News Release

Title
Longitudinal analysis of premotor anthropometric and serological markers of Parkinson’sdisease
Key Points• Parkinson’s disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic
neurons, and is characterized by motor signs including bradykinesia, rigidity, resting tremor,and reduced postural reflex• More than 50% of dopaminergic neuron in the substantia nigra are lost at the onset of
motor symptoms in PD.
• Prodromal symptoms, such as dysautonomia, REM sleep behavior disorder (RBD), andhyposmia, antecede the onset of motor of cognitive dysfunction by 10-20 years.
• Our current results showed a premotor blood pressure increase in female PD patients andpremotor decreases in haematocrit, total cholesterol, and low-density lipoprotein cholesterol inthe male PD patients.
• Our study revealed that anthropometric and serological changes occurred before theemergence of motor symptoms in PD.
• Health examination, in combination with other evaluation, may facilitate early detection of
PD before the onset of motor symptoms.
SummaryA group of researchers, headed by Prof. Masahisa Katsuno, Department of Neurology, Nagoya University
Graduate School of Medicine have revealed that the blood pressure, hematocrit, and serum cholesterol levels
change before the onset of motor symptoms in PD patients. This work was published online in Scientific
Reports on November 25 2020.
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such asconstipation and hyposmia, precede the onset of motor symptoms by 20 years. At the timing of motor
symptom onset, more than 50% of dopaminergic neurons are lost. The aim of this study was to identify
biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes inanthropometric and serological indices obtained from health check-up data before and after the onset ofmotor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23
female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate
the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD
subjects, which were then compared with the trajectories of the healthy controls. The results showed apremotor blood pressure increase in female PD patients and premotor decreases in haematocrit, totalcholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that bloodpressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, thechanges in anthropometric and serological indices before PD motor symptoms onset were sex specific.

Research Background
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after
Alzheimer’s disease. The frequency of the disorder is relatively high at 1.3 cases per 10,0000
people < 45 years old, 3,100 per 10,0000 in those 75–85 years old and 4,300 per 10,0000 in those> 85 years old. PD is characterized by motor signs of bradykinesia, rigidity, resting tremor, andreduced

posturalreflex,as

well

asbynonmotorsymptoms,

includingcognitive,neuropsychiatric, sleep, autonomic and sensory disturbances. Some nonmotor symptoms, suchas constipation, rapid eye movement sleep behavior disorder (RBD), and hyposmia, are known
as premotor/prodromal symptoms. Because these symptoms manifest decades before motor
symptoms, the pathogenesis of PD is thought to emerge long before the onset of motor
symptoms.
Initiation of neurodegenerative process before neurological symptoms is a common feature ofneurodegenerative disorders including Alzheimer’s disease, in which the deposition of amyloid
beta precedes the onset of dementia by mora than 20 years. This is the reason why attempts to
identify biological markers for the preclinical stages have received increased attention.
However, little is known about the longitudinal changes in biomarkers at a premotor stage ofPD.
The aim of the present study was to examine longitudinal changes in biochemical andanthropometric indices at the premotor stage of PD. To this end, we investigated changes
before and after motor symptoms onset in PD patients by analyzing health check-up
longitudinal data.
Research Results
We analyzed 45 PD patients (22 males and 23 females) whom health check-up data before
the onset of motor symptoms were available, and 120 healthy controls (60 males and 60females) whom health check-up data > 4 years from their last evaluation were available, andwho did not have prodromal symptoms of PD (any of hyposmia, RBD and constipation).
First, we compared the baseline values of each item between the PD and healthy subjects foreach sex separately. We defined the baseline as the onset of motor symptoms for PD groups andas the last evaluation for the healthy subjects. In males, there were significant differences
between the PD patients and healthy controls in weight, body mass index (BMI), haematocrit(Ht), T-Cho, LDL-Cho and creatinine (Cr), and all the values of all these indices were lower inmale PD patients than in the male healthy controls. In females, significant differences were
found in height, systolic blood pressure (BP), diastolic BP, aspartate aminotransferase (AST)and T-Cho between the groups. The values of AST, systolic BP and diastolic BP were higher infemale PD patients, whereas the values of other indices were lower in female PD patients thanin the female healthy controls.

Todetectpremotorchanges in indices, weanalyzed the estimatedtrajectories
factorsofthat

statisticallytheshowed

significant

differences at baseline
betweenhealthysubjects and those with
PD for either sex: height,weight, BMI, systolic BP
and diastolic BP. There
was no premotor change
in height and weightand BMI in either sex.
By contrast, the values of systolic and diastolic BP were elevated before motor onset in thefemale PD patients when compared with the female controls, and the difference decreased as
the manifestation of motor symptoms increased, although these trends were not detected inmales (Fig. 1A, D). To confirm the results of our linear mixed model analysis, we also directlycompared the actual data of each item between the PD and healthy subjects for each PD
disease stage (Fig. 1C, D). Increases in systolic and diastolic BP were observed >6 years before
motor onset in the female PD patients, but the differences from the control values decreased
with disease progression, as shown in the estimated trajectories.
Next, we analyzed the estimated trajectories of the blood examination items, which showedstatistically significant differences at baseline between PD and healthy subjects for either sex:
Ht, AST, T-Cho, LDL-Cho and Cr. In the male PD patients, the haematocrit values started todecrease before the onset of motor symptoms (Fig. 2A). The premotor changes of the serum
values of AST and Cre were not observed in either sex. The T-Cho and LDL-Cho values began
to decrease before the onset of motor symptoms in the male PD patients (Fig. 2B, C). Thesevalues showed progressive declines after the onset in both sexes, but a premotor change was
not observed in the female PD patients. In the direct comparison of actual data, thehaematocrit levels in the male PD patients showed a decrease from 5 years to 1 year before themotor onset (Fig. 2D). Serum T-Cho levels in the male PD subjects began to decrease 5 to 1years before the onset of motor symptoms, whereas the values decreased only after motor onsetin females (Fig. 2E). Similar results were obtained for the serum LDL-Cho levels (Fig. 3F).

Research Summary and Future Perspective
Our results showed apremotor blood pressure
increase in female PDpatients and premotordecreases in haematocrit,totalcholesterol

low-density

andlipoproteincholesterol in the malepatients.

Our

results

indicatedthatbloodpressure,haematocrit

andserumcholesterol

arepotential

levelspremotor markers of PD,
and may be used withother examinations on
premotor symptoms forearly diagnosis of PD.
We

arecurrently

performing a prospective
study on subjects at the prodromal phase of PD, and will start a clinical trial of neuroprotective
therapy in such individuals.
Publication
Katsunori Yokoi, Makoto Hattori, Yuki Satake, Yasuhiro Tanaka, Maki Sato, AtsushiHashizume, Akihiro Hori, Motoshi Kawashima, Akihiro Hirakawa, Hirohisa Watanabe, andMasahisa Katsuno.
“Longitudinal analysis of premotor anthropometric and serological markers of Parkinson’s
disease”

Scientific Reports, 2020, in press.
10.1038/s41598-020-77415-1
Japanese ver.
https://www.med.nagoya-u.ac.jp/medical_J/research/pdf/Sci_Rep_201126.pdf