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Table 1 Studies investigating the association between mental health and behavioural disorders

From: Factors associated with brain ageing - a systematic review

Reference

Study (Design, country)

n, Mean age ± SD (Range), Sex, Other information

Modality (Protocol)

Features

Model (Cross-validation)

Exposure

Main findings outcome

Adjustments

[27]

Multisite psychiatric database (Retrospective; US)

SZ: n = 657, 30.5 ± 13.7 yrs.; ADHD: n = 1462, 21.2 ± 15.5 yrs.; MDD: n = 4753, 38.4 ± 17.0 yrs.; BD: n = 2524, 31.9 ± 16.1 yrs.; CAD: n = 1089, 26.6 ± 10.4 yrs.; AUD: n = 1457, 38.4 ± 14.6 yrs.; GAD: n = 6457, 32.6 ± 17.3 yrs.; Sex unknown

SPECT (rs-99mTc-HMPAO)

Regional cerebral perfusion

LR

Psychiatric co-morbidities

↑ CA-BA in SZ (−4.0 yrs), CAD (− 2.8 yrs) BD (− 1.7 yrs), ADHD (− 1.4 yrs), AUD (− 0.6 yrs) & GAD (− 0.5 yrs); ↓ in MDs (0.85 yrs)

None

[44]

In- or out-patient services & matched controls (Germany)

MDD: n = 38, 45.7 ± 15.7 (19–66) yrs., 21♀; HC: n = 40, 42 ± 13.2 (21–73) yrs., 20♀

MRI (T1[3T])

Voxel-wise GM volume

RVR

MDD without axis I/II co-morbidity

NS BrainAGE

aScanner

[43]

Cases and controls from multiple ENIGMA MDD cohorts (Spain, Germany, UK, US, Canada, AUS, Brazil)

MDD: n = 2675, 43.08 ± 14.0 yrs., 1689 ♀; HC: n = 2126, 40.99 ± 15.82 yrs., 1199 ♀

MRI (T1[1.5/3 T])

CT, SA, subcortical GM volume, lateral ventricles, ICV

RR [Data splitting & 10-fold]

MDD & clinical characteristics

GAP ↑ in MDDs (b = 1.08, p < 0.0001). ↑ in first episode (b = 1.22), recurrent depression (b = 0.97), remittance (b = 2.19), current MDD (b = 1.47), AD use (b = 1.36), AD free (b = 0.67), early, mid & late age of onset (~b = 0.91–1.21) respectively (all p < 0.05). NS with severity

bAge, age2, sex, site

[60]

Community dwelling adults from 1 of 6 studies (US)

n = 185, 64.9 ± 8.3 yrs., 91♀

MRI (T1[3T])

Voxel-wise WB volume

RVR

Depression

↑ BrainAGE (r = 0.23, p = 0.01)

bAge, gender, diabetes duration

[37]

Cases & matched controls from LeAD study (Germany)

HC: n = 97, 43.7 ± 10.8 (21–65) yrs., 16♀; AlcD: n = 119, 45.0 ± 10.7 (20–65) yrs., 18♀

MRI (T1[3T])

Cortical & subcortical GM volume

MRR [LOO]

AlcD; lifetime alcohol consumption

60-69 yr AlcD GAP 11.7 yrs. ↑ than HCs (p < 0.01). NS in AlcD < 39 yrs. 71 standard drinks correspond to approximately ½ day of GAP in AlcD (β = 0.56, p = 0.03)

aGender, site, smoking, LC, general health; bAge

[32]

Icelandic dataset (Iceland)

HC: n = 291; SZ: n = 68; ID: n = 6; ASD: n = 10; BD: n = 31; Age & sex unknown

MRI (T1[1.5 T])

Voxel-wise MNI, Jacobian map, GM & WM volume

CNN [Data splitting]

SZ, ID, ASD, & BD

SZ GAP 2.2 yrs. ↑ than HC (2.3y vs. 0.1 yrs.; p < 0.01). NS for ID, ASD, & BD

aAge, sex, TICV

[38]

Cases from the Early Stages of Schizophrenia; community dwelling controls (Czech Republic)

FEP: n = 120, 27.0 ± 4.9 (18–35) yrs., 46♀; HC: n = 114, 25.7 ± 4.0 (18–35) yrs., 51♀

MRI (T1[3T])

Voxel-wise WB volume

RVR

FEP

FEP directly associated with BrainAGE (B = 1.15 yrs., p <  0.01)

bAge

[41]

1) Cases from the Early Stages of Schizophrenia & matched controls (Czech Republic); 2) HR offspring from ORBIS, & controls from similar SES (Canada, Prague)

1) FEP: n = 43, 27.1 ± 4.9 yrs., 17♀; HC: n = 43, 27.1 ± 4.4 yrs., 17♀; 2) HR: n = 48, 20.9 ± 4.2 yrs., 29♀; Early BD: n = 48, 23.1 ± 4.5 yrs., 33♀; HC: n = 60, 23.4 ± 2.9 yrs., 36♀

MRI (T1[1.5/3 T])

Voxel-wise WB volume

RVR

FEP; HR & early BD

1) FEP BrainAGE 2.64 yrs.; HC −0.01 yrs. (Cohens D = 0.64, p = 0.008); 2) HR & early staged BDs comparable to HC (− 0.96, −1.02 yrs. & 0.25 yrs., respectively; NS)

bAge

[66]

Patients, at risk, & healthy adults from Munich or FePsy database (Retrospective; Germany, Switzerland)

HC: n = 437, 32.6 ± 10.9 yrs., 214♀; ARMS: n = 89, 24.9 ± 5.8 yrs., 33♀; SZ: n = 141, 28.5 ± 7.3 yrs., 33♀; MDD: n = 104, 42.3 ± 12.0 yrs., 52♀; BPD: n = 57, 25.6 ± 6.7 yrs., 57♀

MRI (T1[1.5 T])

Voxel-wise GM volume & density

SVR [Repeated (×10) nested 10-fold]

SZ, MDD, BPD, & ARMS; SZ disease stage & clinical factors

SZ (5.5 yrs), MD (4.0 yrs), BPD (3.1 yrs), & ARMS (1.7 yrs) GAP ↑ than HC (all p <  0.05). ↓ age of onset for MDs (r = − 0.26) & BPDs (r = − 0.34; both p < 0.002). RE- (6.4 yrs), RO-SZ (4.2 yrs), & L-ARMS (2.7 yrs) GAP ↑ than E-ARMS (all p < 0.05). ↑ severity in SZ (r ~ 0.20 to 0.26), BPD (r ~ 0.37 to 0.47), & RO-SZ (r ~ 0.27 to 0.30; all p < 0.05)

None

[49]

Cases from in- or out-patient services, & community dwelling controls (Germany)

SZ: n = 45, 33.7 ± 10.5 (21.4–64.9) yrs., 16♀; BD: n = 22, 37.7 ± 10.7 (23.8–57.7) yrs., 12♀; HC: n = 70, 33.8 ± 9.4 (21.7–57.8) yrs., 30♀

MRI (T1[1.5 T])

Voxel-wise GM volume

RVR [Data splitting]

SZ & BD

SZ brainAGE (2.56 yrs) ↑ than BD (− 1.25 yrs) & HC (− 0.22 yrs.; both p = 0.01). BD comparable to HC (NS). SZ♂(3.37 yrs) ↑ than SZ♀(1.07 yrs.; no p-value)

bGender

[30]

1&2) Utrecht Schizophrenia Project, First-Episode Schizophrenia Research Program or GROUP (Longitudinal); 4) Cases & controls from exercise based RCT (both Netherlands)

1&2) SZ: n = 341, 29.5 ± 10.0 yrs.; HC: n = 386, 34.1 ± 11.8 yrs., at b/line (1-13 yrs. FU); 4) HC: n = 55; SZ: n = 60, 19-48 yrs.; Sex unknown

MRI (T1[1.5/3 T])

Voxel-wise GM density

SVR [Nested-LOO]

SZ & clinical factors

1&2) SZ GAP + 3.08 yrs. at b/line; ↑ at FU (change = 1.24 yrs.; crate = 1.36 yrs). Associated with severity & antipsychotic dose at FU (both p < 0.0025). Five yrs. post onset, crate ↓ from 2.5 to 1 yr (no p-value). Associated with severity, no. & duration of hospitalisations, & cumulative antipsychotics (all p <  0.0025) 4) SZ GAP + 5.59 yrs

None

[34]

Two independent samples of outpatients, & healthy adults from CAMH (Canada)

1) HC: n = 41; SSD: n = 81, 20–83 yrs.; BD: n = 53, 18-81 yrs.; 2) HCs: n = 30; SZ: n = 67, 40.6 ± 16.3 yrs.; Sex unknown

MRI (T1&DWI[1.5/3 T])

CT, FA, & with (1) or without (2) cognitive scores

RF

SDD & BD

1) SSD GAP (7.8 yrs) ↑ than HCs (0.67 yrs) & BDs (0.14 yrs.; both p = 0.001). BDs comparable to HCs (no p-value). 2) SZ GAP (6.12 yrs) ↑ than HC (1.8 yrs., p = 0.005)

None

[50]

BD cases from registry, Mood Disorders Program, or University treatment clinic; Controls recruited via advertisement (Canada)

Li: n = 41, 47.0 ± 13.8 (20.1–72.3) yrs., 23♀; Non-Li: n = 43, 48.2 ± 11.5 (26.9–74.4) yrs., 26♀; HC: n = 45, 42.3 ± 13.8 (20.8–70.9) yrs., 21♀

MRI (T1[1.5 T])

Voxel-wise WB volume

RVR [k-fold]

BD with/without Lithium; treatment response (Aldas < 7)

Non-Li brainAGE 4.10 & 4.96 yrs. ↑ than Li & HC, respectively (both p < 0.01). Li comparable to HC (NS). Li with partial prophylactic response ↓ than non-Li (p = 0.03)

bAge

  1. Bold = Results corrected for multiple comparisons; aBrain age adjustment; bModel adjustment; cCalculated by dividing the change in brain age by the time interval between imaging acquisitions; ADHD Attention-Deficit/Hyperactivity Disorder; AlcD Alcohol dependent patients; ARMS At-risk mental states for psychosis; ASD Autism spectrum disorder; AUD Alcohol Use Disorder; BD Bipolar Disorder; BEA Brain estimated age; B/line Baseline; BPD Borderline personality disorder; CA Chronological age; CAD Cannabis Use Disorder; CAMH Centre for Addiction and Mental Health; CNN Convolutional Neural Networks; CT Cortical thickness; E-ARMS Early at-risk mental states for psychosis; FA Fractional anisotropy; FEP First-episode psychosis; FePsych = Früherkennung von Psychosen database; FU Follow-up; GAD Generalised Anxiety Disorder; GM Grey matter; GROUP Genetic Risk and Outcome of Psychosis; HC Healthy controls; HR High risk; ID Intellectual disability; L-ARMS Late at-risk mental states for psychosis; LeAD Learning and Alcohol Dependence; LC Lifetime alcohol consumption; LI Bipolar Disorder with Lithium treatment; LOO Leave one out; LR Linear regression; MDD Major depression; MNI Montreal Neurological Institute registered image; MRI Magnetic resonance imaging; MRR Multilinear ridge regression; Non-Li Bipolar Disorder without Lithium treatment; NS Not significant; ORBIS Offspring Risk for Bipolar disorders Imaging Study; RCT Randomised controlled trial; RE-ARMS Recurrently ill at-risk mental states for psychosis; RO-ARMS Recent onset at-risk mental states for psychosis; RR Ridge regression; RVR Relevance vector regression; SES Socioeconomic status; SPECT Single-photon emission computerized tomography; SSD Schizophrenia Spectrum Disorder; SZ Schizophrenia; SVR Support vector regression; TICV Total intracranial volume; WB Whole brain; WM White matter; 99mTc-HMPAO Technetium-99 m hexamethylpropylene amine oxime