Table 1.

The classification of subtypes according to the clinical features in patients with Parkinson’s disease (summary).

Criteria of Classifier	Classification of Subtype	Other Variables of Classifier Profile	Findings	Reference
Motor symptoms	TD PIGD	Non-motor and motor symptoms; mortality	More severe non-motor symptoms (cognitive impairment, hallucinations, psychosis, sleep impairment, fatigue, urinary disturbance) [25,26,27] and QOL ↓ [27] in PIGD More severe motor symptoms (H&Y, UPDRS-motor) [29] in PIGD Mortality ↑ [28] in PIGD Severe olfactory impairment in TD [30]	[25,26,27,28,29,30]
	TD PIGD	Gait pattern using a single body-fixed sensor under single and dual task; balance; fall risk [23] Spatiotemporal parameter under two conditions (unobstructed walking and obstacle avoidance) [31]	Gait speed ↓, stride L ↓, stride variability ↑, stride regularity ↓, performance test score ↓ in PIGD [23] Stride L ↓, velocity ↓, double support ↑ in PIGD and stride velocity ↓ in PIGD and TD during unobstructed walking [31] Trailing toe clearance ↓, leading and trailing velocity ↓, leading crossing step width ↑ in PIGD during obstacle avoidance [31]	[23,31]
	TD PIGD	IMU sensor; spatiotemporal parameter, kinematic parameter	Stride length ↓, stride time ↑, step length variability ↑ Cadence ↑, ankle joint ROM ↓, toe-off angle ↓ in PIGD	[32]
	TD PIGD	Behavioral marker	Interoceptive accuracy and sensibility↓ using heat beat perception task in TD	[33]
	RFOG URFOG No FOG	UPDRS, Mini-mental status exam, Visual hallucinations; Scale for the Assessment of Positive Symptoms, Comprehensive battery of neuropsychological measures	UPDRS ↑ in URFOG compared with RFOG, MMSE ↓ in URFOG and RFOG compared with no FOG, Visuospatial performance ↓ URFOG compared with RFOG and no FOG, Dyskinesia ↑ in URFOG and RFOG compared with no FOG	[35]
	TD PIGD	MRI [37], fMRI [36]	More distrusted hub in cerebellum in PIGD [36] ReHo value ↑ in right para-hippocampal gyrus in TD [37] * Compensatory performance slow progressive cognitive decline	[36,37]
	TD PIGD Intermediate	Total bilirubin, IBIL, Direct bilirubin in serum	IBIL ↓ in PD than control, IBIL ↓ in PIGD than TD * antioxidative property of IBIL	[38]
	SPPD EPPD NPPD MIPD	Serum, CSF, neuroimaging	Differentiated NPPD from EPPD: Serum IGF1, SFT HVLT-R Delayed Recall, HVLT-R Retention, Mean Striatum SBR, Mean Caudate SBR, and Mean Putamen SBR Differentiated NPPD from SPPD: Serum IGF1Differentiated NPPD from MIPD: CSF αSyn, Benton Judgement of Line Orientation Test	[41]
Non-motor symptoms	PD-aMCI (amnestic MCI) PD-naMCI (non-amnestic MCI)		Dementia conversion risk ↑, cognitive decline in frontal/executive function ↑, functional connectivity in the left posterior parietal region ↑, memory domain score ↓ in PD-aMCI	[42]
Motor and non-motor symptoms	Lowest motor and non-motor Motor disability Motor disability with apathy and hallucination	Dopaminergic dysfunction measured by 123(I)-FP-CIT SPECT scan	Motor disability burden paralleled with dopaminergic dysfunction and negatively correlated with depression	[44]
	Akinetic/rigidity-predominant tremor-predominant non-motor (dPD, aPD, coPD, nPD)	MRI	GMV ↓ in the left Crus I in dPD GMV ↓ in the tonsil and the right lobule VIII in aPD than nPD GM atrophy including the tonsil, the left lobule VIII, the right lobule VI, the left Crus I, vermis IV, and V in coPD than HC	[45]
	PIGD tremor Mixed non-motor	Serum uric acid	Serum uric acid ↑ in tremor subtype Serum uric acid ↓ in mixed motor subtype	[49]
	Mild motor predominant [4,46] or slow progression [43] Diffuse malignant Intermediate	Lewy pathology and AD-related pathology [46]; CSF amyloid-β and atrophy using MRI [4]	Disease milestones development risk ↑ and survival ↓ [46]; level of CSF amyloid-β and amyloid-β/total-tau ratio↓ and whole brain atrophy ↑ [4]; MCI ↑, orthostatic hypotension ↑, RBD ↑ and rapid progression [43] in diffuse malignant subtype	[4,43,46]
	Subtype I (Mild baseline, moderate motor progression) Subtype II (Moderate baseline, mild progression) Subtype III (Severe baseline, rapid progression)	Clinical information (motor and non-motor assessment), biospecimen examinations, neuroimaging using a deep learning algorithm, LSTM	CSF t-tau level ↓ in subtype I Subtype II DaTScan SBR value ↓ in subtype III	[47]
	Fast motor progression Mild motor diseaseSevere motor diseaseSlow motor progression	Apolipoprotein A1, CRP, uric acid, vitamin D [48]	Apolipoprotein A1 ↓, CRP ↑ in severe motor disease, poor psychological well-being, and poor sleep with intermediate motor progression [48]	[48,50]

TD, tremor-dominant; PIGD, postural instability and gait difficulty; UPDRS, unified Parkinson’s disease rating scale; QOL, quality of life; IMU, inertial measurement unit; ROM, range of motion; RFOG, responsive freezing of gait; URGOG, unresponsive freezing of gait; MMSE, mini mental status examination; MRI, magnetic resonance imaging; fMRI, functional magnetic resonance imaging; IBIL, indirect bilirubin; dPD, depressive but not anxious; aPD, anxious but not depressive; coPD, comorbid depressive and anxious (n = 8); nPD, without depressive or anxious symptoms; GMV, gray matter volume; SPPD, Secondarily Progressive PD, H&Y progression between V04 and V08; EPPD, Early Progressive PD, H&Y progression between V0 and V04; NPPD, Non-Progressive PD, no H&Y progression; MIPD, Minimally Improving PD; DaTScan SBR, Striatal Binding Ratio, ReHo, regional homogeneity; IGF1, insulin-like growth factor 1; SFT, serum insulin-like growth factor-1; HVLT-R, Hopkins verbal learning test—revised; MCI, mild cognitive impairment; aMCI, amnestic MCI; naMCI, non-amnestic MCI; 123(I)-FP-CIT SPECT, iodine I 123–radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane SPECT; RBD, rapid eye movement sleep behavior disorder; CRP, C-reactive protein.