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. 2022 Jul 18;29(11):3395–3417. doi: 10.1111/ene.15481

TABLE 2.

Domain‐based subtypes

Citation Sample characteristics, mean ± SD Cluster method Cluster variables Imaging method Description of clusters, % prevalence Neuroimaging results
N Age, years Education, years Global cognition Gender, % female Disease duration, years
Alonso‐Recio et al. (2018) 71 PD 63.9 ± 7.7 15.1 ± 6.1 MMSE: 28.8 ± 1.3 48% 7.0 ± 4.1 Latent profile analysis

Memory: Test de Aprendizaje Verbal España‐Complutense (immediate & delayed) 7/24 spatial recall (immediate & delayed), semantic fluency, BNT

Executive: phonemic fluency, TMT (A & B‐A), digit span (backward)

NA
  1. Executive dysfunction (32%): deficits in executive measures

  2. Memory and executive dysfunction (28%): deficits in memory and executive measures

  3. Memory dysfunction (24%): deficits in memory measures

  4. Noncognitive dysfunction (16%): cognitively intact

NA
Brennan et al. (2017) 199 PD 70.6 ± 7.5 16.2 ± 2.3 DRS‐2: 136.8 ± 5.6 33% 6.9 ± 5.2 Latent class analysis

Executive: LNS, phonemic fluency

Language: BNT, semantic fluency

Verbal episodic memory: HVLT‐R (delayed & recognition)

Visuospatial: JLO, clock drawing

NA
  1. Intact cognition (55%)

  2. Amnestic (32%): impaired verbal recall and recognition memory, but intact performance on other measures

  3. Mixed impairment (13%): impairments in phonemic and semantic fluency, verbal recall, and visuospatial ability and below average on all cluster variables

NA
Crowley et al. (2021) 116 PD 78.7 ± 6.2 16.3 ± 2.5 28.4 ± 1.4 28% 7.1 ± 4.8 k‐means cluster analysis

Composite scores used for each domain

Executive: SDMT, LNS, TMT‐B, Stroop

Memory: Logical memory, HVLT (delayed & recognition)

3‐T structural MRI: voxel‐based morphometry and fractional anisotropy
  1. PD executive (22%): primarily impaired on executive composite; also impaired in language and visuospatial composites compared to healthy controls and the cognitively well group

  2. PD memory (30%): primarily impaired on memory composite; also impaired in language composite compared to healthy controls and the cognitively well group

  3. PD cognitively well (48%): not derived using cluster analysis

PD executive: lower total brain volume and higher ventricular volume compared to PD cognitively well and healthy controls. Reduced putamen volume and right entorhinal‐hippocampal connectivity compared to healthy controls. Reduced thalamus volume compared to PD cognitively well. Reduced right dorsolateral‐prefrontal cortex to caudate nucleus connections connectivity compared to all groups

PD memory: bilaterally reduced entorhinal‐hippocampal connections compared to healthy controls

PD cognitively well: only reduced putamen volume and right entorhinal‐hippocampal connectivity compared to healthy controls

Inguanzo et al. (2021) 62 PD NA NA NA 26% NA Hierarchical clustering with Ward's method on grey matter and fractional anisotropy data

Attention/working memory: TMT (A & B), digit span (forward & backward), Stroop, SDMT

Executive: phonemic fluency, semantic fluency

Language: BNT

Memory: RAVLT (immediate, delayed, recognition)

Visuospatial: JLO, VFDT, FRT

3‐T structural MRI: voxel‐based morphometry and fractional anisotropy
  1. PD1 (24%): widespread cortical and subcortical grey matter degeneration and white matter reductions with mild cognitive deficits across most measures

  2. PD2 (34%): cortical atrophy only and more specific cognitive impairments in Stroop, TMT, and SDMT

  3. PD3 (42%): no detectable atrophy or cognitive impairment

PD1: showed characteristic posterior‐cortical atrophy. Reduced grey matter in occipital, medial frontal, orbital and temporal cortices compared to controls. Reduced grey matter of subcortical regions (bilateral putamen, caudate, thalamus, nucleus accumbens, hippocampus) compared to controls and PD3. Reduced grey matter of subcortical regions (thalamus, amygdala, putamen, hippocampus) compared to PD2. Reduced fractional anisotropy compared to controls mainly in fronto‐occipital tracts

PD2: cortical atrophy only (bilateral orbital, medial prefrontal, and temporal) compared to controls. Reduced grey matter in right middle temporal gyrus compared to PD3. Greater grey matter volume of the cerebellum compared to controls and PD3

PD3: no detectable atrophy compared to HC

Kawabata et al. (2018) 72 PD 68.5 ± 7.8 13.8 ± 3.2

MMSE: 28.7 ± 0.7

ACE‐R: 88.5 ± 4.1

54% 5.6 ± 3.3 Hierarchical clustering with Ward's method

The five sub‐scores of the ACE‐R:

Attention/Orientation

Memory

Fluency

Language

Visuospatial

3‐T rs‐fMRI: group‐ICA dual regression, and regional FC analyses
  1. PD‐A (28%): poorer performance on memory, fluency, and visuospatial subscales of the ACE‐R compared to HC, with greatest impairment in memory domain

  2. PD‐NA (33%): poorer performance on fluency and visuospatial subscales compared to HC

  3. PD‐NC (39%): not identified through cluster analysis; all ACE‐R subdomain scores within 1.5 SD of relevant norms

Compared to PD‐NC and PD‐NA, PD‐A had reduced FC in precuneus and posterior cingulate cortex within the ventral DMN. PD‐A also showed lower FC compared to HC in left cuneus within the visuospatial network. Compared with the HC and PD‐NC, PD‐NA demonstrated reduced FC in lingual gyrus within the primary visual network and in lingual gyrus and calcarine gyrus within the medial visual network. This difference was larger between PD‐NA and HC than PD‐NA and PD‐NC. PD‐NA showed reduced FC in bilateral cerebellar lobule within the cerebellum–brainstem network relative to PD‐A. PD‐A displayed lower mean regional FC in the ventral DMN than PD‐NA and PD‐NC. PD‐A and PD‐NA were likely to show lower mean regional FC in the visuospatial network, primary visual network, and medial visual network ROIs compared to HC
3‐T MRI: voxel‐based morphometry PD‐A group showed reduced grey matter volume in left amygdala, right rectal gyrus, and right middle occipital gyrus compared to age‐ and gender‐ matched HC. No differences between PD‐A, PD‐NC, and PD‐NA
LaBelle et al. (2017) 424 de novo PD 61.7 ± 9.7 15.5 ± 3 NR 34% 0.5 ± 0.5 Latent class analysis

Learning and memory: HVLT‐R (immediate & delayed)

Visuospatial: JLO

Working memory: LNS

Processing speed: SDMT

Language: semantic fluency

NA
  1. Weak‐overall (5%): below‐average performance in all domains

  2. Typical‐overall (35%): average performance in all domains

  3. Strong‐overall (32%): above‐average performance in all domains

  4. Strong‐memory (5%): strong memory performance but poor performance in visuospatial ability

  5. Weak‐visuospatial (11%): deficits in visuospatial ability, episodic memory, and processing speed

  6. Amnestic (12%): deficits in episodic and semantic memory

NA
Bayram et al. (2019), using LaBelle et al. (2017) clusters 122 de novo PD 63.5 ± 7.3 14.8 ± 2.6 MoCA: 27.0 ± 2.2 28% 0.5 ± 0.5 3‐T structural MRI: deformation‐based morphometry

Weak: most widespread pattern of atrophy compared to typical class (lateral and inferior temporal regions, posteromedial and lateral frontal regions, insula and motor cortex)

Weak‐visuospatial/strong‐memory: atrophy in prefrontal, lateral temporal, parietal, insular, motor cortex, and subcortical regions compared to typical class. Atrophy in left frontotemporal, precentral gyrus, right frontal, and putamen compared to typical

Weak‐visuospatial: atrophy in left rolandic operculum including the precentral gyrus and the insula compared to typical

Amnestic: atrophy in lateral temporal, parietal, occipital, insular, and motor cortex compared to typical

Strong: no atrophy patterns compared to typical

Liepelt‐Scarfone et al. (2012) 97 PD, 24 PDD 68.7 ± 6.9 NR MMSE: 26.6 ± 2.6 33% 6.6 ± 5.1 Hierarchical cluster analysis

19 neurocognitive variables (Tower of London, TMT (A & B), digit span (forward & backward), figure test, word‐list memory (false positives, recall, recognition), BNT, semantic & phonemic fluency, CERAD (praxis & delay), WMS‐R logical memory, VOSP, BAXT, alertness, Go‐Nogo) reduced down to six factors through PCA:

Factor 1: frontal lobe function

Factor 2: word‐list memory and recall

Factor 3: attention

Factor 4: logical memory

Factor 5: praxis and visual perception

Factor 6: fluency and naming ability

NA
  1. Cluster I (44%): higher global cognitive ability; deficits in attention, logical memory, and visuospatial ability

  2. Cluster II (56%): lower global cognitive ability; deficits within all domains, particularly word‐list memory, frontal lobe function, and fluency and naming

NA
Pourzinal et al. (2020) 85 PD 68.5 ± 8.5 13.0 ± 3.5 MoCA: 25.2 ± 2.8 42% 5.9 ± 5.8 k‐means cluster analysis

Posterior‐cortical: BVMT and HVLT (immediate & delayed), category fluency, BNT

Frontal: TMT (A & B‐A), phonemic fluency, working memory subscale from the PD‐CRS

NA
  1. Posterior‐cortical dominant impairment (42%): impairment on posterior‐cortical measures

  2. Global impairment (21%): impairment across all measures

  3. Cognitively intact (28%): no cognitive impairment

  4. Frontal dominant impairment (8%): impairment on frontal measures

NA
Uribe et al. (2016) 88 PD 60.4 ± 9.3 10.6 ± 4.8 MMSE: 29.0 ± 1.0 42% 8.0 ± 5.6 Hierarchical clustering with Ward's method on cortical thickness data

Executive: phonemic and semantic fluency

Memory: RAVLT (total & recall)

Attention/working memory: digit span (forward & backward), Stroop (word, colour, & word‐colour), SDMT, TMT (A, B, & A‐B)

Language: BNT

Visuospatial: VFDT, JLO

3‐T structural MRI
  1. Pattern 1 (34%): parietotemporal pattern of atrophy and worse cognitive performance, particularly on semantic and episodic memory, and processing speed and attention/working memory

  2. Pattern 2 (33%): orbitofrontal cortical atrophy with younger disease onset, worst performance in processing speed and attention/working memory measures

  3. Pattern 3 (33%): patients without detectable cortical atrophy, relatively preserved cognition, slight slowing of processing speed

Pattern 1: cortical thinning in posterior cingulate/isthmus of the cingulate gyrus, precuneus, precentral gyrus compared to Pattern 2. Significant cortical thinning in lateral and medial regions bilaterally, including precentral gyrus, inferior and superior parietal areas, cuneus, posterior cingulate gyrus, and parahippocampal gyrus compared to Pattern 3. Reduced cortical thickness in lateral and medial regions bilaterally, including the precentral gyrus, inferior and superior parietal areas, cuneus, posterior cingulate gyrus, and parahippocampal gyrus compared to healthy controls

Pattern 2: cortical thinning in dorsolateral and orbital frontal regions compared to Pattern 1, and cortical thinning in superior parietal and occipital areas and left dorsolateral frontal cortex compared to Pattern 3. Also showed cortical atrophy in bilateral superior parietal and occipital areas and bilateral frontal regions such as middle frontal, orbitofrontal, and right anterior superior frontal regions compared to controls

Pattern 3: cortical thinning in the left medial orbitofrontal cortex compared to Pattern 1 and no cortical thinning compared to controls

Uribe et al. (2018) 77 de novo PD 63.1 ± 8.1 16.0 ± 6.0 MoCA: median = 27.5, IQR = 3.0 38% 1 ± 1.9 Hierarchical clustering with Ward's method on cortical thickness data

Memory: HVLT‐R (total, delayed, recognition)

Visuospatial: JLO

Attention/working memory: SDMT and LNS

Executive: phonemic (letter "f") and semantic (animal) fluency

3‐T structural MRI
  1. Pattern 1 (43%): average performance across all measures, except for HVLT delayed recall memory, which was above average

  2. Pattern 2 (57%): poorer HVLT and SDMT performance, generally lower performance across all measures compared to Pattern 1 and healthy controls

Pattern 1: cortical thinning in bilateral orbitofrontal, anterior cingulate, and lateral and medial anterior temporal gyri

Pattern 2: cortical thinning in bilateral occipital gyrus, cuneus, superior parietal gyrus, and left postcentral gyrus

Abbreviations: ACE‐R, Addenbrooke's Cognitive Examination‐Revised; BAXT, Berlin Apraxia Test; BNT, Boston Naming Test; BVMT, Brief Visuospatial Memory Test; CERAD, Consortium to Establish a Registry for Alzheimer's Disease; DMN, default mode network; DRS‐2, Dementia Rating Scale 2; FC, functional connectivity; FRT, forced response test; HC, healthy controls; HVLT‐R, Hopkin's Verbal Learning Test Revised; ICA, independent component analysis; IQR, interquartile range; JLO, Judgment of Line Orientation; LNS, Letter Number Sequencing; MMSE, Mini‐Mental State Examination; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; NA, not applicable; NR, not reported; PCA, principal component analysis; PD, Parkinson disease; PD‐A, PD‐amnestic; PD‐CRS, Parkinson's Disease Cognitive Rating Scale; PDD, PD dementia; PD‐NA, PD‐nonamnestic; PD‐NC, PD‐normal cognition; RAVLT, Rey Auditory Verbal Learning Test; ROI, region of interest; rs‐fMRI, resting‐state functional MRI; SDMT, Symbol Digit Modality Test; TMT, Trail Making Test; VFDT, Visual Form Discrimination Test; VOSP, Visual Object and Space Perception; WMS‐R, Weschler Memory Scale Revised.