Journal of Affective Disorders 99 (2007) 127 132 www.elsevier.

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Investigation of Alzheimer's disease-related pathology in community dwelling older subjects who committed suicide
C. Peisah a,b,, J. Snowdon c , C. Gorrie d , J. Kril e , M. Rodriguez f
Academic Department for Old Age Psychiatry, Prince of Wales Hospital, Australia b School of Psychiatry, University of NSW, Australia c Discipline of Psychological Medicine, The University of Sydney, Sydney, Australia d School of Medical Sciences, University of NSW, Australia e Disciplines of Medicine and Pathology, The University of Sydney, Sydney, Australia f Department of Forensic Medicine, Sydney South West Area Health Service, Australia Received 18 July 2006; received in revised form 23 August 2006; accepted 23 August 2006 Available online 28 September 2006
a

Abstract Background: Older people have a higher risk of completed suicide than any other age group worldwide. The contribution of neurodegenerative disease to this risk remains controversial. Aims: To investigate prevalence of Alzheimer's disease-related (AD) pathology in older suicide victims. Methods: Ratings of AD pathology using Braak and CERAD protocols were compared in 143 community-dwelling suicide victims aged 65 years or more and 59 motor vehicle accident victims autopsied at the request of an Australian Coroner's Court. Results: There were no significant differences in plaque score or neurofibrillary tangle staging between suicide and control groups. None of the subjects with a history of dementia had neuropathologically confirmed AD. Conclusions: Our study is the second and largest investigation of the prevalence of AD neuropathology in the elderly suicide population. Unlike the previous study, we did not find an increased prevalence of AD neuropathology despite a history of dementia in 6.3%, implicating other pathologies such as Lewy Body or Vascular dementia in the aetiology of dementia in elderly suicide victims. 2006 Elsevier B.V. All rights reserved.
Keywords: Suicide; Elderly; Alzheimer's disease; Dementia; Neurodegenerative; Pathology

1. Introduction Older people have a higher risk of completed suicide than any other age group worldwide, with men over 75 having the highest risk of all (WHO, 2000; Conwell

Corresponding author. 256 Edgecliff Rd Bondi Junction, 2022, NSW, Australia. Tel.: +61 2 93890155; fax: +61 2 93890355. E-mail address: cpeisah62@optusnet.com.au (C. Peisah). 0165-0327/$ - see front matter 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2006.08.030

et al., 2002; O'Connell et al., 2004). These figures have prompted a call for a focusing of attention on this hitherto neglected area with a view to identifying aetiological factors and ultimately preventative strategies. In older people, as in younger people, suicide is a complex and multifactorial phenomenon and the challenge is to identify the biological, psychological and social factors that are relevant to suicide in older people (Conwell et al., 2002; Snowdon and Baume, 2002; O'Connell et al., 2004).

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While there is no doubt that psychiatric disorder, especially depression, is commonly an important factor in late life suicide (Hepple and Quinton, 1997; Conwell et al., 2002; Waern et al., 2002a), the contribution of dementia to the aetiology of suicide in old age remains controversial. The risk of suicide in cases of dementia has often been considered low, and this has been partly attributed to the higher levels of personal supervision provided in such cases and to the difficulties that persons with cognitive deficits might have in planning and carrying out suicidal acts. In a meta-analysis of 249 reports on the mortality of mental disorders, Harris and Barraclough (1997) found that virtually all mental disorders have an increased risk of suicide except dementia and mental retardation. The findings for dementia were based on two papers (Knopman et al., 1988; Burns et al., 1990) which reported on a population of 277 followed for up to 4 years. As these studies were of patients with established dementia, the authors suggested that impaired competence may be protective. In a psychological autopsy study of 100 suicides, Harwood et al. (2001) found rates of dementia (4%) and other cognitive impairments (6%) that were comparable to those found in population surveys of cognitive impairment in older people. A study of coroner's files showed evidence pointing to clinical diagnoses of mild to moderate dementia in 7% of 210 persons aged 65 years or more who had killed themselves (Snowdon and Baume, 2002). Others have observed suicide attempts in less than 1% of all patients with dementia (Chiu et al., 1996; Schneider et al., 2001). In contrast, Barak and Aizenberg (2002) observed that suicide attempts were not rare in elderly Alzheimer's disease (AD) patients, especially amongst those who had made previous suicide attempts and those with higher levels of daily functioning. In a 10 year retrospective analysis, they found that 7.4% of all elderly inpatients diagnosed with AD were admitted following suicide attempts. Others have emphasised the risk associated with features of the earlier stages of the disease such as preserved awareness and insight into declining cognition and the ability to perform planned actions (Margo and Finkel, 1990; Vega et al., 2002; Ferris et al., 1999; Lim et al., 2005), although even in more advanced stages of the disease when cognitive disturbance might result in less-deliberate acts of suicide, it does not appear to influence their potential lethality (Upadhyaya et al., 1999). Common co-morbid symptoms such as depression (Hepple and Quinton, 1997; Vega et al., 2002), hopelessness and a wish to die (Harwood and Sultzer, 2002; Draper et al., 1998) and aggressive behavior (Aarsland et al., 1996) seen throughout all stages of the

disease are also thought to be risk factors for suicide in AD patients. Many questions thus remain unanswered. Is dementia a risk factor for suicide? If so, at what stage of the illness and in what types of dementia is this risk relevant? The focus of much preceding work has been on the relationship between suicide and AD. In a study of suicidal ideation in patients referred to a memory disorders clinic, Draper et al. (1998) found that patients with depressive symptoms and NINCDS-ADRDA diagnosed probable and possible Alzheimer's disease were more likely than depressed patients with other types of dementia (e.g. vascular dementia) to be preoccupied by thoughts of suicide or death. Such clinical observations have not been investigated in neuropathological studies. Investigation of the neuropathological basis for suicide in older persons has received little research attention. Neuropathological confirmation of AD changes in elderly subjects who committed suicide has been limited to a handful of case reports (Rohde et al., 1995; Lecso, 1989) and a single pilot case-control study by Rubio et al. (2001). The latter examined for AD pathology in cases where autopsies of elderly people dying by suicide (n = 28) had been conducted at the direction of a US Medical Examiner and compared them with data concerning individuals who died naturally and had a routine autopsy at a University hospital (n = 56). They demonstrated that people with moderate to severe AD pathology were over-represented among those who completed suicide, suggesting that the presence of AD pathology may increase the risk of completed suicide. Availability of autopsy material from a consecutive series of older people who killed themselves (Snowdon and Baume, 2002) provided a unique opportunity to examine the prevalence of AD pathology among elderly suicide victims. We hypothesized that AD pathology would be over-represented in this group of subjects compared with controls. 2. Methods and materials A retrospective review of files from the NSW State Coroner's Department provided clinical data concerning suicides of 210 persons aged 65 years or more between 19941998 (Snowdon and Baume, 2002). Cause of death was determined by coronial investigation of the scene, full enquiries by coroner's officers, a post mortem examination and sometimes an inquest. Deaths that received an open verdict (i.e. undetermined cause) were not included. The ratio of suicide to open verdict deaths for males in Australia in 2001/2002 was

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35:1 (Snowdon, 2004). The suicide rates in Australia during the study period for males aged between 65 and 74 years and over 75 years were 22.12 and 30.98 per 100,000 respectively; while for females aged 65 74 years and over 75 years the rates were 5.76 and 6.24 respectively (Snowdon and Hunt, 2002). The suicide rates in the study area were 27.83 per 100, 000 for males aged over 65 and 8.04 per 100,000 for females (Australian Bureau of Statistics, 2000). After repeated review of the coroner's files, two researchers categorised all cases according to causes of suicide using ICD-10 and DSM-IV diagnoses where appropriate. All 210 cases had undergone routine autopsy. In order to more adequately approximate the ambulant, community based controls, 20 subjects (five each in hostels and nursing homes, 10 in hospitals) were excluded because they were in residential care or inpatients of a hospital at the time of death. Of the remaining 190 subjects, 143 cases had sufficient brain tissue available for neuropathologic staging of AD. Tissue availability was determined by factors such as mode of death (e.g. gunshot to the head), tissue sites sampled by the pathologist at dissection and time to discovery of the body. Ethics approval for the study was obtained from the Ethics Review Committee of Central Sydney Area Health Service. Control data were derived from a previous neuropathological study of fatalities in older drivers and pedestrians autopsied at the same Coroner's Department (Gorrie et al., 2006; Gorrie et al., 2004). Control cases (n = 59) included consecutive fatalities between 1997 and 2003 of people aged 65 years or older attributable to a medical condition or traumatic injuries sustained in an incident other than as a pedestrian or driver in a motor vehicle accident. All control subjects were assessed as being capable of pedestrian activity or held a current NSW driver's license at the time of their death. For visualisation of neurofibrillary tangles (NFT) and senile plaques (diffuse and neuritic) a modified Bielschowsky (Garvey) silver technique was used (Garvey et al., 1990) on 6um paraffin-embedded sections. Each silver stained section was examined for the presence and density of both senile plaques and NFT. A modified Braak score was calculated since the transentorhinal cortex was not uniformly available to distinguish between Stage 0 and III. Stage 0II comprised cases with no or few NFT in the entorhinal cortex and/or CA1 sector of the hippocampus; in Stage IIIIV there were moderate to frequent NFT in the CA1 region of the hippocampus and entorhinal pre-alpha layer, and in the deeper layers of the entorhinal cortex and few to moderate NFT in the inferior temporal cortex; in Stage

VVI there was frequent to severe involvement of the CA1 region of the hippocampus and other hippocampal areas, severe involvement of the pre-alpha layer and deeper layers of the entorhinal cortex and frequent NFT in the inferior temporal lobes and neocortex (Braak and Braak, 1997; Harding et al., 2000). Plaque density was rated using the CERAD criteria to give an age-related plaque score which distinguishes frequency of plaques (none, sparse, moderate and frequent) in subjects aged less than 50, those aged 5075, and those aged N 75 years to give scores of O, A, B, C indicating the certainty of histological evidence of AD (Mirra et al., 1991). CERAD criteria and collapsed Braak score were combined to give an estimate of the likelihood that AD pathological changes underlie dementia using the NIA-Reagan criteria (i.e. Low = infrequent plaques by CERAD criteria and Braak stage I/II; Intermediate = CERAD moderate plaques and Braak stage III/IV; High = frequent CERAD plaques and Braak stage V/VI) (NIA-Reagan Institute Working Group, 1997). Neuropathological rating was performed blind to the subjects' clinical status. Inter-rater reliability was assessed between Rater A (CP), who rated the subjects, and Rater B (CG) who rated the controls. Kappas for independent ratings of a randomly selected subgroup of 11 subjects using Braak staging and CERAD scores were 0.83 and 1.00 respectively. A further 41 cases were also rated by Rater A and Rater C (MR, a senior neuropathologist) and the kappa for inter-rater reliability between Raters A and C was 0.80 for Braak staging and 0.91 for CERAD scores. Kappas N 0.8 are indicative of near perfect agreement (McGinn et al., 2004). Data were analysed using the SPSS (V13.0) statistical package. For normally distributed continuous data, two-sample t tests were employed. In the case of skewed data (e.g. age) non-parametric MannWhitney U analyses were used (denoted by U z). Pearson's Chi-square analyses, to determine associations between categorical data (except in the case of two by two cross-

Table 1 Demographic data Suicide M/F Mean age (S.D.), years Range, years History of dementia, N (%) 102:41 75 (6) 6590 9 (6.3%) a Control 38:21 77 (8) 6594 3 (5%)

a Of 20 excluded institutional cases, 5 had a history of dementia. One community-dwelling subject with a history of dementia was excluded from the study because of insufficient tissue.

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C. Peisah et al. / Journal of Affective Disorders 99 (2007) 127132 Table 3 Neuropathological data of subjects with history of dementia Age (years) Cases 81 83 81 83 89 78 76 79 77 Controls 70 74 84 Sex Braak CERAD age-related NIAscore plaque score Reagan M M M M M M M M M III IV 0II III IV 0II III IV 0II 0II 0II 0II A C B Insufficient tissue 0 0 B A 0 DFC DFC DFC DFC DFC DFC Low Low Brain weight (g) 1240 1220 1440 1520 1320 1420 1200 1340 1360

tabs the continuity correction value denoted by CC 2), are reported. 3. Results Demographic data are presented in Table 1. There were no significant differences in age at death between the suicide cases and controls (MannWhitney U z = 1.79, p = 0. 074) nor were there gender differences in the data set. There were no significant differences in Braak staging between suicide and control groups. Small case numbers in Braak stage VVI necessitated merging stages IIIVI for valid analysis (CC 2 = 0.51, df = 1, p = 0.474). There were no significant differences in either age-related plaque scores (2 = 0.56, df = 3, p = 0.906) or NIA Reagan criteria (CC 2 = 0.00, df = 1, p = 0.695) between suicide and control groups (Table 2). Of the 15 subjects with a clinical history of dementia in the case review study (Snowdon and Baume, 2002), three were residents of nursing homes just prior to death, one was in a hostel and one was in a psychiatric hospital. These five subjects were excluded from the neuropathTable 2 Braak tangle staging, age-related plaque scores and NIA-Reagan category Suicide cases Braak stage 0II IIIIV VVI Age related plaque score 0b A B C NIA-Reagan category Low e Intermediate High n = 141a(%) 122 (86.5) 19 (13.5) 0 n = 102 (%) a 68 (66.7) 9 (8.8) 17 (16.7) 8 (7.8) n = 82 c 78 (95.1) 4 (4.9) 0 Controls n = 59 (%) 48 (81.4) 10 (16.9) 1 (1.7) n = 59 (%) 36 (61) 6 (10.2) 12 (20.3) 5 (8.5) n = 46 d 43 (93.5) 3 (6.5) 0

M F F

0II C 0II B VVI B

Mod Low DFC

1210 1120 1190

DFC: Does not fit criteria.

ological study. Of the remaining 10 subjects with a history of dementia, one had insufficient brain material for AD rating. None of the remaining nine suicide subjects and one of the three control subjects with a clinical history of dementia had neuropathologically confirmed AD (Table 3). Of the 20 subjects excluded because they were in residential care or inpatients of a hospital prior to death, 15 had sufficient tissue for examination. Of these, one had frequent plaques and Braak stage VVI changes, and another had Braak stage VVI changes alone. 4. Discussion To our knowledge, there has been only one other case-controlled investigation of the prevalence of AD changes in the elderly suicide population, that being based on 28 cases (Rubio et al., 2001). Our study was of 143 cases of suicide of older people living at home, and unlike the previous study, we did not find an increased prevalence of AD-related pathology. We conclude that AD pathology is not over-represented in elderly community-based suicide victims. It may be that selection biases are responsible for these contrasting results. Firstly, differences between the NSW and Monroe County Coronial systems may have accounted for these differences. For example, at the time our subjects were autopsied, all suicides were routinely autopsied rather then being selected for autopsy by the coroner. Secondly, our study excluded residential-care and hospital based subjects while the previous study included

a Two suicide cases were unclassifiable using Braak staging and 41 suicide cases had no neo-cortex for plaque examination because either neocortex was not collected at the time of autopsy or cortex was destroyed due to means of death. b 0 = No histological evidence of AD; A = uncertain evidence; B = suggests diagnosis of AD; C = indicates diagnosis of AD. c 61 suicide cases had no neo-cortex or did not fit NIA-Reagan categorization (see below) (e.g. had infrequent plaques with Braak stage V/VI). d 13 controls did not fit NIA-Reagan categorization. e Low = infrequent plaques by CERAD criteria and Braak stage I/II; Intermediate = CERAD moderate plaques and Braak stage III/IV; High = frequent CERAD plaques and Braak stage V/VI.

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all subjects who completed suicide compared with those who died at the university hospital. However, the prevalence of clinically rated dementia did not change after these subjects were excluded and only one of the excluded subjects had neuropathologically confirmed AD. Our study must be interpreted in the light of several important limitations. Choosing appropriate control subjects is always a key issue; however, the prevalence of AD changes in our controls approximated that of the previous study of elderly suicides (Rubio et al., 2001). Secondly, although our attrition rate was high due to lack of tissue availability, the factors which determined tissue availability were unlikely to have introduced bias into our sample. Importantly, only one of the subjects excluded due to insufficient tissue had a clinical history of dementia. Further, the problems we faced in terms of attrition due to loss of tissue may well be ubiquitous in postmortem studies of this group. Thirdly, our retrospective study was limited, by the availability of tissue sections, to hippocampal and neocortical examination (as was the study by Rubio et al., 2001). Thus, only prevalence of AD-related changes could be reliably assessed. Importantly, none of the suicide subjects with a clinical history of dementia had neuropathologically confirmed AD. In the absence of AD, other causes of dementia such as Lewy body pathology or cerebrovascular disease remain prime candidates for an aetiological role in suicidal behavior in the elderly. There is a body of research based on neuroimaging which has linked structural and functional abnormalities, particularly subcortical ischaemic changes in key anatomical areas of the brain, with mood disorders in later life (Krishnan, 2005; Phillips et al., 2003; Thomas et al., 2003; Thomas, 2005; Ahearn et al., 2001). The relationship between stroke and suicide in older people is also highly suggestive of the role of cerebrovascular disease in suicidal thoughts and behavior (O'Connell et al., 2004; Waern et al., 2002b). Similarly, mood disturbances associated with Lewy body dementia (Samuels et al., 2004; Hirono and Cummings, 1999) and frontotemporal dementia, and the frequency of autopsy-confirmed cerebrovascular disease and Lewy body dementia pathology in subjects with late onset depression with and without dementia (Sweet et al., 2004), necessitates an investigation of the potential role (either alone or synergistically) of these pathologies in suicide in older subjects. Further, brain damage and neurobehavioral deficits are associated with alcohol use disorders and may contribute to suicidal behavior in persons with alcohol dependence or abuse (Sher, 2006).

There is good reason to plan a neuropathological study investigating the prevalence of neurodegenerative disease in older suicide victims in conjunction with psychological autopsy data. By planning to collect brain material from all relevant regions from the time of death it will be possible to provide informed views on the importance of different types of dementia as factors contributing to suicidal acts. Acknowledgement We would like to thank Georgina Luscombe for her assistance with the statistics. Pfizer provided financial support to Dr. Peisah to present early data from this project at the 12th IPA Congress. Many thanks are due to the NSW Coroner and his staff for their support in collection of data, and to the pathologists who conducted the autopsies at which material examined in this study was collected. References
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