Cerebrospinal fluid levels of hypothalamic-pituitary-adrenal axis hormones in MCI and dementia due to Alzheimer’s disease: a systematic review

Duarte-Zambrano, Felipe; Barrero, Jorge A.; Mockus, Ismena

doi:10.1590/1980-5764-DN-2023-0031

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View and Review • Dement. neuropsychol. 17 • 2023 • https://doi.org/10.1590/1980-5764-DN-2023-0031 linkcopy

Cerebrospinal fluid levels of hypothalamic-pituitary-adrenal axis hormones in MCI and dementia due to Alzheimer’s disease: a systematic review

Níveis dos hormônios do eixo hipotálamo-pituitária-adrenal no líquido cefalorraquidiano de pacientes com CCL e demência devido à doença de Alzheimer: uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Underlying the neuropsychological manifestations of Alzheimer’s disease (AD), hypothalamic-pituitary-adrenal (HPA) axis dysregulation and subsequent hypercortisolemia have been proposed as major mechanisms driving AD progression from mild cognitive impairment (MCI) to the onset of dementia. Nonetheless, changes in cerebrospinal fluid (CSF) levels of HPA axis hormones remain controversial despite their potential in AD diagnosis and prognosis testing.

Objective: This study aimed to review the evidence of the variation in CSF levels of CRH, ACTH, and cortisol in subjects with mild cognitive impairment (MCI) and AD compared with subjects without cognitive disorders.

Methods: A systematic review was conducted in MEDLINE, EMBASE, and Web of Science databases on July 5, 2022.

Results: Seventeen observational studies were included. The results from the compiled investigations showed that individuals with AD exhibit a significant elevation of CSF cortisol levels which appear to correlate with the presence of the ApoE-ε4 allele, being higher in those homozygous for this allele. The variation of CSF CRH and ACTH levels in AD, on the other hand, is still inconclusive. Moreover, most studies found no significant difference in CSF cortisol levels in individuals with MCI compared to healthy subjects and patients with AD.

Conclusion: The findings gathered in this review disclose a significant elevation of CSF cortisol levels in AD. Future investigations are warranted to elucidate the potential use of CSF cortisol as a biomarker in AD-associated dementia.

Keywords:
Alzheimer Disease; Cerebrospinal Fluid; Corticotropin-Releasing Hormone; Adrenocorticotropic Hormone; Hydrocortisone

Reference	Population	Diagnostic criteria	Hormone	Main outcomes	Quality*
Nappi et al.²⁵	DAT group (n=20): 15 men and 5 women classified according to age at onset of AD: [1] presenile DAT [<65 years]: 14 subjects (57.3±5.5 years). Duration of disease: 2.9±1.9 years. [2] Senile DAT [≥65 years]: 6 subjects (77.5±5.9 years). Duration of disease: 3.1±2.7 years. Control group (n=12): 11 men and 1 woman (65.1±11.3 years (range 43-76 years)) under investigation for peripheral or spinal neurological diseases, with no evidence of other neurological diseases.	AD diagnosis: DSM-III criteria and exclusion of differential diagnoses. Assessment of dementia severity/cognitive status: CDR scale, MMSE, Information-Memory-Concentration test. No specific tests to assess the cognitive status of controls were described.	ACTH	CSF ACTH levels were significantly lower in subjects with DAT (4.2±3.8 fmol/mL) compared to controls (9.4±5.4 fmol/mL) (p<0.05). There was no significant difference between ACTH levels in CSF of subjects with senile DAT and presenile DAT.	High
Roelandts²⁶	AD group: 17 subjects with AD. Control group: 17 subjects (age and gender matched).	AD diagnosis: 1984 NINCDS-ADRDA criteria and DSM-III criteria. No specific tests to assess the cognitive status of controls were described.	ACTH	There was no significant difference in CSF ACTH levels between subjects with AD (mean 35 pg/ml) and controls (mean 36 pg/ml) (p>0.05).	Moderate
Mouradian et al.²⁷	AD group (n=16): 9 men and 7 women (63.0±1.7 years (range 53-80 years)). Subjects with moderate to severe dementia: Mattis dementia scale 105±5.7, full scale IQ 78±4.1, Wechsler memory scale 68±4. Duration of symptoms: 4.8±0.5 years (range 2-10 years). Control group (n=9): 6 men and 3 women (65.0±3.4 years (range 54 - 81 years)).	AD diagnosis: 1984 NINCDS-ADRDA criteria. Assessment of dementia severity/cognitive status: Mattis dementia scale, WAIS-R, full scale IQ, and Wechsler memory scale. No specific tests to assess the cognitive status of controls were described.	CRH	CSF CRH levels were significantly lower in AD subjects (43.0±2.5 pg/ml) versus control subjects (51.0±2.9 pg/ml) (p<0.05).	Moderate
Pomara et al.²⁸	AD group (n=15): 7 men and 8 women (61.7±2.5 years). Subjects with moderate dementia: MMSE of 16.9±3.5, GDS of 4.7±0.5, WAIS-R of 78.7±11.7. Control group (n=10): 3 males and 7 females (63.8±3.5 years).	AD diagnosis: 1984 NINCDS-ADRDA criteria and DSM-III criteria. Assessment of dementia severity/cognitive status: MMSE, GDS, WAIS-R, and GNI scale. No specific tests to assess the cognitive status of controls were described.	CRH	There was no significant difference in CSF CRH levels between subjects with AD (65.8±5.4 pg/ml) and controls (67.1±7.1 pg/ml) (p>0.05).	Moderate
Martignoni et al.²⁹	DAT group (n=16): 13 men and 3 women (65.8±8.18 years (range 56-81 years). Subjects with mild to moderate dementia: CDR scale between 1-2. Duration of symptoms: 3.5±2.8 years (range 0.5-10 years). Control group (n=21): 18 men and 3 women (65.2±0.4 years).	AD diagnosis: DSM-III criteria and exclusion of differential diagnoses. Assessment of dementia severity/cognitive status: CDR scale. No specific tests to assess the cognitive status of controls were described.	CRH	CSF CRH levels were significantly higher in subjects with AD (1.99±0.68 ng/mL (range 0.78-2.99 ng/mL)) compared to controls (0.90±0.57 ng/mL (range 0.18–2.45 ng/mL)) (p<0.01).	High
Martignoni et al.³⁰	DAT group (n=10): 8 men and 2 women (mean 63.8 years (range 48-78 years). Control group (n=11): 9 men and 2 women (67.3±6.9 years (range 55-79 years) who underwent lumbar puncture for diagnostic purposes, with no evidence of neurodegenerative diseases.	AD diagnosis: DSM-III criteria and exclusion of differential diagnoses. Assessment of dementia severity/cognitive status: CDR scale. No specific tests to assess the cognitive status of controls were described.	CRH	CSF CRH levels were significantly higher in subjects with AD (462±288 pg/ml (range 156–1071 pg/ml)) compared to controls (158±122 pg/ml (range 38-470 pg/ml)) (p<0.01). CSF CRH values in AD subjects were inversely correlated with MMSE score (r=-0.53; p<0.05), but not with CDR scale score or symptom duration.	High
Molchan et al.³¹	AD group (n=49): 26 men and 23 women (66.3±8.6 years). Age of disease onset at 62.1±8.9 years. Duration of disease: 4.2±2.6 years. Control group (n=13): 10 men and 3 women (63.5±10.0 years).	AD diagnosis: DSM-III criteria and exclusion of differential diagnoses. Assessment of dementia severity/cognitive status: CDR scale. Cognitive evaluation of controls: Wechsler Memory Scale.	CRH	There was no significant difference in CSF CRH levels between subjects with AD (76.7±26.1 pg/mL) and control subjects (87.1±15.8 pg/mL) (p>0.05).	Moderate
Edvinsson et al.³²	AD group: 39 subjects. No age reported. Control group: 11 subjects (range 23–58 years).	No diagnostic criteria for AD were specified. No specific tests to assess the cognitive status of controls were described.	CRH	There was no significant difference in CSF CRH levels in subjects with AD (9.0 pmol/L) compared to controls (15.5 pmol/L) (p>0.05).	Moderate
Heilig et al.³³	†AD group (n=36): 13 men and 23 women (71.7±0.8 years (range 57–79 years)). Control group (n=40): 18 men and 22 women (79±0.8 years (range 75–85 years)).	AD diagnosis: 1984 NINCDS-ADRDA criteria. Cognitive evaluation of controls: MMSE.	CRH	CSF CRH levels were significantly lower in subjects with AD versus control subjects (p<0.001). CSF CRH concentration values are not reported.	Moderate
Suemaru et al.³⁴	AD group: 16 subjects (79.1±4.8 years). Control group: 5 subjects (79.0±7.0 years).	No diagnostic criteria for AD were specified. Cognitive evaluation of controls: HDS.	CRH	CSF CRH levels were significantly lower in subjects with AD (43.9±4.1 pg/mL) versus control subjects (107.0±18.7 pg/mL) (p<0.01).	Low
Peskind et al.³⁵	†AD group (n=64): 44 men and 20 women (67±1 years (range 35-85 years)). Of these, 7 subjects had familial AD (5 of 7 with ApoE ε3/ε3 genotype). Control group (n=34): 22 men and 12 women (71±1 years (range 61–86 years)). Of these, 11 had ε3/ε4 genotype, 17 had ε3/ε3 genotype, and 6 had ε2/ε3 genotype.	AD diagnosis: 1984 NINCDS-ADRDA criteria. Familial AD diagnosis: mutations in presenilin 1 or 2. Cognitive evaluation of controls: MMSE and CDR.	Cortisol	CSF cortisol levels were significantly higher in subjects with AD (0.82±0.03 ng/mL) compared to control subjects (0.73±0.03 ng/mL) (p<0.05). CSF cortisol concentrations varied in relation to ApoE genotype; both in control subjects (ε3/4>ε3/3>ε2/3) and in subjects with AD (ε4/4>ε3/4>ε3/3) (p<0.05).	High
Gil-Bea et al.³⁶	AD group (n=27): 8 men and 19 women (68.92±9.11 years). Stable MCI group (n=26): 17 males and 9 females (61.64±10.31 years). Of these, 13 subjects had MCI with progression to AD (PMCI) (63.12±8.13 years). Control group (n=33): 14 men and 19 women with subjective cognitive impairment [complaints of cognitive impairment but no objective evidence of impairment] (57.51±6.42 years).	AD diagnosis: 1984 NINCDS-ADRDA and DSM-IV criteria. Evaluation of MCI: Criteria of the Key Symposium in Stockholm (2003). No difference between PMCI and stable MCI is stated. No specific tests to assess the cognitive status of controls were described.	Cortisol	CSF cortisol levels were significantly higher in subjects with AD compared to the control group (p<0.01). In the evaluation according to ApoE genotype, the difference in CSF cortisol was significant in ApoE ε4 carriers (p<0.05) but not in ApoE ε4 non-carriers (p=0.25). Subjects with AD and at least one ApoE-ε4 allele exhibited higher CSF cortisol levels compared to AD patients without ApoE ε4 alleles.	High
Czech et al.³⁷	AD group with mild to moderate dementia [MMSE: >22] (n=53): 23 men and 30 women (69.7±69.5 years). AD group with moderate to severe dementia [MMSE: 14-22] (n=26): 12 men and 14 women (69.6±10.1 years). Control group (n=51): 24 men and 27 women (63.1±67.7 years).	AD diagnosis: 1984 NINCDS-ADRDA and DSM-IV criteria. The Hachinski ischemia scale was used to exclude vascular dementia. Assessment of dementia severity/cognitive status: MMSE. No specific tests to assess the cognitive status of controls were described.	Cortisol	CSF cortisol levels were significantly higher in subjects with mild to moderate AD (mean 6.64 ng/mL) and moderate to severe AD (mean 7.06 ng/mL) compared to control subjects (mean 5.24 ng/mL) (p<0.05). No significant difference was evident between CSF cortisol levels of patients with mild to moderate AD compared to the moderate to severe AD group.	Moderate
Popp et al.³⁸	†AD group (n=105): 42 men and 63 women (72.95±7.42 years). †MCI-AD group (n=102): 60 men and 42 women (67.35±7.92 years). †Other type of MCI group (n=45): 32 men and 13 women (66.22±8.16 years). Control group (n=37): 21 men and 16 women (64.35±8.08 years) with indication for lumbar puncture for neurological conditions other than dementia.	AD diagnosis: 1984 NINCDS-ADRDA criteria. Evaluation of MCI: Key Symposium in Stockholm (2003) criteria, CERAD-NP test, TMTs A and B, and Bayer Activities of Daily Living. MCI-AD diagnosis: Memory impairment present and no evidence of cerebrovascular disease on physical examination or MRI. Diagnosis of MCI-O: Cases that did not meet MCI-AD criteria. Assessment of dementia severity/cognitive status: CDR scale. Cognitive evaluation of controls: CDR, CERAD-NP test, and TMTs A and B.	Cortisol	CSF cortisol levels were significantly higher in subjects with AD (0.555±0.387 mg/dL) and MCI-AD (0.493±0.480 mg/dL) compared to control subjects (0.252±0.251 mg/dL) (p<0.05). Subjects with MCI-AD exhibited significantly higher CSF cortisol levels versus subjects with MCI-O (0.239±0.218 mg/dL) (p<0.05). AD subjects exhibited significantly higher CSF cortisol levels versus MCI-O subjects (p<0.01). CSF cortisol levels did not differ significantly between: [1] MCI-AD and AD dementia, [2] MCI-O and control group.	High
Johansson et al.³⁹	AD group (n=32): 15 men and 17 women (75 years (range 71-77 years)). Control group (n=20): 5 men and 8 women (75 years (range 70-78 years)).	AD diagnosis: 1984 NINCDS-ADRDA and DSM-IV criteria. Assessment of dementia severity/cognitive status: MMSE.	Cortisol	There was no significant difference in CSF cortisol levels between subjects with AD (6989 pg/mL (6289–7970)) and control subjects (6665 pg/mL (5705–7450)) (p>0.05).	High
Wang et al.⁴⁰	Data extracted from the ADNI database (n=310): [1] 69 subjects with mild AD (74.9±7.6 years). [2] 149 subjects with MCI (74.8±7.2 years). [3] 92 controls (75.7±5.4 years). More than 50% of patients with MCI and AD were carriers of at least one ApoE ε4 allele.	The diagnosis of AD and MCI was assumed based on the classification of the subjects in the ADNI database. Assessment of dementia severity/cognitive status of both cases and controls: MMSE y Rey Auditory Verbal Learning Test.	Cortisol	There was no significant difference in CSF cortisol levels between subjects with AD (15.7±6.2 ng/mL), MCI (16.8±5.8 ng/mL), and controls (15.6±6.2 ng/mL) (p>0.05).	High
Wang et al.⁴¹	AD group (n=94): 49 men and 45 women (71.2±9.3 years (range 52–88 years)). aMCI group (n=22): 13 men and 9 women (72.3±8.2 years (range 56–84 years)). Control group (n=305): [1] <50 years (n=97): 53 men and 44 women (33.6±9.4 years (range 20–49 years)). [2] ≥50 years (n=208): 86 men and 122 women (66.7±10.0 years (range 50–100 years)).	AD diagnosis: 1984 NINCDS-ADRDA criteria. aMCI diagnosis: CDR scale and Logical Memory score. Assessment of dementia severity/cognitive status of both cases and controls: MMSE, CDR.	Cortisol	CSF cortisol levels showed a significant difference between the groups of subjects with AD, aMCI and controls; CSF cortisol concentration was significantly higher by 1.6±0.4 ng/mL in the AD group compared to control subjects (p<0.001). CSF cortisol levels in the aMCI group were higher than controls by 0.8±0.7 ng/mL and lower than those in the AD group by the same amount (0.8±0.7 ng/mL). Neither difference was significant (p>0.05).	High

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Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br

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[tfn1] Abbreviations: DAT, dementia of Alzheimer’s disease type; AD, Alzheimer’s disease; DSM-III, Diagnostic and Statistical Manual of Mental Disorders Third Edition; CDR, Clinical dementia rating scale; MMSE, Mini mental state exam; ACTH, adrenocorticotropic hormone; CSF, cerebrospinal fluid; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s disease; WAIS-R, Wechsler adult intelligence scale-revised; CRH, corticotropin-releasing hormone; GDS, Global deterioration scale; GNI, Global neuropsychological impairment scale; HDS, Hasegawa Dementia Scale; ApoE, apolipoprotein E gene; MCI, mild cognitive impairment; PMCI, mild cognitive impairment with progression to Alzheimer’s disease; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; MCI-AD, Alzheimer’s disease type mild cognitive impairment; CERAD-NP test, consortium to establish a registry for Alzheimer’s disease test; TMTs A and B, trial making tests A and B; ADNI, Alzheimer’s disease Neuroimaging Initiative; aMCI, amnestic mild cognitive impairment. Notes: ^*Quality assessed with the Newcastle-Ottawa scale; ^†Significant difference in age compared with controls.