IPA Bulletin
Recent Advances - Volume 16, Number 4
John O'Brien and Bob Barber
A multicenter, randomized, double-blind, 26-week, placebo-controlled study of the symptomatic treatment of Alzheimer’s disease (AD) with rivastigmine was published in the BMJ (Rösler et al. 1999;318:633-40). Subjects were aged 50-85 years with MMSE scores between 10-26. Concomitant, non-life threatening conditions were not exclusion criteria. Patients were randomized to receive placebo, lower dose (1-4mg) or higher dose rivastigmine (6-12mg/day) over a 12-week dose escalation period. The study found the higher dose was more effective with statistically significant improvements in cognitive function (as measured by ADAS-Cog), global evaluation of improvement (using CIBIC) and activities of daily living (as measured by the Progressive Deterioration Scale). As with other cholinesterase inhibitors, the effect was relatively modest: for example only 8% more patients on higher dose (mean 10.4mg/day) improved by 4 points or more on ADAS-Cog compared to the placebo group (24% vs. 16%). Gastrointestinal adverse events were relatively common, especially during dose escalation.
Serial MRI scans of younger subjects at risk of AD (by virtue of a positive family history) may help predict those who become affected (Fox et al. Lancet 1999; 333:2125). Five subjects who developed AD from a cohort of 28 at-risk subjects had a median rate of global cerebral atrophy of 1.5% per year, compared to 0.1% in unaffected subjects and 0.2% in controls. In some cases volume changes were evident even before the onset of symptoms. Whether this technique is useful in older patients remains to be determined.
Screening for depression can be both effective and quick according to a preliminary study (Hoyl et al. JAGS 1999;47:873-878). Developing and testing yet another version (this time, a five-item form) of the Geriatric Depression Scale (GDS) for use in frail community-dwelling older patients, they found the five-item GDS was as effective as the 15-item GDS. Unsurprisingly, it was also quicker to administer. The five questions identified were: (1) Are you basically satisfied with your life? (2) Do you often get bored? (3) Do you often feel helpless? (4) Do you prefer to stay at home rather than going out and doing new things? (5) Do you feel pretty worthless the way you are now?
The link between depression and increased mortality is well recognized. Whether this relationship also holds true in subjects with dementia was the focus of a study by Janzing and associates (Psychological Medicine 1999;29: 979-983). Examining 73 subjects with dementia (median age = 87 years, MMSE = 19) they found 32% died over 12 months. Baseline depressive symptoms predicted short-term mortality, suggesting the same mechanisms underlying the link between depression and mortality in cognitively intact subjects may still be relevant in people with dementia.
Emotional lability following stroke can distress in both patients and their families, and has been attributed to abnormalities in serontonergic activity. To test this hypothesis, Burns et al. (International Journal of Geriatric Psychiatry 1999;14:681-685) examined the benefits of treatment with an SSRI (sertraline, 50mg/day) in 28 non-depressed patients with post-stroke labile mood using a double-blind, randomized, placebo-controlled design. The findings were consistent with the original hypothesis, with the treatment group showing significant improvements in overall emotionalism, and more specifically, levels of tearfulness.
“Do broken hearts lead to broken bones?” Researchers from Norway conducted a 3-year prospective study of over 18,000 women aged 50 and above to examine the relationship between mental distress and risk of hip fractures (Forsen et al. J Epidemiology and Community Health 1999;53:343-347). Controlling for the effects of medication, higher levels of mental distress were independently associated with increased fractures. In a separate community study of healthy older people, higher baseline urinary cortisol levels were also an independent predictor of future fractures (Greendale et al. JAGS 1999;47:799-803). Perhaps mental distress leads to elevated cortisol levels which in turn increase the risk of osteoporosis and eventual fractures?
Exposure to cortisol may also impair cognitive function, according to American scientists (Newcomer et al. Archives of General Psychiatry 1999;56:527-533). During the period of administration of cortisol (at doses comparable to concentrations experienced with physical and psychological stress) memory function became impaired in otherwise healthy individuals. This effect may be mediated by impaired hippocampal metabolism and could, theoretically, be relevant in linking stress and memory impairment.
Additional factors that may influence or hasten cognitive decline in elderly subjects were examined in two large community studies. Haan et al. (JAMA 1999; 282:40-46) recruited 5888 subjects (over 65 years) and followed them for five to seven years as part of a Cardiovascular Health Study. The majority of subjects (70%) showed no evidence of cognitive decline. A range of vascular risk factors, including systolic blood pressure, atherosclerosis of the carotid arteries, peripheral vascular disease, and diabetes mellitus, among others, were associated with a deterioration in cognitive function. The presence of ApoE e4 allele modulated the impact of these factors, substantially increasing the risk of cognitive decline. In a separate study, Moroney et al. (JAMA 1999;282:254-260) followed up 1111 non-demented subjects (mean age 75 years) for just over two years. Approximately a quarter developed dementia. Of those classified as having dementia with stroke, higher levels of low-density lipoprotein (LDL) cholesterol were associated with a three-fold increase in risk of dementia. Whether treatment to reduce LDL levels will reduce the risk of dementia remains to be proved.
The 276 people in Denmark who became centenarians between 1 April 1995 and 31 May 1996 took part in a large study (n=3351) to examine the relationship between physical disability and age (from 75 to 100 years) (Andersen-Ranberg et al. Age and Ageing 1999;28:373-377). Physical abilities gradually declined with advancing age, with the lowest levels among 100-year-olds, though one-fifth of female centenarians, and over two-fifths of male centenarians, were still performing well on a range of activities of daily living. The authors concluded that although men die at an earlier age, women tend to be more disabled in later life.
Can exercise improve cognitive function in late life? Perhaps so, according to correspondence in Nature (Kramer et al. 1999;400: 418-419). The researchers examined the relationship between aging, fitness, and neurocognitive function by randomly allocating 124 previously sedentary adults (aged 60-75 years) to either aerobic (walking) or anaerobic (stretching) exercises. Overall, subjects engaged in aerobic exercise showed greater improvements in cognitive function compared to the anaerobic group, especially in frontal executive functions. To explain this potential link, the authors drew on previous animal studies that have reported improved cerebral metabolic and neurochemical function following aerobic exercise. The other good news was that cognitive function improved with only small increases in aerobic fitness.
Further evidence of the benefits of exercise and physical activity came from a Dutch study (Hopman-Rock et al. International Journal of Geriatric Psychiatry 1999;14:633-642). Over one hundred subjects with dementia living in residential homes were randomized to receive either “Psychomotor Activation Program” (PAP) or the control intervention. They found PAP had benefits on both cognitive performance and behavior. In a separate study with similar findings, increased physical activity coupled with improvements in the night-time environment eased agitation and improved sleep in nursing home residents (Alessi et al. JAGS 1999;47:784-791).
Readers may find the September-October edition of Dementia useful. The entire edition reports on the symposium on Aging and Aging Disorders held in Stockholm in September 1998, and is entitled “Delirium in the elderly: epidemiological, pathogenic, diagnostic and treatment aspects.” A supplement to Neurology (1999;52:Suppl. 3) covers another important topic, that of depression, psychosis, and dementia in Parkinson’s disease.
The enzyme transglutaminase may be the missing link in the pathogenesis of Huntington’s disease. An Israeli-US collaboration found increased activity of transglutaminase in the cortex, cerebellum, and brain nuclei of patients with Huntington’s disease (Karpuj et al. Proc Natl Acad Sci USA 1999;96:7388-7393). The team suggested that this enzyme may catalyze the formation of huntingtin aggregates in nuclear inclusions, a pathological marker of the disease, opening the window for potential therapeutic interventions.
Dementia guidelines have their supporters and opponents, but either way they are becoming more and more common. A team of researchers from New York set about evaluating whether an educational program could improve adherence by neurologists to guidelines promoting six recommendations for the evaluation and management of dementia (Gifford et al. Annals of Internal Medicine 1999;131:237-246). Hypothetical clinical scenarios were used to measure the response to the educational interventions. It appeared physicians could be encouraged to adopt the guidelines, though questions remain as to whether this effect would carry through in to routine clinical practice.
The therapeutic implication of the inflammatory hypothesis of AD was assessed in a 25-week pilot study (Scharf et al. Neurology 1999;53:197-201). Using a double-blind, placebo-controlled trial design with standard outcome measures, 41 patients with mild to moderate AD were randomized to either placebo or diclofenac (nonsteroidal anti-inflammatory drug), co-administered with misoprostol, a gastro-protective agent. No group differences were observed across a range of scales measuring cognitive function, non-cognitive symptoms, functioning, and global impression of change, though there were some non-significant trends. Withdrawal rates were high (12/24) in the treatment limb but no major adverse events occurred. The authors suggest further, larger, studies are necessary.
The use of neuroleptic drugs in the treatment of dementia with Lewy bodies (DLB) can be both troublesome and dangerous. Whether newer, atypical neuroleptic drugs with lower affinity for D2 receptors are better tolerated and more effective is still uncertain. Walker and colleagues carried out a small study (n=8) to examine the effects of olanzapine (2.5-7.5mg/day) on psychotic and behavioral symptoms in DLB (International Journal of Geriatric Psychiatry 1999;14:459-466). Two patients had clear improvements, three tolerated the treatment but without any obvious gain, and three could not tolerate treatment, even at the lowest dose. The authors reiterate the need for caution when using neuroleptics in DLB, and suggest atypical drugs confer little advantage over conventional neuroleptics.
Drs. John O'Brien and Bob Barber are the IPA Bulletin's
research editors. They welcome comments via (fax) +44 191 219 5040 or (e-mail)J.T.O'Brien@ncl.ac.uk
Drs. John O'Brien and Bob Barber are the Research
Editors of the IPA Bulletin. They welcome readers' comments via
e-mail (J.T.O'Brien@ncl.ac.uk) or
fax (+44 191 219 5040). John O’Brien
also is Deputy Editor of the IPA Bulletin.
