Is later-life depression a risk factor for Alzheimer's disease or a prodromal symptom: a study using post-mortem human brain tissue?

BACKGROUND: Depression and dementia are both common diseases. Although new cases of depression are more common in younger adults, there is a second peak at the age of 50 years suggesting a different pathological process. Late-life depression (LLD) is associated with dementia. However, it remains unclear whether depression represents a dementia prodrome or is a true risk factor for its development. LLD is thought to have a vascular component and this may be a possible link between depression and dementia. We hypothesised that later-life depression is a prodromal manifestation of dementia and would therefore be associated with more AD, and/or ischaemic brain abnormalities that are present in earlier-life depression or in age- and sex-matched controls. METHODS: We assessed post-mortem orbitofrontal cortex and dorsolateral pre-frontal cortex from 145 individuals in 4 groups: 28 18-50-year-olds with depression, 30 older individuals (ages 51-90) with depression, 28 with early AD (Braak tangle stages III-IV) and 57 matched controls (17 early-life, 42 later-life). Levels of Aß, phospho-tau and α-synuclein were assessed by immunohistochemistry and ELISA. To quantify chronic ischaemia, VEGF, MAG and PLP1 were measured by ELISA. To assess pericyte damage, PDGFRB was measured by ELISA. For blood-brain barrier leakiness, JAM-A, claudin 5 and fibrinogen were measured by ELISA. To quantity endothelial activation, the ratio of ICAM1:collagen IV was assessed by immunohistochemistry. RESULTS: There was no evidence of chronic cerebral hypoperfusion or increased Aß/tau in either depression group. There was also no indication of pericyte damage, increased blood-brain barrier leakiness or endothelial activation in the OFC or DLPFC in the depression groups. CONCLUSIONS: Contrary to some previous findings, we have not found evidence of impaired vascular function or increased Aß in LLD. Our study had a relatively small sample size and limitations in the availability of clinical data. These results suggest that depression is a risk factor for dementia rather than an early manifestation of AD or a consequence of cerebral vascular insufficiency.

Characterization of Depressive Symptoms in Dementia and Examination of Possible Risk Factors.

Background: Depression in individuals with Alzheimer's disease (AD) is common, distressing, difficult to treat, and inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure. Objective: We aimed to characterize depression in AD and to identify risk factors. Methods: We used data from three large dementia focused cohorts: ADNI (n = 665 with AD, 669 normal cognition), NACC (n = 698 with AD, 711 normal cognition), and BDR (n = 757 with AD). Depression ratings were available using the GDS and NPI and in addition for BDR the Cornell. A cut-off of≥8 was used for the GDS and the Cornell Scale for Depression in Dementia,≥6 for the NPI depression sub-scale, and≥2 for the NPI-Q depression sub-scale. We used logistic regression to examine potential risk factors and random effects meta-analysis and an interaction term to look for interactions between each risk factor and the presence of cognitive impairment. Results: In individual studies there was no evidence of a difference in risk factors for depressive symptoms in AD. In the meta-analysis the only risk factor which increased the risk of depressive symptoms in AD was previous depression, but information on this was only available from one study (OR 7.78 95% CI 4.03-15.03). Conclusion: Risk factors for depression in AD appear to differ to those for depression per se supporting suggestions of a different pathological process, although a past history of depression was the strongest individual risk factor.

Recurrent depression has persistent effects on cognition but this does not appear to be mediated by neuroinflammation.

BACKGROUND: Later-life depression appears to be different to depression in younger adults. The underlying pathology may also differ. Depression is linked to dementia but whether it is a risk factor or an early sign of a developing dementia remains unclear. Neuroinflammation is increasingly recognised in both depression and Alzheimer's Disease. AIMS: To investigate the link between depression, inflammation and dementia. We hypothesised that recurrent depression has adverse effects on performance in cognitive tests in middle to older age and that this effect is modified by anti-inflammatory medication. METHODS: We identified UK based cohort studies which included individuals aged >50, had medical information, results from detailed cognitive testing and had used reliable measures to assess depression. Individuals with recurrent depression had ≥ 2 episodes of depression. Controls had no history of depression. The presence/absence of inflammatory illness was assessed using a standardised list of inflammatory conditions. Individuals with dementia, chronic neurological and psychotic conditions were excluded. Logistic and linear regression were used to examine the effect of depression on cognitive test performance and the mediating effect of chronic inflammation. RESULTS: Unexpectedly in both studies there was evidence that those with recurrent depression performed better in some cognitive tasks (e.g Mill Hill vocabulary) but worse in others (e.g. reaction time). In UK Biobank there was no evidence that anti-inflammatories moderated this effect. LIMITATIONS: Cross-sectional assessment of cognition. CONCLUSIONS: Although previous recurrent depression has small effects on cognitive test performance this does not appear to be mediated by chronic inflammatory disease.

Possible positive effect of the APOE ε2 allele on cognition in early to mid-adult life.

BACKGROUND: ε4 allele possession is associated with an increased risk of Alzheimer's disease. Its effects earlier in life are less well understood. Previous studies have reported both detrimental effects and a lack of effect on cognition outside dementia. We used genotype based recall from the ALSPAC study to investigate whether APOE genotype influences cognition in earlier adult life. METHODS: We invited all individuals with the rarer ε22 or ε44 genotypes and equal numbers of those with ε32, ε33 or ε34 APOE genotypes (total n invited = 1936, ages 23-67). Participants were screened for dementia using the Addenbrooke's Cognitive Examination Revised (ACE-R). Participants were asked to complete a 3 h battery of neuropsychological tests covering a range of cognitive domains. The primary outcome was performance on the Rey Auditory Verbal Learning Test (RAVLT). Transformation of variables was used where required to permit parametric testing. As genotypes are unlikely to be confounded unadjusted analyses were performed. RESULTS: 114 participants were recruited to the study (39 ε33, 27 ε34, 15 ε44, 26 ε32 & 7 ε22). ε4+ participants had higher scores on the cognitive failures questionnaire (10 point increase, p = 0.006) but no deficits on objective cognitive testing. ε2 carriers had slightly better episodic memory performance (p = 0.016), slightly improved n-back accuracy and better executive functioning (trails A&B, p = 0.005). CONCLUSIONS: It is intriguing that the ε2+ group performed better as this group have a lower risk of Alzheimer's disease. Most previous studies have analysed as ε4/non ε4 so may have missed this effect.

Effect of APOE Genotype on Synaptic Proteins in Earlier Adult Life.

BACKGROUND: Possession of APOEɛ4 is a strong risk factor for late-onset Alzheimer's disease and is associated with loss of synaptic proteins in the elderly even in the absence of Alzheimer's disease. OBJECTIVE: We hypothesized that ɛ4 allele possession in non-demented adults aged under-75 would also be associated with alterations in the levels of synaptic proteins. METHODS: We measured synaptophysin, PSD95, drebrin, SNAP-25, and septin 7 by ELISA in hippocampus and superior temporal gyrus from 103 adults aged <75 without dementia. Corresponding gene expression was measured by RT-PCR. RESULTS: There was no evidence that ɛ4 affected levels of the proteins measured. Instead we found an increase in post-synaptic proteins in the hippocampi of those with an ɛ32 genotype. The evidence was strongest for drebrin (p = 0.011). There was some evidence of increased synaptic protein gene expression in ɛ4 carriers. CONCLUSIONS: People with an APOEɛ32 genotype have a reduced risk of Alzheimer's disease. It may be relevant that they have a higher level of post-synaptic proteins in the hippocampus even in earlier adulthood.

Possible Association of APOE Genotype with Working Memory in Young Adults.

BACKGROUND: Possession of the ε4 allele of the Apolipoprotein E (APOE) gene is associated with an increased risk of Alzheimer's disease. Early adult life effects of ε4 are less well understood. Working memory has been relatively little studied (compared to episodic memory) in relation to APOE genotype despite its importance in cognitive functioning. Our hypothesis was that ε4 would lead to an impairment in working memory in young adults. METHODS: We studied working memory using a computerised n-back task in the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 18. Data was available for 1049-1927 participants and for the 2- and 3-back versions of the task. Using multiple and multi-level regression controlling for important confounders we examined the association between APOE genotype on accuracy and reaction times. RESULTS: There was no evidence of a genotype effect on accuracy when the two difficulty levels were examined separately. There was some evidence to support a deleterious effect of the ε4 allele on n-back accuracy in the multi-level regression. There was weak evidence that the ε22 group were less accurate but the numbers were very low in this group. The ε34 group had faster reaction times than the reference ε33 group in all adjusted analyses but the ε44 group were only faster in the 3-back condition in multi-level analyses. CONCLUSIONS: There was no evidence of benefit in ε4 carriers, but there was some evidence of a detrimental effect on working memory in this large study.

Synaptic protein levels altered in vascular dementia.

INTRODUCTION: Cerebral ischaemia is the defining pathophysiological abnormality in most forms of vascular dementia (VAD), but the pathogenesis of the dementia remains poorly understood. In Alzheimer's disease (AD), there is early loss of synaptic proteins, but these have been little studied in VAD. MATERIALS AND METHODS: We measured synaptophysin, postsynaptic density protein 95 (PSD-95), drebrin, synaptosomal-associated protein 25 (SNAP-25) and vascular endothelial growth factor (VEGF) by enzyme-linked immunosorbent assays in superior temporal cortex from 11 patients with VAD and, initially, 11 non-dementia controls. We corrected for neuronal content by measurement of neuron-specific enolase. A further 11 controls were subsequently used in a validation study. Simulation of post-mortem delay found that PSD-95 was stable at 4°C but declined slightly at RT. SNAP-25 and drebrin showed good post-mortem stability. Previous studies had shown good post-mortem preservation of synaptophysin and VEGF. RESULTS: The VAD cases had lower synaptophysin (but P > 0.05 in initial study), significantly lower SNAP-25 (P = 0.024) and significantly higher drebrin (P = 0.020). On comparison with the second control group, the reduction in synaptophysin was significant (P = 0.008), and the other results were confirmed. CONCLUSION: There is probably a reduction in presynaptic proteins in the temporal cortex in VAD, although not as marked as in AD. In VAD, there is also an increase in drebrin, which may be a response to reduced synaptic input.

Drug-drug interactions in general hospital and psychiatric hospital in-patients prescribed psychotropic medications.

Abstract Objectives. Drug-drug interactions (DDIs) present a serious, ever increasing clinical problem. Previous studies identified DDIs among psychiatric inpatients prescribed psychotropics, but none have focused on psychotropics prescribed to General Hospital inpatients. This study aimed to identify: putative drug-drug interactions; mechanisms; potential seriousness among patients prescribed psychotropes in both psychiatric and general hospital inpatients settings. We hypothesised that potential interactions per person would be greater in General Hospital inpatients on psychotropics, due to polypharmacy. Method. We surveyed psychotropic prescribing in hospital wards in a public sector mental health organisation and a 500-bed general hospital. Ward pharmacists collected drug prescription data. A computer based protocol evaluated DDIs. Results. A total of 7.4% of General Hospital inpatients and 100% of Psychiatric Unit inpatients surveyed were prescribed psychotropic medication. The General Hospital group had significantly more potential interactions per person (3.0) than Psychiatric inpatients (1.3) (P<0.05). There were significantly more potentially serious interactions in the general hospital group (P<0.025). Conclusions. DDIs affect those prescribed psychotropics in both General and Psychiatric Hospitals. The General Hospital patients had a higher number per person and more serious potential interactions, yet are often poorly served by psychiatric services, suggesting that liaison psychiatrists have a role in physician education and DDI assessment.

Modulation of ion channels in clinical psychopharmacology: adults and younger people.

This review focuses on the use of Na(+), Ca(2+) and Cl(-) channel modulators in psychiatric disease. Drugs that modulate ion channels have been used in psychiatry for more than a century, and in this review we critically evaluate clinical research that reports the therapeutic effects of drugs acting on GABA(A), voltage-gated Na(+) and voltage-gated Ca(2+) channels in pediatric and adult patients. As in other fields, the evidence underpinning the use of medicines in younger people is far less robust than for adults. In addition, we discuss some current developments and highlight clinical disorders in which current molecules could be further tested. Notable success stories, such as benzodiazepines (in sleep and anxiety disorders) and antiepileptics (in bipolar disorder), have been the result of serendipitous discoveries or refinements of serendipitous discoveries, as in all other major treatments in psychiatry. Genomic, high-throughput screening and molecular pharmacology discoveries may, however, guide further developments in the future. This could include increased research in promising targets that have been perceived as commercially risky, such as selective α-subunit GABA(A) receptors.

Antidepressant-induced jitteriness/anxiety syndrome: systematic review.

BACKGROUND: Early worsening of anxiety, agitation and irritability are thought to be common among people commencing antidepressants, especially for anxiety disorders. This phenomenon, which may be termed jitteriness/anxiety syndrome, is cited as an explanation for early treatment failure and caution in using selective serotonin reuptake inhibitors (SSRIs). However, we believe that it is inconsistently defined and that robust evidence to support the phenomenon is lacking. AIMS: To review systematically all evidence relating to jitteriness/anxiety syndrome to identify: constituent symptoms; medications implicated; disorders in which it was reported; incidence; time course; management strategies; relationship of this syndrome to therapeutic response; distinction between syndrome and akathisia; relationship between syndrome and suicide; and genetic predispositions. METHOD: A systematic search identified articles and these were included in the review if they addressed one of the above aspects of jitteriness/anxiety syndrome. RESULTS: Of 245 articles identified, 107 articles were included for review. No validated rating scales for jitteriness/anxiety syndrome were identified. There was no robust evidence that the incidence differed between SSRIs and tricyclic antidepressants, or that there was a higher incidence in anxiety disorders. Published incidence rates varied widely from 4 to 65% of people commencing antidepressant treatment. Common treatment strategies for this syndrome included a slower titration of antidepressant and the addition of benzodiazepines. Conclusive evidence for the efficacy of these strategies is lacking. There was conflicting and inconclusive evidence as to whether the emergence of this syndrome had a predictive value on the response to treatment. It appears to be a separate syndrome from akathisia, but evidence for this assertion was limited. The effect of jitteriness/anxiety syndrome on suicide rates has not been evaluated. Three studies examined genetic variations and side-effects from treatment, but none was specifically designed to assess jitteriness/anxiety syndrome. CONCLUSIONS: Jitteriness/anxiety syndrome remains poorly characterised. Despite this, clinicians' perception of this syndrome influences prescribing and it is cited to support postulated mechanisms of drug action. We recommend systematised evaluation of side-effects at earlier time points in antidepressant trials to further elucidate this clinically important syndrome.

Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined. We set out to determine the precise abnormalities of gene expression in the blood of patients with CFS/ME. We analyzed gene expression in peripheral blood from 25 patients with CFS/ME diagnosed according to the Centers for Disease Control and Prevention diagnostic criteria and 50 healthy blood donors, using a microarray with a cutoff fold difference of expression of >or=2.5. Genes showing differential expression were further analyzed in 55 patients with CFS/ME and 75 healthy blood donors, using quantitative polymerase chain reaction. Differential expression was confirmed for 88 genes; 85 were upregulated, and 3 were downregulated. Highly represented functions were hematological disease and function, immunological disease and function, cancer, cell death, immune response, and infection. Clustering of quantitative polymerase chain reaction data from patients with CFS/ME revealed 7 subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical phenotypes, and severity.