Jay Nierenberg, M.D., Ph.D. ... Pankaj D. Mehta, Ph.D. .... of Alzheimer's disease pathology (23). ..... correspondence to Dr. Pomara ([email protected]).
A r t ic le
L o w e r C S F A m y lo id B e ta P e p tid e s a n d H ig h e r F 2 -Iso p ro sta n e s in C o g n itiv e ly In ta c t E ld e rly In d iv id u a ls W ith M a jo r ; e p re ssiv e ; iso rd e r Nunzio Pomara, M.D. Davide Bruno, Ph.D. Antero S. Sarreal, M.D. Raymundo T. Hernando, M.D. Jay Nierenberg, M.D., Ph.D. Eva Petkova, Ph.D. John J. Sidtis, Ph.D. Thomas M. Wisniewski, M.D. Pankaj D. Mehta, Ph.D. Domenico Pratico, M.D. Henrik Zetterberg, M.D., Ph.D.
O b je c tiv e : M ajor depressive disorder is com m on in the elderly, and sym ptom s are often not responsive to conventional antidepressant treatm ent, especially in the long term . Soluble oligom eric and aggregated form s of am yloid beta peptides, especially am yloid beta 42, im pair neuronal and synaptic function. Am yloid beta 42 is the m ain com ponent of plaques and is im plicated in Alzheim er’s disease. Am yloid beta peptides also induce a depressive state in rodents and disrupt m ajor neurotransm itter system s linked to depression. The authors assessed w hether m ajor depression w as associated w ith CSF levels of am yloid beta, tau protein, and F2-isoprostanes in elderly individuals w ith m ajor depressive disorder and age-m atched nondepressed com parison subjects. M e th o d : CSF w as obtained from nitively intact volunteers (m ajor sion group, N=28; com parison N=19) and analyzed for levels of
47 cogdepresgroup, soluble
am yloid beta, total and phosphorylated tau proteins, and isoprostanes. R e s u lts : Am yloid beta 42 levels w ere signifcantly low er in the m ajor depression group relative to the com parison group, and am yloid beta 40 levels w ere low er but only approaching statistical signifcance. In contrast, isoprostane levels w ere higher in the m ajor depression group. No differences w ere observed in total and phosphorylated tau proteins across conditions. Antidepressant use w as not associated w ith differences in am yloid beta 42 levels. C o n c lu s io n s : Reduction in CSF levels of am yloid beta 42 m ay be related to increased brain am yloid beta plaques or decreased soluble am yloid beta production in elderly individuals w ith m ajor depression relative to nondepressed com parison subjects. These results m ay have im plications for our understanding of the pathophysiology of m ajor depression and for the developm ent of treatm ent strategies.
Kaj Blennow, M.D., Ph.D. (A m J P sy c h ia try 2 0 1 2 ; 1 6 9 :5 2 3 –5 3 0 )
A
n association between Alzheimer’s disease and major depressive disorder has been reported in some studies, suggesting that depression could be considered either a risk factor for or a prodromal condition of Alzheimer’s disease (1–7). In a meta-analysis of studies of depression and dementia, Jorm (1) concluded that depressed individuals are, on average, nearly twice as likely to develop dementia, often in the form of Alzheimer’s disease, compared with nondepressed comparison subjects. Similarly, depression was reported to be signifcantly associated with a higher rate of Alzheimer’s disease in a population-based case-control study (2). Multiple studies using a range of methods have generally strengthened the notion that major depression is a risk factor for Alzheimer’s disease, even when it occurs earlier in life (3–7). However, there are exceptions (e.g., references 8, 9), and the presence of conficting results suggests that there is heterogeneity among
individuals with major depression with respect to the risk of Alzheimer’s disease and that multiple pathological processes may be at play. A potential link between major depression and Alzhei mer’s disease involves the role of amyloid beta in the brain. Disturbances in amyloid beta may be the earliest sign of Alzheimer’s disease (10). There are numerous amyloid beta peptide species, with the major isoforms consisting of two amino acid peptide fragments: 1–40 and 1–42 amino acid peptides. Amyloid beta peptides are a physiological product of the amyloid beta protein precursor through beta and gamma secretase cleavage (11). Importantly, neuritic plaques, which are widespread in parenchymal brain tissue, are one of the neuropathological hallmarks of all forms of Alzheimer’s disease (12). Amyloid beta 42 in particular is known to be deposited early in plaques (13) and is believed to be the initial trigger in Alzheimer’s
This article is the subject of a C M E course (p. 547)
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C S F amy lo id b e ta and F 2 -Isop r ostan e s L e v e ls in ; e p r e ss ion
pathogenesis. CSF amyloid beta 42 is now considered a biomarker of Alzheimer’s disease, and its levels appear to inversely refect brain amyloid beta deposition, as demonstrated by in vivo studies using amyloid tracers, such as Pittsburgh compound B (14). Consistent with these fndings, lower CSF concentrations of amyloid beta 42 have been observed in individuals with Alzheimer’s disease and mild cognitive impairment relative to comparison subjects (15). Other important CSF biomarkers of Alzheimer’s disease are levels of total tau protein, a marker of neuronal degeneration, and levels of hyperphosphorylated tau protein, a marker of neurofbrillary tangles. Both total and phosphorylated tau protein CSF levels are reported to be greater in individuals with Alzheimer’s disease than in comparison subjects (16). Several lines of evidence suggest that amyloid beta disturbances may also be associated with major depressive disorder and depressive symptoms. Results from preclinical research, including primate studies, have associated various risk factors for depression with increased soluble amyloid beta production in the brain and increased amyloid plaques; among them are acute and chronic stress, glucocorticoid administration, sleep deprivation, and increased levels of corticotropin-releasing factor and cortisol secretion (17–19). Furthermore, it has been reported that when injected into the cerebral ventricles in rodents, amyloid beta 42 induces depression (20). Lastly, several researchers have reported plasma amyloid beta 42 disturbances in humans, although the results have been inconsistent, with some depressed individuals having lower (e.g., reference 21) or higher (e.g., reference 22) amyloid beta 42 levels than comparison subjects. A major drawback of these studies is that plasma concentrations of amyloid beta 42 typically are not correlated with CSF or brain concentrations and are not considered a reliable marker of Alzheimer’s disease pathology (23). CSF levels of amyloid beta and tau protein have also been studied in conjunction with major depression in elderly individuals. Gudmundsson et al. (24, 25) compared elderly women (exclusively) with major depressive disorder with age- and sex-matched comparison subjects without depressive symptoms. Neither group had dementia, and the depressed group had higher CSF levels of amyloid beta 42 than comparison subjects. The exact signifcance of this fnding is unclear but may correspond to increased amyloid beta production in the brain, increased amyloid beta clearance, or decreased amyloid beta brain deposition in individuals with major depression relative to comparison subjects with no depressive symptoms. In order to isolate the reasons behind increased amyloid beta 42 levels, researchers have employed in vivo positron emission tomography (PET) technology with ligands, such as Pittsburgh compound B to detect amyloid beta and [18F]FDDNP (2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2naphthyl}ethylidene)malononitrile) to detect both amyloid beta and tau neurofbrillary tangles. Studies using this
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technology have revealed increased amyloid beta deposition in the brain in individuals with depression relative to nondepressed comparison subjects (26). In particular, increased brain amyloid beta and tau protein binding were observed in currently depressed individuals with major depressive disorder and no mild cognitive impairment, relative to comparison subjects, in recent PET studies using Pittsburgh compound B (27) and [18F]FDDNP (28). Collectively, these results suggest that amyloid betarelated neurobiological mechanisms may play a role not only in Alzheimer’s disease but also in late-life major depression. However, to our knowledge, the only studies to date to investigate CSF markers of Alzheimer’s disease, such as amyloid beta and tau proteins, in cognitively intact elderly individuals with major depressive disorder examined women exclusively (24, 25). The purpose of our study was to investigate CSF markers of Alzheimer’s disease in cognitively intact elderly men and women alike. We predicted that, in line with previous fndings from PET studies, those with major depressive disorder, regardless of gender, would have lower CSF levels of amyloid beta 42 relative to comparison subjects, indicating higher brain amyloid beta deposition, as seen in individuals with Alzheimer’s disease and mild cognitive impairment. In contrast, we expected no signifcant differences in CSF levels of amyloid beta 40, total tau, or phosphorylated tau across groups, which is consistent with results reported previously by Gudmundsson et al. (24) and Buerger et al. (29). In some studies, CSF isoprostane levels, considered to be a biomarker of oxidative stress (30), which is characteristic of infammation (31), have been associated with CSF levels of amyloid beta 42 (32). Both oxidative stress and infammatory mechanisms have also been implicated in depression, and higher plasma isoprostane levels have been observed in elderly depressed patients relative to healthy comparison subjects (33). Consequently, we also incorporated a measure of oxidative stress (F2-isoprostanes) as part of the present study. Finally, three neuropsychological tests were administered to all participants: the Buschke Selective Reminding Test (34), which measures memory performance; the Trail-Making Test, parts A and B (35), which measures attentional and psychomotor performance skills; and the category fuency test (36), which measures spontaneous verbal generative ability. These tests assess primary cognitive domains and were used to determine whether any cognitive differences were observable across groups.
M e th o d P a rtic ip a n ts This study was approved by the institutional review boards of the Nathan Kline Institute for Psychiatric Research and the New York University School of Medicine. Participants were volunteers who responded to advertisements in local newspapers and fyers or were recruited from our currently active Memory Education and Research Initiative Program. All participants provided formal
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A m J Psych ia try 1 6 9 :5 , M ay 2 0 1 2
P oma r a , B r uno , S a r r e a l , e t a l . TA B LE 1 . ; e m o g ra p h ic a n d C lin ic a l C h a ra c te ristic s o f C o g n itiv e ly In ta c t In d iv id u a ls W ith M a jo r ; e p re ssiv e ; iso rd e r a n d A g e -M a tc h e d C o m p a riso n S u b je c ts Characteristic Age (years) Education (years)a Body mass index Hamilton Depression Rating Scale score Mini-Mental State Examination score Total recall rating Delayed recall rating Trail-Making Test score Part A Part B Category fuency test Diabetes Female Apolipoprotein e level e4 e2 Family history of Alzheimer’s disease a Data
Comparison Group (N=19)
Major Depression Group (N=28)
Mean 68.1 16.7 28.1 1.2 29.5 64.4 8.5
SD 7.3 2.7 4.7 1.9 0.5 12.3 2.8
Mean 66.5 16.5 28.8 14.9 29.8 64.9 9.5
SD 5.4 2.7 6.7 8.8 0.6 13.9 2.5
t 0.835 0.274 0.378 8.02 1.56 0.110 1.258
df 45 44 45 45 45 45 45
p 0.41 0.79 0.71
