Nappi et al.2525. Nappi G, Sinforiani E, Martignoni E, Petraglia F, Facchinetti F, Rossi F, et al. Aging brain and dementias: changes in central opioids. Eur Neurol. 1988;28(4):217-20. https://doi.org/10.1159/000116270
https://doi.org/10.1159/000116270...
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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 |
Roelandts2626. Roelandts F. A single measurement of adrenocorticotrophic hormone in cerebrospinal fluid is of no value in the diagnosis of dementia. Age Ageing. 1989;18(5):337-8. https://doi.org/10.1093/ageing/18.5.337
https://doi.org/10.1093/ageing/18.5.337...
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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.2727. Mouradian MM, Farah Jr JM, Mohr E, Fabbrini G, O’Donohue TL, Chase TN. Spinal fluid CRF reduction in Alzheimer’s disease. Neuropeptides. 1986;8(4):393-400. https://doi.org/10.1016/0143-4179(86)90010-7
https://doi.org/10.1016/0143-4179(86)900...
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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.2828. Pomara N, Singh RR, Deptula D, LeWitt PA, Bissette G, Stanley M, et al. CSF corticotropin-releasing factor (CRF) in Alzheimer’s disease: its relationship to severity of dementia and monoamine metabolites. Biol Psychiatry. 1989;26(5):500-4. https://doi.org/10.1016/0006-3223(89)90071-1
https://doi.org/10.1016/0006-3223(89)900...
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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.2929. Martignoni E, Petraglia F, Costa A, Monzani A, Genazzani AR, Nappi G. Cerebrospinal fluid corticotropin-releasing factor levels and stimulation test in dementia of the Alzheimer type. J Clin Lab Anal. 1990;4(1):5-8. https://doi.org/10.1002/jcla.1860040104
https://doi.org/10.1002/jcla.1860040104...
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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.3030. Martignoni E, Petraglia F, Costa A, Bono G, Genazzani AR, Nappi G. Dementia of the Alzheimer type and hypothalamus-pituitary-adrenocortical axis: changes in cerebrospinal fluid corticotropin releasing factor and plasma cortisol levels. Acta Neurol Scand. 1990;81(5):452-6. https://doi.org/10.1111/j.1600-0404.1990.tb00994.x
https://doi.org/10.1111/j.1600-0404.1990...
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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.3131. Molchan SE, Hill JL, Martinez RA, Lawlor BA, Mellow AM, Rubinow DR, et al. CSF somatostatin in Alzheimer’s disease and major depression: relationship to hypothalamic-pituitary-adrenal axis and clinical measures. Psychoneuroendocrinology. 1993;18(7):509-19. https://doi.org/10.1016/0306-4530(93)90044-l
https://doi.org/10.1016/0306-4530(93)900...
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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.3232. Edvinsson L, Minthon L, Ekman R, Gustafson L. Neuropeptides in cerebrospinal fluid of patients with Alzheimer’s disease and dementia with frontotemporal lobe degeneration. Dementia. 1993;4(4):167-71. https://doi.org/10.1159/000107318
https://doi.org/10.1159/000107318...
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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.3333. Heilig M, Sjögren M, Blennow K, Ekman R, Wallin A. Cerebrospinal fluid neuropeptides in Alzheimer’s disease and vascular dementia. Biol Psychiatry. 1995;38(4):210-6. https://doi.org/10.1016/0006-3223(94)00239-y
https://doi.org/10.1016/0006-3223(94)002...
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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.3434. Suemaru S, Suemaru K, Kawai K, Miyata S, Nobukuni K, Ihara Y, et al. Cerebrospinal fluid corticotropin-releasing hormone in neurodegenerative diseases: reduction in spinocerebellar degeneration. Life Sci. 1995;57(24):2231-5. https://doi.org/10.1016/0024-3205(95)02215-5
https://doi.org/10.1016/0024-3205(95)022...
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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.3535. Peskind ER, Wilkinson CW, Petrie EC, Schellenberg GD, Raskind MA. Increased CSF cortisol in AD is a function of APOE genotype. Neurology. 2001;56(8):1094-8. https://doi.org/10.1212/wnl.56.8.1094
https://doi.org/10.1212/wnl.56.8.1094...
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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.3636. Gil-Bea FJ, Aisa B, Solomon A, Solas M, Mugueta M, Winblad B, et al. HPA axis dysregulation associated to apolipoprotein E4 genotype in Alzheimer’s disease. J Alzheimers Dis. 2010;22(3):829-38. https://doi.org/10.3233/jad-2010-100663
https://doi.org/10.3233/jad-2010-100663...
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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.3737. Czech C, Berndt P, Busch K, Schmitz O, Wiemer J, Most V, et al. Metabolite profiling of Alzheimer’s disease cerebrospinal fluid. PLoS One. 2012;7(2):e31501. https://doi.org/10.1371/journal.pone.0031501
https://doi.org/10.1371/journal.pone.003...
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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.3838. Popp J, Wolfsgruber S, Heuser I, Peters O, Hüll M, Schröder J, et al. Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer’s type. Neurobiol Aging. 2015;36(2):601-7. https://doi.org/10.1016/j.neurobiolaging.2014.10.031
https://doi.org/10.1016/j.neurobiolaging...
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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.3939. Johansson P, Almqvist EG, Wallin A, Johansson JO, Andreasson U, Blennow K, et al. Cerebrospinal fluid substance P concentrations are elevated in patients with Alzheimer’s disease. Neurosci Lett. 2015;609:58-62. https://doi.org/10.1016/j.neulet.2015.10.006
https://doi.org/10.1016/j.neulet.2015.10...
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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.4040. Wang Q, Zhou W, Zhang J; Alzheimer’s Disease Neuroimaging Initiative. Levels of cortisol in CSF are associated with SNAP-25 and tau pathology but not amyloid-ß. Front Aging Neurosci. 2018;10:383. https://doi.org/10.3389/fnagi.2018.00383
https://doi.org/10.3389/fnagi.2018.00383...
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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.4141. Wang LY, Raskind MA, Wilkinson CW, Shofer JB, Sikkema C, Szot P, et al. Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia. Int J Geriatr Psychiatry. 2018;33(5):763-8. https://doi.org/10.1002/gps.4856
https://doi.org/10.1002/gps.4856...
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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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Abbreviations: AD, Alzheimers’ disease; HPA axis, Hypothalamic-pituitary-adrenal axis; PVN, Paraventricular hypothalamic nucleus; CRH, Corticotropin-releasing hormone; BNST, Bed nucleus of the stria terminalis; POMC, Proopiomelanocortin; ACTH, Adrenocorticotropic hormone. Notes: (+) Indicates a stimulatory signal; (-) Indicates an inhibitory signal.