InstituteforLongevitySciences
2001Scientist,MaxPlanckInstituteforHumanCognitiveand
BrainSciences 2005-Currentposition
Alzheimer's disease （AD） is considered as a continuum of preclinical, prodromal and dementia stages, which courses span about three decades. Although most of disease-modifying clinical trials for AD have been not successful, earlier interventions, in the preclinical and prodromal stages of the disease, are expected to be efficacious. To facilitate such clinical trials, biomarkers for the brain amyloid β （Aβ） deposition, which is the earliest pathognomonic signature of AD, are necessary.
However, currently available validated methods are only Aβ-PET imaging or CSF-Aβ levels that are invasive and/or expensive. Therefore, a minimally invasive and cost-effective blood-based biomarkers are strongly desired. Recently, we （NCGG and Koichi Tanaka Mass Spectrometry Research Laboratory at Shimadzu Corporation） have developed a high-performance plasma biomarker that can reliably predict individual brain status of Aβ deposition. The key technology is based on immunoprecipitation and mass spectrometry （IP-MS）
assay that measures plasma levels of Aβ-related peptides, including Aβ 1-42, Aβ 1-40, and APP669-711. Then, the ratios of these peptides （APP669-711/Aβ1-42, Aβ1-40/A β1-42） were computed, and composite biomarker values
were generated by averaging normalized scores of these two peptide ratios. If referring PiB-PET imaging as a standard of truth, the composite biomarker showed very high performance in predicting individual status of brain Aβ burden with an accuracy approximately 90% in two independent datasets, derived from Japan （n=121） and Australia （n=111）. Also, the composite biomarker values were significantly correlated with Aβ-PET burden and CSF-Aβ1-42 levels. Further investigation suggested that the composite biomarker may be able to detect initial stages of Aβ pathology. Thus, our plasma Aβ biomarker is expected to contribute to efficient population screening in identifying at-risk subjects for primary and secondary prevention trials.
23 日 シ ン ポ ジ ウ ム
5月23日（木）15：35 ～ 17：35 第12会場(大阪国際会議場11F 会議室1101-1102)
公募 En
S-18-2 Preclinical pathogenesis of Parkinson's disease
○ NorikoNishikawa
National Center of Neurology and Psychiatry, Japan
【Curriculum Vitae】
2018- present
Medical director, Department of Neurology, National Center of Neurology and Psychiatry
2012-2017
Associate professor, Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine 2009-2012
Assistant Professor, Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine 2005-2009
Clinical Fellow, Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine 2000-2005
Resident, Department of Medicine （Neurology & Rheumatology）, Shinshu University School of Medicine
Half of the number of dopamine neurons in the substantia nigra has already disappeared when diagnosed in patients with Parkinson's disease （PD）. In PD, dopamine replacement therapy including L-dopa is only symptomatic treatment, there is no disease modifying therapeutic drug yet. For the development of disease modifying therapy, it is necessary to diagnose prodromal PD before dopamine neuronal loss and the onset of motor symptoms, and it is urgent to identify biomarkers reflecting the disease condition in prodromal PD.
In the stage of prodromal PD, the patients have olfactory disorder, depression, slight movement disorder, constipation, daytime sleep and so on. REM sleep behavior disorder （RBD） characterized by action of dream contents has recently attracted attention as a highly specific symptom in prodromal PD. According to a prospective cohort study of RBD, 33.1% in 5 years, 75.7% in 10 years and 90.9% in 14 years develop neurodegenerative diseases such as PD, DLB, MSA or mild cognitive impairment.
Prior to the appearance of Parkinson's symptoms, almost all cases of RBD showed a decrease in cardiac accumulation of MIBG myocardial scintigraphy, and in about half, the reduction of accumulation of striatum by DAT-SPECT was observed. RBD is already considered to be the precursor stage of α-synucleinopathy.
It is urgent for us to identify what risk factors to phenoconvert RBD patients into neurodegenerative diseases.It is our desire to provide a platform for developing neuroprotective drugs, clarifying the clinical clues leading to risk stratification of the onset of neurodegenerative diseases.
S-18-3 Preclinical
pathogenesis and biomarkers of motor neuron diseases
○ MasahisaKatsuno
Department of Neurology, Nagoya University Graduate School of Medicine, Japan
【Curriculum Vitae】
Dr. Masahisa Katsuno received his M.D. in 1995 and his Ph.D. in Neurology in 2003, both from Nagoya University in Nagoya, Japan.
Following an postdoctoral fellowship at Japan Foundation for Aging and Health, he became an associate professor of Institute of Advanced research, Nagoya University, at 2006, and then an associate professor of Department of Neurology, Nagoya University, at 2012. From July 2015, he has been a professor of Department of Neurology, Nagoya University. He received Japan Society of the Promotion of Science Prize at 2009, and Japanese Society of Neurology Award at 2014, and serves as a board member of Japanese Society of Neurology, a councilor of Japanese Society of Neurological Therapeutics, and an external evaluator of Ministry of Health, Labour, and Welfare （MHLW）, Japan.
Neurodegenerative diseases are disorders that are characterized by a progressive decline of the motor and/or cognitive function caused by a selective loss of neurons within the central nervous system. Recent advancements in the translational research have facilitated extensive insights into the molecular pathophysiology of neurodegenerative diseases. Nonetheless, a number of compounds that suppressed the disease progression in cellular and animal models have not clearly shown efficacy in clinical trials. Various biological, medical, and methodological factors could be attributed to unfavorable results of clinical trials of such disease-modifying therapies. Primarily, the fact that pathological changes at molecular and cellular levels precede the clinical onset by several years underscores a pressing need for the initiation of interventions before the emergence of neurological symptoms. To identify a candidate biomarker reflecting biological changes during the preclinical progression of spinal and bulbar muscular atrophy （SBMA）, we analyzed longitudinal changes in biochemical indices obtained during health examinations before and after the diagnosis of SBMA. We estimated trajectories of clinical markers across years from the onset of weakness using linear mixed models and compared these trajectories with those estimated for male healthy controls and patients with other neurodegenerative diseases. Moreover, we examined the relationship between serum creatinine level and the onset of symptoms using Kaplan-Meier curves.
The results showed that decreases in serum creatinine occurred approximately 15 years before the onset. The mean serum creatinine concentration was 0.56 mg/dl at the onset of weakness in SBMA patients. These findings suggest that serum creatinine begins to decrease prior to the onset of clinical symptoms, and is a biomarker for disease progression as well as the efficacy of therapeutics in preclinical SBMA.
23 シ ン ポ ジ ウ ム 日
5月23日（木）15：35 ～ 17：35 第12会場(大阪国際会議場11F 会議室1101-1102)
公募 En
S-18-4 RISCA: preclinical cohort of
spinocerebellar ataxia
○ ThomasKlockgether
Department of Neurology, University of Bonn, Germany
【Curriculum Vitae】
1974-1980 University of Göttingen, Medical School 1980 Promotion （summa cum laude）
1981-1983 Resident, Dept. of Medicine and Anaesthesiology, Oldenburg
1983-1987 Dept. of Pharmacology, Max-Planck-Institute for Experimental Medicine, Göttingen
1987-1991 Resident, Dept. of Neurology, University of Tübingen 1991-1998 Senior Physician, Dept. of Neurology, University of
Tübingen
since 1998 Professor of Neurology and Clinical Director, Dept. of Neurology, University of Bonn
2008-2011 Dean of the Medical Faculty, University of Bonn since 2011 Director of Clinical Research, German Center for
Neurodegenerative Diseases （DZNE）
The preclinical stages of neurodegenerative diseases are attracting increasing research interest, because they could provide a window for early therapeutic intervention before irreversible brain damage has occurs. To study the preclinical stage of the polyglutamine spinocerebellar ataxias （SCAs）, we enrolled 276 first degree non-ataxic relatives of patients with SCA1, SCA2, SCA3, and SCA6.
Estimated time to ataxia onset ranged from 8 （SCA2）
to 1 8 years （SCA6）. Compared with non-carriers, SCA1 and SCA2, mutation carriers performed worse in coordination tests. Further, the prevalence of gaze-evoked nystagmus was increased in SCA3, and that of muscle cramps in SCA1 and SCA2. 251 of the individuals at risk were included in the longitudinal analysis. During the observational period of 4.4 ± 2.2 years, 52% of SCA1, 53%
of SCA2, 40% of SCA3 and 13% of SCA6 mutation carriers converted to manifest ataxia. In SCA1, SCA2 and SCA3 mutation carriers, but not in non-carriers, clinical outcomes
（SARA, SCAFI, CCFS, INAS） deteriorated. MRI studies in a subset of the RISCA cohort revealed mild cerebellar and brainstem volume loss that was more pronounced in individuals who were closer to the expected onset of ataxia. In non-ataxic SCA3 mutation carriers, the volume of the pallidum and mesencephalon was reduced, while the cerebellar volume and cervecal spinal cord cross-sectional area decreased only in SCA3 mutation carriers with manifest ataxia. Serum levels of the neurodegeneration marker neurofilament light chain （NfL） were increased to almost the same level in non-ataxic and ataxic SCA3 mutation carriers.
Our results require revision of the traditional view that the polyglutamine SCAs start with the manifestion of ataxia. Instead, manifest ataxia in these disorders is preceded by a pre-ataxia period of several years that is characterized by mild coordination deficits, manifestation of non-ataxia symptoms and abnormal imaging and biochemical biomarkers.
23日
シ ン ポ ジ ウ ム
5月23日（木）15：35 ～ 17：35 第13会場(大阪国際会議場8F 会議室801-802)