Original ArticlesStructural and functional abnormalities in elderly patients clinically recovered from early- and late-onset depression
Introduction
Organic brain changes, cognitive impairment, and alterations in brain electrophysiological activity have all been described in elderly patients with unipolar affective disorder. Since Post’s original suggestion (Post 1972) evidence has accumulated that at least some of these changes, for example, cognitive impairment Cole and Hicking 1976, Hickie et al 1995 and structural abnormalities Baldwin et al 1993, Hickie et al 1995, O’Brien et al 1996, are more marked in patients with late-onset depression. Such patients appear to be more refractory to treatment, to suffer more frequent relapses than those who develop depression earlier in life (Baldwin 1994), and to be less likely to make a full recovery. The degree or rate of reversibility of structural or functional changes after clinical recovery in elderly patients with either early- or late-onset depression is not known. No studies have investigated the interrelationships between structural brain abnormalities, cognitive performance, and electrophysiological activity in the same group of patients. Baldwin (1994) remarked: “More research is needed and elderly patients are a rich source for exploring neurobiological concepts of depression. It is a pity that they are so often excluded from much of psychopharmacological research.”
Computerized tomographic (CT) studies in elderly depressed patients showed that those with late-onset depression had greater ventricular size and more evidence of cortical atrophy than those with early onset Jacoby and Levy 1980, Alexopoulos et al 1992. Significant relationships have been found between larger ventricular size and poorer neuropsychological performance Beats et al 1996, Pearlson et al 1989, Abas et al 1990 in elderly depressed patients. Furthermore, ventricular dilatation has been related to a poor response to tricylic antidepressant drugs (Young et al 1988) and increased mortality (Jacoby et al 1981).
Investigations using magnetic resonance imaging (MRI) have confirmed and extended the earlier CT findings. In particular, elderly depressed patients appear to have a particularly high rate of structural abnormalities, including periventricular white matter hyperintensity lesions (PVWMLs), subcortical white matter lesions (SCWMLs), and lesions in subcortical grey matter, especially in the basal ganglia Coffey et al 1990, Zubenko et al 1990, Churchill et al 1991, Krishnan 1991, Rabins et al 1991, Baldwin et al 1993, Baldwin 1994, O’Brien et al 1996. The etiopathology of white matter hyperintensities is not fully understood; however, it is probable that PVWMLs and SCWMLs have different origins. SCWMLs are probably vascular in origin, whereas PVWMLs may result from loss of ventricular ependymal lining leading to local edema Chimowitz et al 1992, Fazekas et al 1993. White matter lesions are not specific to depression, but are seen in mania (Moore et al 1995) and late-onset schizophrenia (Breitner et al 1990), and are also associated with increased age, higher mean arterial blood pressure (Schmidt et al 1993), and reduced white matter perfusion (Kobari et al 1990). In severely depressed patients, white matter lesions may be associated with a later age of onset and impaired psychomotor speed, and may predict a poorer response to antidepressant treatment (Hickie et al 1995). Other studies have shown that patients with depression or bipolar disorders may have reduced caudate nucleus and putamen volumes compared with age-matched controls Krishnan et al 1992, Husain et al 1991, Moore et al 1995.
Many studies have shown abnormalities of cortical evoked responses in patients with depression. In particular, the magnitude of the contingent negative variation (CNV) is decreased in most, though not all, untreated depressed patients compared with controls Shagass et al 1978, Bolz et al 1979, Giedke and Heimann 1987, Small and Small 1971, Small et al 1971, Timsit-Berthier 1981, Thier et al 1986, Giedke et al 1987, Ashton et al 1988. CNV magnitude has been shown to be related monotonically to degree of attention (Tecce et al 1976) and is associated with increased cortical activation (Rockstroh et al 1993). This negative potential is thought to arise from activity in cortical pyramidal cells (Rockstroh et al 1993) and is probably generated from the reticular system and limbic arousal systems Rebert 1972, Marczynski 1986. Ashton et al 1988, Ashton et al 1994) found a significant negative correlation between CNV magnitude and clinically rated severity of depression. Reaction times (associated with the CNV) are prolonged in depression Ashton et al 1988, Thier et al 1986, Knott et al 1991, and some authors have reported an increased postimperative negative variation (PINV) in depressed patients Timsit-Berthier 1981, Giedke and Bolz 1980, Thier et al 1986, Ashton et al 1988, Knott et al 1991. The PINV is thought to represent continued cortical activation following a response and appears to be related to anxiety, uncertainty, and indecision (McCallum 1988). Some of these changes reverse during antidepressant treatment, but in some patients they persist after clinical recovery, with or without antidepressant treatment Timsit-Berthier 1981, Ashton et al 1988.
Evidence concerning other evoked potentials in depression is conflicting. The P300 component (evoked by “oddball” tasks) appears to be generated from temporal, hippocampal (Tarkka et al 1995), and frontal (Ebmeier et al 1995) brain areas, regions known to be related to various cognitive functions including memory that are often dysfunctional in depression. Several authors have measured P300 amplitude and latency in depressed patients. Most report a decrease in P300 amplitude, which reverses on clinical recovery, but no change in P300 latency compared with controls Pfefferbaum et al 1984, Pfefferbaum et al 1995, Blackwood et al 1987, Muir et al 1991, Gangadhar et al 1993, Hansenne et al 1994. In contrast, patients with dementia show an increased P300 latency as well as a reduction in P300 amplitude Goodin et al 1983, St Clair et al 1985, Pfefferbaum et al 1984; however, Hendrickson et al (1979) reported an increased auditory P300 latency in elderly depressed patients; the increase was not so marked as in demented patients, but did not return to normal after clinical recovery from depression. More recently Kalayam (1997) reported the results of a preliminary study that also showed prolonged P300 latency in nondemented elderly depressed patients compared with control subjects.
The latency of the P300 component correlates with degree of impairment in various cognitive tests and is thought to reflect speed of information processing and memory functions Pritchard 1981, Polich 1996, Halgren et al 1995. Thus, prolonged P300 latency might be expected to correlate with impaired cognitive performance (especially memory and speed of information processing), and with the cortical or subcortical atrophy, especially of the temporal lobes, on the MRI scans of patients with depression. Cortical atrophy and increased ventricular size have been noted in late-onset depression Jacoby and Levy 1980, Alexopoulos et al 1993. Hickie et al (1995) found an association between white matter hyperintensities on MRI, late-onset depression, and impaired psychomotor speed.
Background EEG activity is related to states of arousal and attention. In general, increased slow-wave (delta, theta) activity is associated with decreased levels of arousal, and is found in dementia and, to a lesser degree, in elderly depressed patients Pozzi et al 1993, Nystrom et al 1986, Have et al 1991, Brenner et al 1986. Increased slow-wave activity might be expected to correlate with impaired cognitive performance and with evidence of cortical atrophy on MRI scanning. There appear to be no long-term studies of electroencephalographic (EEG) changes and cognitive performance after clinical recovery from depression in the elderly, and it is not clear to what extent the changes are reversible.
Although it is probable that elderly patients with depression are at no greater risk of developing dementia than the general population (Baldwin et al 1993), they often show residual deficits in cognitive function that are largely independent of age and distinct from dementia Weingartner et al 1982, Abas et al 1990, Austin et al 1992, Tarbuck and Paykel 1995, Beats et al 1996. These impairments may result from several factors: “psychological” mechanisms such as decreased attention and motivation, unwillingness to pursue effortful tasks, learned helplessness, and “catastrophic” responses to failure Miller 1975, Weingartner et al 1981, Weingartner et al 1982, Beats et al 1996, Elliott et al 1996, Hasher and Zachs 1979, Mialet et al 1996. In addition, many authors have noted associations of cognitive impairment with structural brain abnormalities, including ventricular dilatation, cortical atrophy, and white matter hyperintensities Pearlson et al 1989, Abas et al 1990, Junque et al 1990, Baldwin et al 1993, Hickie et al 1995, and with regional decreases in cerebral blood flow (Bench et al 1992). Thus poor cognitive function in elderly depressives may reflect both functional and structural deficits. Structural changes occur most frequently in patients with late-onset depression Baldwin et al 1993, Baldwin 1994, Hickie et al 1995, but it is not clear whether or not these patients are more cognitively impaired than those with early-onset depression. The degree to which cognitive function improves after clinical recovery from depression in the elderly is also unclear. Recent studies suggest that return of normal cognitive function is incomplete, and that persisting cognitive impairment is directly related to the number of episodes of depression and to indices of organic brain pathology Abas et al 1990, Austin et al 1992, Beats et al 1996. It is possible that in some elderly patients depression heralds the onset of irreversible dementia Alexopoulos et al 1993, Baldwin 1994. Cerebral blood flow in late-onset depression appears to be intermediate between that seen in Alzheimer’s disease and early-onset depression (Ebmeier et al 1996).
Computerized cognitive testing is used increasingly to assess cognitive function. The Cambridge Neuropsychological Test Automated Battery (CANTAB) has been utilized in many studies of cognitive performance in depression, dementia, and brain injury, and has been described in detail by Sahakian et al 1988, Owen et al 1990, Sahakian and Owen 1992, and Robbins et al (1994). It consists of three different batteries designed to measure visual memory, attention, and spatial working memory and planning. Beats (Beats et al 1996) applied the battery to elderly depressed subjects and found numerous impairments, some of which persisted after clinical recovery.
The present study addressed the question of whether there are structural, electrophysiological, and cognitive abnormalities in depression in the elderly, and whether changes persist after clinical recovery. Two hypotheses were explored: first, that elderly patients in remission from late-onset depression would show more structural abnormalities than those in remission from earlier onset depression; second, that following apparent clinical recovery the late-onset group would show more evidence of persisting functional impairment. Structural changes were investigated by MRI in elderly patients after clinical recovery from early- or late-onset depression. In both patients and in a control group of elderly subjects EEG evoked potentials and power spectral analysis were recorded, and cognitive performance was assessed in neuropsychological tests.
Section snippets
Subjects
Two well-matched comparison groups of recovered, elderly unipolar subjects, differing only in age of illness while free of risk factors for structural brain abnormalities, were recruited from the clinics of Newcastle Mental Health Trust.
Patients (aged 55–75 years, either sex) who had been treated for a primary unipolar depression (DSM-IV) and had made a satisfactory, persisting, clinical recovery were considered for inclusion when they had remained asymptomatic for a minimum of 4 weeks (mean
Early- and late-onset patients
Twenty depressed subjects agreed to attend for a MRI, but 2 patients became agitated by the procedure and were unable to complete the investigation. One subject, who normally wears a hearing aid, was unable to hear the technician’s requests to stop moving his head and as a result the images obtained were not of sufficient quality to make all the measurements. In the remaining 17 patients third ventricular width was significantly increased in the late-onset compared to the early-onset group
Discussion
Two principal findings emerge from this study. First, the MRI results showed that elderly depressed patients with late-onset depression have more structural brain abnormalities than those with early-onset depression. Second, functional impairments, as evidenced by electrophysiological and neuropsychological tests, persist long after the patient is clinically euthymic; however, there were no significant differences in these measures between early- and late-onset cases, suggesting that the
Acknowledgements
This investigation was supported by a grant from the Newcastle Mental Health NHS Trust Research Committee.
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