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Major Depression May Lead to Elevations in Potentially Neurotoxic Amyloid Beta Species Independently of Alzheimer Disease
Accepted Manuscript Title: Major Depression May Lead to Elevations in Potentially Neurotoxic Amyloid Beta Species Independently of Alzheimer's Disease Author: Nunzio Pomara, Davide Bruno PII: DOI: Reference:
S1064-7481(16)30108-7 http://dx.doi.org/doi: 10.1016/j.jagp.2016.05.003 AMGP 613
To appear in:
The American Journal of Geriatric Psychiatry
Received date: Accepted date:
3-5-2016 4-5-2016
Please cite this article as: Nunzio Pomara, Davide Bruno, Major Depression May Lead to Elevations in Potentially Neurotoxic Amyloid Beta Species Independently of Alzheimer's Disease, The American Journal of Geriatric Psychiatry (2016), http://dx.doi.org/doi: 10.1016/j.jagp.2016.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Major depression may lead to elevations in potentially neurotoxic amyloid beta species independently of Alzheimer’s disease
Nunzio Pomara, MD1,2, and Davide Bruno, PhD3 Affiliation: 1Nathan Kline Institute, Orangeburg, NY; 2NYU Cohen Veterans Center, New York, NY, USA 3
Liverpool John Moores University, Liverpool, UK
Corresponding address: 140 Old Orangeburg Road, Bldg.35, Orangeburg, NY 10962 Phone: 845-398-5579 Email:[email protected] Conflict of interest: Dr. Pomara, the author, has a potential conflict of interest related to this work. Keywords: major depressive disorder, amyloid-beta disturbances, AD risk
Page 1 of 8
2 Monomeric forms of soluble amyloid peptides (Aβ40 and Aβ42) arise from proteolytic cleavage of the APP through the action of beta and gamma secretases. In the brain, they are physiological products of neuronal activity. An increase in their levels in the Interstitial Fluid (ISF), especially of the longer Aβ42 peptide, which has greater tendency to form potentially neurotoxic oligomeric forms and then fibrils, which aggregate into senile plaques, is believed to be an early, necessary event in the pathogenesis of Alzheimer’s disease (AD). In cases of familial autosomal forms of AD this occurs through increases in production, whereas in sporadic AD, which accounts for most of the cases in the elderly, it mostly follows decreased clearance. The paper by Inoue and colleagues in this issue of the American Journal of Geriatric Psychiatry is an important addition to the emerging literature showing that depression, a disorder which has been reported to be associated with increased risk for AD and may or may not represent a prodromal phase, is accompanied by disturbances in Aβ metabolism. Results described in three recent reviews and a meta-analysis 1,2,3,4, while still conflicting and largely limited to peripheral indices, do provide support for the notion that a subset of elderly depressives show a pattern of in vivo Aβ abnormalities similar to those found in AD. However, this conclusion seems at odds with results from post-mortem studies in cognitively intact elderly, which have found no relationship between AD brain pathology and major depression or depressive symptoms 5,6. Interestingly, in one of these studies 6, increased density of amyloid plaques was associated with the diagnosis of MDD during the approximate 8-year evaluation period. Brain amyloid plaques are known to emerge in the preclinical phase of AD, years, if not decades, before the development of widespread tau pathology and neurodegeneration. Thus, it is possible that a relationship between depression and other features of AD-related pathology would have emerged if the follow up period had been longer. The amyloid cascade hypothesis posits that cerebral amyloidosis is necessary but not sufficient for AD, and it is believed to facilitate, through mechanisms that are not completely understood, the hyperphosphorylation of the intracellular microtubule-associated protein tau, which results in the formation of paired helical filaments and
Page 2 of 8
3 NFTs. In normal aging, NFTs are limited to the entorhinal cortex, but the emergence of neurodegeneration and cognitive decline in AD coincides with the spread of these lesions in the neocortex and limbic areas. Thus, future studies of amyloid beta indices in depression should include measures of tau pathology using emerging plasma assays and brain tau PET tracers. A major unique contribution of Inoue and colleagues’ investigation is that, in contrast to most of the prior studies, this study included younger individuals with depression. This is important because in elderly depressives, the possible effects of depression on Aβ metabolism are very difficult, if not impossible, to distinguish from those which may be due to preclinical or prodromal AD, but this is not likely to be true in younger cohorts. Importantly, Inoue et al. found that while serum levels of albumin-bound Aβ were significantly decreased only in elderly depressives which they speculated might have reflected AD pathologies, a reduction in serum Aβ42 and an increase in the serum Aβ40/Aβ42 ratio were found not only in older depressives but also in a younger population. Additionally, an earlier age of onset of first depressive episode was associated with an increased ratio. This suggests that the presence of underlying preclinical or prodromal AD is unlikely to explain the latter results, and that factors which are intrinsic to depression should be considered as a possible basis for the altered Aβ metabolism observed in depressives. Therefore, depression may lead to potentially neurotoxic Aβ disturbances independently of Alzheimer’s disease pathology. A major limitation of the current report is that it was not designed to address how changes in peripheral Aβ indices might relate to cerebrospinal fluid (CSF) and brain amyloid beta indices. This is a critical issue for future studies since the precise origin of circulating Aβ is not known, although evidence points to a CNS contribution and that Aβ42 and Aβ40 levels, or their ratios, might reflect brain amyloid burden as determined by PET scan7. Thus, it is imperative for future studies of serum/plasma Aβ indices in depression to also include simultaneous measurement of brain amyloid burden using various PET amyloid tracers. CSF Aβ42 levels, which are also sensitive to increases in diffuse amyloid plaques not detected by PET, should also be determined
Page 3 of 8
4 as well as Aβ40, whose reduction might help to gauge the extent of its preferential deposition in cerebral blood vessels and possible cerebral amyloid angiopathy which is especially pertinent to elderly depression for which both vascular factors and AD have been implicated. The notion that AD-independent mechanisms may contribute to elevated circulating Aβ levels in elderly individuals with recurrent major depressive disorder was first suggested by my colleague and I 8; to our knowledge, only one prior study 9 had determined CSF Aβ levels in cognitively-intact elderly with depression, and tested the hypothesis that they would have normal levels that would distinguish depression from AD. Interestingly, the depressed group had comparable Aβ levels to the AD group. However, the possibility that the two disorders might share common Aβ abnormality was not considered at that stage. If not pre-clinical or prodromal AD, then what factors could result in Aβ disturbances in individuals with depression across all ages? Neither the current report nor existing literature have considered so far the potential role of AD-independent factors in Aβ dynamics in depression. Increased platelet activation has been described in depression and implicated in the increased cardiovascular risk associated with this disorder. Platelet activation is also believed to be a major source of circulating soluble serum plasma Aβ, especially Aβ40. Because of the presence of a bidirectional receptor-mediated active transport of Aβ peptides across the BBB, primary increases in circulating Aβ levels are likely to influence ISF and parenchymal brain concentrations, and vice versa. In our previous study 10, we found no evidence that this factor contributed to plasma Aβ levels in elderly depressives. However, our study was not designed to specifically address this question since our depressed group was not limited to those with recurrent depression and showed no evidence of increased platelet activation. Therefore future investigations should be carried out using more targeted populations and more comprehensive measures of platelet activation to address this question. A number of reports in non-depressed populations have found associations between reductions in self-ratings of poor sleep quality and increased brain amyloid burden 11,12. The
Page 4 of 8
5 underlying mechanisms for this association are not fully understood, but preclinical evidence suggests that neuronal activity, which is a major cause of Aβ production in the brain, is increased during periods of wakefulness and decreased during sleep, especially slow wave sleep. Since insomnia and poor quality of sleep are quite common in depression and may actually be important risk factors, it is possible that they might contribute to increased Aβ production in this disorder. Sleep deprivation has also been shown to interfere with a glia-mediated glymphatic clearance mechanism for toxic substances in the brain, including Aβ. Thus given reports of glia abnormalities in depression, it is possible that they could accentuate any insomnia-related reduction in glymphatic Aβ clearance in depression. In preclinical experiments, both acute and chronic stress, which are commonly experienced by depressive individuals, have also been shown to have very powerful effects in increasing neuronal soluble Aβ production and ICS levels as well as senile plaques, both through CRF-dependent and independent mechanisms 13. Independently from the increased risk for AD associated with cerebral amyloidosis, increases in potentially neurotoxic soluble Aβ, especially Aβ42 and aggregated forms associated with the aforementioned factors, have been shown to have profound deleterious effects on major neurotransmitter systems implicated in depression and to induce a depressive state in rodents 14. Thus, they could contribute to a subtype of depression potentially responsive to relatively safe emerging amyloid-β lowering strategies presently undergoing trials not only for the treatment of AD, but also for its prevention in healthy older adults with cerebral amyloidosis or the APOEe4e4 genotype, which is likely to be a proxy for increased brain amyloid burden 15-16. Elderly individuals with recurrent depression and significant depressive symptoms are currently and understandably excluded from these trials. However, based on the aforementioned considerations, cognitively intact elderly depressives may be especially at increased risk for cerebral amyloidosis and AD, or may already have preclinical AD. Thus they represent a potential enriched population for the amyloid beta-based interventions for the prevention of progressive cognitive decline and
Page 5 of 8
6 AD. Such studies might also provide important data if the approach can reduce depressive symptoms and relapse in this population. The success which has been achieved in conjunction with the ADNI study in identifying AD biomarkers among healthy elderly individuals required the use of a uniform protocol across many centers; a large sample size; a multimodal approach using peripheral and central candidate biomarkers; multiple neuroimaging modalities; and the use of the same pre-analytic and analytic procedures for collection, storage and analyses of blood and CSF samples. We believe that the same approach would also greatly benefit research tackling depression, including issues raised by this report and commentary.
Page 6 of 8
7 References 1. Osorio RS, Gumb T, Pomara N. Soluble amyloid-β levels and late-life depression. Curr Pharm Des. 2014;20(15):2547-54. 2. Abbasowa L, Heegaard NH. A systematic review of amyloid-β peptides as putative mediators of the association between affective disorders and Alzheimer׳s disease. J Affect Disord. 2014 Oct;168:167-83. doi: 10.1016/j.jad.2014.06.050. Epub 2014 Jul 6. Review. 3. Harrington KD, Lim YY, Gould E, Maruff P. Amyloid-beta and depression in healthy older adults: a systematic review. Aust N Z J Psychiatry. 2015 Jan;49(1):36-46. doi: 10.1177/0004867414557161. Epub 2014 Nov 20. 4. Nascimento KK, Silva KP, Malloy-Diniz LF, Butters MA, Diniz BS. Plasma and cerebrospinal fluid amyloid-β levels in late-life depression: A systematic review and meta-analysis. J Psychiatr Res. 2015 Oct;69:35-41. doi: 10.1016/j.jpsychires.2015.07.024. Epub 2015 Jul 26. 5. Wilson RS, Capuano AW, Boyle PA, Hoganson GM, Hizel LP, Shah RC, Nag S, Schneider JA, Arnold SE, Bennett DA. Clinical-pathologic study of depressive symptoms and cognitive decline in old age. Neurology. 2014 Aug 19;83(8):702-9. doi: 10.1212/WNL.0000000000000715. Epub 2014 Jul 30. 6. Wilson RS, Boyle PA, Capuano AW, Shah RC, Hoganson GM, Nag S, Bennett DA. Late-life depression is not associated with dementia-related pathology. Neuropsychology. 2016 Feb;30(2):135-42. doi: 10.1037/neu0000223. 7. Devanand DP, Schupf N, Stern Y, Parsey R, Pelton GH, Mehta P, Mayeux R. Plasma Aβ and PET PiB binding are inversely related in mild cognitive impairment. Neurology. 2011 Jul 12;77(2):125-31. 8. Pomara N, Murali Doraiswamy P. Does increased platelet release of Abeta peptide contribute to brain abnormalities in individuals with depression? Med Hypotheses. 2003 May;60(5):640-3. 9. Hock C, Golombowski S, Müller-Spahn F, Naser W, Beyreuther K, Mönning U, Schenk D, Vigo-Pelfrey C, Bush AM, Moir R, Tanzi RE, Growdon JH, Nitsch RM. Cerebrospinal fluid levels of amyloid precursor protein and amyloid beta-peptide in Alzheimer's disease and major depression - inverse correlation with dementia severity. Eur Neurol. 1998;39(2):111-8. 10. Pomara N, Doraiswamy PM, Willoughby LM, Roth AE, Mulsant BH, Sidtis JJ, Mehta PD, Reynolds CF 3rd, Pollock BG. Elevation in plasma Abeta42 in geriatric depression: a pilot study. Neurochem Res. 2006 Mar;31(3):341-9. Epub 2006 Apr 1. 11. Branger P, Arenaza-Urquijo EM, Tomadesso C, Mézenge F, André C, de Flores R, Mutlu J, de La Sayette V, Eustache F, Chételat G, Rauchs G. Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood. Neurobiol Aging. 2016 May;41:107-14. doi: 10.1016/j.neurobiolaging.2016.02.009. Epub 2016 Feb 17.
Page 7 of 8
8 12. Sprecher KE, Bendlin BB, Racine AM, Okonkwo OC, Christian BT, Koscik RL, Sager MA, Asthana S, Johnson SC, Benca RM. Amyloid burden is associated with self-reported sleep in nondemented late middle-aged adults. Neurobiol Aging. 2015 Sep;36(9):2568-76. doi: 10.1016/j.neurobiolaging.2015.05.004. Epub 2015 May 14. 13. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. doi: 10.1126/science.1180962. Epub 2009 Sep 24. 14. Colaianna M, Tucci P, Zotti M, Morgese MG, Schiavone S, Govoni S, Cuomo V, Trabace L. Soluble beta amyloid(1-42): a critical player in producing behavioural and biochemical changes evoking depressive-related state? Br J Pharmacol. 2010 Apr;159(8):1704-15. doi: 10.1111/j.1476-5381.2010.00669.x. Epub 2010 Mar 9. 15. Pomara N, Sidtis J. Possible therapeutic implication of Abeta disturbances in depression. Int J Geriatr Psychiatry. 2007 Sep;22(9):931-2; author reply 930. 16. Pomara N, Sidtis JJ. Brain neurotoxic amyloid-beta peptides: their potential role in the pathophysiology of depression and as molecular therapeutic targets. Br J Pharmacol. 2010 Oct;161(4):768-70.
Page 8 of 8
S1064-7481(16)30108-7 http://dx.doi.org/doi: 10.1016/j.jagp.2016.05.003 AMGP 613
To appear in:
The American Journal of Geriatric Psychiatry
Received date: Accepted date:
3-5-2016 4-5-2016
Please cite this article as: Nunzio Pomara, Davide Bruno, Major Depression May Lead to Elevations in Potentially Neurotoxic Amyloid Beta Species Independently of Alzheimer's Disease, The American Journal of Geriatric Psychiatry (2016), http://dx.doi.org/doi: 10.1016/j.jagp.2016.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Major depression may lead to elevations in potentially neurotoxic amyloid beta species independently of Alzheimer’s disease
Nunzio Pomara, MD1,2, and Davide Bruno, PhD3 Affiliation: 1Nathan Kline Institute, Orangeburg, NY; 2NYU Cohen Veterans Center, New York, NY, USA 3
Liverpool John Moores University, Liverpool, UK
Corresponding address: 140 Old Orangeburg Road, Bldg.35, Orangeburg, NY 10962 Phone: 845-398-5579 Email:[email protected] Conflict of interest: Dr. Pomara, the author, has a potential conflict of interest related to this work. Keywords: major depressive disorder, amyloid-beta disturbances, AD risk
Page 1 of 8
2 Monomeric forms of soluble amyloid peptides (Aβ40 and Aβ42) arise from proteolytic cleavage of the APP through the action of beta and gamma secretases. In the brain, they are physiological products of neuronal activity. An increase in their levels in the Interstitial Fluid (ISF), especially of the longer Aβ42 peptide, which has greater tendency to form potentially neurotoxic oligomeric forms and then fibrils, which aggregate into senile plaques, is believed to be an early, necessary event in the pathogenesis of Alzheimer’s disease (AD). In cases of familial autosomal forms of AD this occurs through increases in production, whereas in sporadic AD, which accounts for most of the cases in the elderly, it mostly follows decreased clearance. The paper by Inoue and colleagues in this issue of the American Journal of Geriatric Psychiatry is an important addition to the emerging literature showing that depression, a disorder which has been reported to be associated with increased risk for AD and may or may not represent a prodromal phase, is accompanied by disturbances in Aβ metabolism. Results described in three recent reviews and a meta-analysis 1,2,3,4, while still conflicting and largely limited to peripheral indices, do provide support for the notion that a subset of elderly depressives show a pattern of in vivo Aβ abnormalities similar to those found in AD. However, this conclusion seems at odds with results from post-mortem studies in cognitively intact elderly, which have found no relationship between AD brain pathology and major depression or depressive symptoms 5,6. Interestingly, in one of these studies 6, increased density of amyloid plaques was associated with the diagnosis of MDD during the approximate 8-year evaluation period. Brain amyloid plaques are known to emerge in the preclinical phase of AD, years, if not decades, before the development of widespread tau pathology and neurodegeneration. Thus, it is possible that a relationship between depression and other features of AD-related pathology would have emerged if the follow up period had been longer. The amyloid cascade hypothesis posits that cerebral amyloidosis is necessary but not sufficient for AD, and it is believed to facilitate, through mechanisms that are not completely understood, the hyperphosphorylation of the intracellular microtubule-associated protein tau, which results in the formation of paired helical filaments and
Page 2 of 8
3 NFTs. In normal aging, NFTs are limited to the entorhinal cortex, but the emergence of neurodegeneration and cognitive decline in AD coincides with the spread of these lesions in the neocortex and limbic areas. Thus, future studies of amyloid beta indices in depression should include measures of tau pathology using emerging plasma assays and brain tau PET tracers. A major unique contribution of Inoue and colleagues’ investigation is that, in contrast to most of the prior studies, this study included younger individuals with depression. This is important because in elderly depressives, the possible effects of depression on Aβ metabolism are very difficult, if not impossible, to distinguish from those which may be due to preclinical or prodromal AD, but this is not likely to be true in younger cohorts. Importantly, Inoue et al. found that while serum levels of albumin-bound Aβ were significantly decreased only in elderly depressives which they speculated might have reflected AD pathologies, a reduction in serum Aβ42 and an increase in the serum Aβ40/Aβ42 ratio were found not only in older depressives but also in a younger population. Additionally, an earlier age of onset of first depressive episode was associated with an increased ratio. This suggests that the presence of underlying preclinical or prodromal AD is unlikely to explain the latter results, and that factors which are intrinsic to depression should be considered as a possible basis for the altered Aβ metabolism observed in depressives. Therefore, depression may lead to potentially neurotoxic Aβ disturbances independently of Alzheimer’s disease pathology. A major limitation of the current report is that it was not designed to address how changes in peripheral Aβ indices might relate to cerebrospinal fluid (CSF) and brain amyloid beta indices. This is a critical issue for future studies since the precise origin of circulating Aβ is not known, although evidence points to a CNS contribution and that Aβ42 and Aβ40 levels, or their ratios, might reflect brain amyloid burden as determined by PET scan7. Thus, it is imperative for future studies of serum/plasma Aβ indices in depression to also include simultaneous measurement of brain amyloid burden using various PET amyloid tracers. CSF Aβ42 levels, which are also sensitive to increases in diffuse amyloid plaques not detected by PET, should also be determined
Page 3 of 8
4 as well as Aβ40, whose reduction might help to gauge the extent of its preferential deposition in cerebral blood vessels and possible cerebral amyloid angiopathy which is especially pertinent to elderly depression for which both vascular factors and AD have been implicated. The notion that AD-independent mechanisms may contribute to elevated circulating Aβ levels in elderly individuals with recurrent major depressive disorder was first suggested by my colleague and I 8; to our knowledge, only one prior study 9 had determined CSF Aβ levels in cognitively-intact elderly with depression, and tested the hypothesis that they would have normal levels that would distinguish depression from AD. Interestingly, the depressed group had comparable Aβ levels to the AD group. However, the possibility that the two disorders might share common Aβ abnormality was not considered at that stage. If not pre-clinical or prodromal AD, then what factors could result in Aβ disturbances in individuals with depression across all ages? Neither the current report nor existing literature have considered so far the potential role of AD-independent factors in Aβ dynamics in depression. Increased platelet activation has been described in depression and implicated in the increased cardiovascular risk associated with this disorder. Platelet activation is also believed to be a major source of circulating soluble serum plasma Aβ, especially Aβ40. Because of the presence of a bidirectional receptor-mediated active transport of Aβ peptides across the BBB, primary increases in circulating Aβ levels are likely to influence ISF and parenchymal brain concentrations, and vice versa. In our previous study 10, we found no evidence that this factor contributed to plasma Aβ levels in elderly depressives. However, our study was not designed to specifically address this question since our depressed group was not limited to those with recurrent depression and showed no evidence of increased platelet activation. Therefore future investigations should be carried out using more targeted populations and more comprehensive measures of platelet activation to address this question. A number of reports in non-depressed populations have found associations between reductions in self-ratings of poor sleep quality and increased brain amyloid burden 11,12. The
Page 4 of 8
5 underlying mechanisms for this association are not fully understood, but preclinical evidence suggests that neuronal activity, which is a major cause of Aβ production in the brain, is increased during periods of wakefulness and decreased during sleep, especially slow wave sleep. Since insomnia and poor quality of sleep are quite common in depression and may actually be important risk factors, it is possible that they might contribute to increased Aβ production in this disorder. Sleep deprivation has also been shown to interfere with a glia-mediated glymphatic clearance mechanism for toxic substances in the brain, including Aβ. Thus given reports of glia abnormalities in depression, it is possible that they could accentuate any insomnia-related reduction in glymphatic Aβ clearance in depression. In preclinical experiments, both acute and chronic stress, which are commonly experienced by depressive individuals, have also been shown to have very powerful effects in increasing neuronal soluble Aβ production and ICS levels as well as senile plaques, both through CRF-dependent and independent mechanisms 13. Independently from the increased risk for AD associated with cerebral amyloidosis, increases in potentially neurotoxic soluble Aβ, especially Aβ42 and aggregated forms associated with the aforementioned factors, have been shown to have profound deleterious effects on major neurotransmitter systems implicated in depression and to induce a depressive state in rodents 14. Thus, they could contribute to a subtype of depression potentially responsive to relatively safe emerging amyloid-β lowering strategies presently undergoing trials not only for the treatment of AD, but also for its prevention in healthy older adults with cerebral amyloidosis or the APOEe4e4 genotype, which is likely to be a proxy for increased brain amyloid burden 15-16. Elderly individuals with recurrent depression and significant depressive symptoms are currently and understandably excluded from these trials. However, based on the aforementioned considerations, cognitively intact elderly depressives may be especially at increased risk for cerebral amyloidosis and AD, or may already have preclinical AD. Thus they represent a potential enriched population for the amyloid beta-based interventions for the prevention of progressive cognitive decline and
Page 5 of 8
6 AD. Such studies might also provide important data if the approach can reduce depressive symptoms and relapse in this population. The success which has been achieved in conjunction with the ADNI study in identifying AD biomarkers among healthy elderly individuals required the use of a uniform protocol across many centers; a large sample size; a multimodal approach using peripheral and central candidate biomarkers; multiple neuroimaging modalities; and the use of the same pre-analytic and analytic procedures for collection, storage and analyses of blood and CSF samples. We believe that the same approach would also greatly benefit research tackling depression, including issues raised by this report and commentary.
Page 6 of 8
7 References 1. Osorio RS, Gumb T, Pomara N. Soluble amyloid-β levels and late-life depression. Curr Pharm Des. 2014;20(15):2547-54. 2. Abbasowa L, Heegaard NH. A systematic review of amyloid-β peptides as putative mediators of the association between affective disorders and Alzheimer׳s disease. J Affect Disord. 2014 Oct;168:167-83. doi: 10.1016/j.jad.2014.06.050. Epub 2014 Jul 6. Review. 3. Harrington KD, Lim YY, Gould E, Maruff P. Amyloid-beta and depression in healthy older adults: a systematic review. Aust N Z J Psychiatry. 2015 Jan;49(1):36-46. doi: 10.1177/0004867414557161. Epub 2014 Nov 20. 4. Nascimento KK, Silva KP, Malloy-Diniz LF, Butters MA, Diniz BS. Plasma and cerebrospinal fluid amyloid-β levels in late-life depression: A systematic review and meta-analysis. J Psychiatr Res. 2015 Oct;69:35-41. doi: 10.1016/j.jpsychires.2015.07.024. Epub 2015 Jul 26. 5. Wilson RS, Capuano AW, Boyle PA, Hoganson GM, Hizel LP, Shah RC, Nag S, Schneider JA, Arnold SE, Bennett DA. Clinical-pathologic study of depressive symptoms and cognitive decline in old age. Neurology. 2014 Aug 19;83(8):702-9. doi: 10.1212/WNL.0000000000000715. Epub 2014 Jul 30. 6. Wilson RS, Boyle PA, Capuano AW, Shah RC, Hoganson GM, Nag S, Bennett DA. Late-life depression is not associated with dementia-related pathology. Neuropsychology. 2016 Feb;30(2):135-42. doi: 10.1037/neu0000223. 7. Devanand DP, Schupf N, Stern Y, Parsey R, Pelton GH, Mehta P, Mayeux R. Plasma Aβ and PET PiB binding are inversely related in mild cognitive impairment. Neurology. 2011 Jul 12;77(2):125-31. 8. Pomara N, Murali Doraiswamy P. Does increased platelet release of Abeta peptide contribute to brain abnormalities in individuals with depression? Med Hypotheses. 2003 May;60(5):640-3. 9. Hock C, Golombowski S, Müller-Spahn F, Naser W, Beyreuther K, Mönning U, Schenk D, Vigo-Pelfrey C, Bush AM, Moir R, Tanzi RE, Growdon JH, Nitsch RM. Cerebrospinal fluid levels of amyloid precursor protein and amyloid beta-peptide in Alzheimer's disease and major depression - inverse correlation with dementia severity. Eur Neurol. 1998;39(2):111-8. 10. Pomara N, Doraiswamy PM, Willoughby LM, Roth AE, Mulsant BH, Sidtis JJ, Mehta PD, Reynolds CF 3rd, Pollock BG. Elevation in plasma Abeta42 in geriatric depression: a pilot study. Neurochem Res. 2006 Mar;31(3):341-9. Epub 2006 Apr 1. 11. Branger P, Arenaza-Urquijo EM, Tomadesso C, Mézenge F, André C, de Flores R, Mutlu J, de La Sayette V, Eustache F, Chételat G, Rauchs G. Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood. Neurobiol Aging. 2016 May;41:107-14. doi: 10.1016/j.neurobiolaging.2016.02.009. Epub 2016 Feb 17.
Page 7 of 8
8 12. Sprecher KE, Bendlin BB, Racine AM, Okonkwo OC, Christian BT, Koscik RL, Sager MA, Asthana S, Johnson SC, Benca RM. Amyloid burden is associated with self-reported sleep in nondemented late middle-aged adults. Neurobiol Aging. 2015 Sep;36(9):2568-76. doi: 10.1016/j.neurobiolaging.2015.05.004. Epub 2015 May 14. 13. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. doi: 10.1126/science.1180962. Epub 2009 Sep 24. 14. Colaianna M, Tucci P, Zotti M, Morgese MG, Schiavone S, Govoni S, Cuomo V, Trabace L. Soluble beta amyloid(1-42): a critical player in producing behavioural and biochemical changes evoking depressive-related state? Br J Pharmacol. 2010 Apr;159(8):1704-15. doi: 10.1111/j.1476-5381.2010.00669.x. Epub 2010 Mar 9. 15. Pomara N, Sidtis J. Possible therapeutic implication of Abeta disturbances in depression. Int J Geriatr Psychiatry. 2007 Sep;22(9):931-2; author reply 930. 16. Pomara N, Sidtis JJ. Brain neurotoxic amyloid-beta peptides: their potential role in the pathophysiology of depression and as molecular therapeutic targets. Br J Pharmacol. 2010 Oct;161(4):768-70.
Page 8 of 8