Methods

STUDY POPULATION

A sample of 647 non-institutionalised men and women aged 75 years or older residing in the Central Sydney Area Health Service participated in the Sydney Older Persons Study from 1991 to 1994.20 21 The sample consisted of two groups; randomly selected war veterans and war widows from a war veterans/widows listing in the same local area (n=327, response rate 82%) and non-veterans derived from a local area probability sampling scheme (n=320, response rate 73%). Men were in excess in the veteran sample, comprising 59.3% versus 39.7% of the community. Veteran and community subjects were compared across a range of variables examining demographic, lifestyle, psychological, functional, medical, and related factors to ascertain if they differed in significant ways. No significant differences were identified. Thus, rather than treating veteran and community subjects differently throughout the study data are pooled.

Of the 647 subjects at time 1537 participated in a medical assessment which included a standardised medical history examining past and current health and medication usage; a neuropsychological battery, and physical examination. The neuropsychological battery aimed to examine the following areas of cognition: memory, language, visuospatial function, and frontal and executive function. The neuropsychological battery consisted of well validated tests and included the mini mental state examination (MMSE)22; Reid memory test23; tests of verbal fluency (F, A, and S,24 and animals25); subsets of the Boston naming test26 and similarities27; clock drawing28 and copied drawings of a cube, coils, and interlocking infinity loops.29 Subjects not participating in the medical assessment at time 1 showed no significant differences in age, disability, number of falls, and MMSE scores.21Subjects were reassessed after a mean period of 3.19 years (range 2.61 to 4.51 years (SD 0.21)). Of the original 647 subjects, some information was available on over 95% at time 2. Time 1 and time 2 data indicated that those who died (n=128, 19.8% of the original 647) were sicker, older, more cognitively impaired, and more likely to be men. Time 2 refusals and non-contacts did not differ in age, MMSE score, number of drugs, number of falls, or disability as measured at time 1. At both assessments subjects gave written informed consent and the study had institutional ethics approval.

DEFINING THE PRECLINICAL SYNDROMES

Preclinical syndromes for the three main dementias (Alzheimer's disease, vascular dementia, and PDRD) both singly and in combination were defined. It was necessary to define multipathological preclinical syndromes as 34% of patients with dementia were found to be multiaetiological at time 1.21 With respect to vascular and extrapyramidal features the disorders may be present initially without evidence of cognitive deficits. We defined distinct sets of preclinical syndromes for vascular dementia and PDRD where cognitive deficits were either present or absent.

Subjects hypothesised as having preclinical Alzheimer's disease were defined as having cognitive impairment without either vascular or extrapyramidal features.

Vascular dementia is characterised by dementia with historical or clinical evidence of stroke30 31 in association with possible evidence of cardiac31 32 and peripheral vascular disease33 34 and the presence of vascular risk factors such as atrial fibrillation, hypertension, hypercholesterolaemia, diabetes, and smoking.30 31 35 At a predementia syndromal level any of these characteristics may be expected. Cognitive deficits at a preclinical level will depend on the site and severity of the cerebrovascular disease36 and may be absent. The “cognitive impairment plus prevascular” group included those with vascular features in combination with cognitive deficits whereas the “prevascular” group had no cognitive deficits.

Parkinson's disease and related dementias is characterised by dementia in association with prominent extrapyramidal (EP) features including bradykinesia, rigidity, and tremor. At a predementia level such abnormalities, of lesser severity, would be expected to occur in association with varying levels of cognitive deficits. The extrapyramidal groups are termed “pre-EP” and “cognitive impairment plus pre-EP”.

As both vascular and extrapyramidal features may coexist, two groups termed “prevascular plus pre-EP” and “cognitive impairment plus prevascular plus pre-EP” were also created. Thus a total of seven preclinical groups were created and the features of each of these is summarised in table 1.

There are three delineating features which characterise the seven preclinical groups; the presence of cognitive deficits, vascular features, and extrapyramidal features. Scales measuring these three concepts were defined.

Cognitive impairment

Subjects were clinically defined as having cognitive impairment if the subject did not reach DSM-III-R criteria37 for dementia and displayed mild to moderate deficits in one or more areas of cognition (memory, language, visuospatial, or executive function). Subjects did not display significant functional impairment as a direct consequence of their cognitive deficits. Weekly meetings attended by the examining physician, senior neurologists, and a neuropsychologist were held. Each assessment was reviewed and discussed to maintain diagnostic consistency. All information from the medical assessment and neuropsychological battery was used in the assignation of a diagnosis of cognitive impairment.

Vascular features

Two equally weighted components were defined. The first of these was an arteriopathy score. This score measured evidence of non-cerebral vascular disease in addition to vascular risk. Its components included atrial fibrillation, diabetes, hypertension, heart disease, claudication, self reported hypercholesterolaemia, and smoking history. The first six of these (scored dichotomously) were derived from International Classification of Diseases (ICD)-9 diagnoses assigned by a physician (HC) after review of the clinical assessment notes and diagnostic summaries. Smoking history (scored continuously from zero for lifetime non-smokers to one for the maximum smoking in the study population) was derived from self reports. Each component was scored out of 1 and was summed to create the arteriopathy score (maximum score 7). The mean arteriopathy score was 1.51 in non-demented subjects and 2.47 in subjects with vascular dementia, which was significantly different (p=0.000). No other dementia subgroups had an arteriopathy score that was significantly different from normal subjects. Thus a conservative cut off of three or more in the arteriopathy score was employed.

The second component of the vascular score measured evidence of cerebrovascular disease. International Classification of Diseases-9 diagnoses of transient ischaemic attacks and stroke were derived from the medical history and examination. Subjects met the prevascular criterion if they had either an arteriopathy score greater than or equal to three or an ICD-9 diagnosis of transient ischaemic attack, or stroke, or both of these.

Extrapyramidal features

Two components comprised the extrapyramidal measure. The first component was an extrapyramidal score (EP score) and the second an objective measure of extrapyramidal gait disorder. The EP score included measures of tone (rigidity, cogwheeling, nuchal rigidity), bradykinesia (slowed fine finger movements, reduced arm swing, and an overall clinical assessment of the presence of bradykinesia), resting tremor, postural flexion, and the glabella tap. Each of theses features was graded as zero absent; 0.33 mild; 0.66 moderate; 1 severe. A relatively conservative cut off of one or more in the EP score was used corresponding to either one severe sign, one moderate and one mild sign, or three mild signs. This cut off was therefore stricter than that employed in previous studies.38

The second component of the algorithm defining the pre-EP syndrome was an objective measure of extrapyramidal gait changes as assessed by the time to complete a 5 metre returned walk. In this study population 71% had a diagnosis of arthritis.21 Two procedures were employed to identify a time indicative of extrapyramidal slowing. The first of these was to adjust the timed walk for arthritis. Measures of functional severity of arthritis in both right and left hips and knees were summed to give a total lower limb arthritis score out of four. The timed walk was then adjusted for arthritis using a linear regression model. The second procedure employed was to find a “normal” timed walk. A group of normal subjects was defined as those subjects who did not have any of the following diagnoses: Parkinson's disease, stroke, dementia, lower limb arthritis, or the presence of ataxia as measured by greater than one step out of line or marked sway over 10 steps of tandem gait; 168 subjects fulfilled these criteria. Their mean timed walk was 12.55 seconds with an SD of about 4.50 seconds. A cut off point of the mean plus 2 SD for the adjusted timed walk, free of arthritis, was used to identify abnormal slowing. Thus, those subjects who had an adjusted timed walk of greater than 21.55 seconds were included in the extrapyramidal prodromal group.

DEMENTIA DIAGNOSES

Diagnoses of dementia made by a physician at time 1 fulfilled DSM-III-R criteria.37 Dementia diagnoses were made at the completion of the medical assessment using all information from the medical assessment and neuropsychological battery. Weekly meetings reviewing each assessment were attended by the examining physician, senior neurologists, and a neuropsychologist to maintain diagnostic consistency. The medical assessment at time 2 reflected that done at time 1 and diagnoses of dementia fulfilled the general DSM IV criteria (criteria A and B).39 Limited data are available indicating how the use of different diagnostic criteria may affect disease estimates. In available studies DSM IV may diagnose slightly fewer subjects as demented although the differences are small and further studies to verify these findings are required.40 41 In this study it was not possible to retrospectively apply either DSM IV criteria to time 1 data or DSM-III-R criteria to time 2 data and it is therefore not known how the use of different diagnostic criteria over the two waves may affect the results. However, to the extent that DSM-III-R may be more inclusive in the diagnosis of dementia, DSM IV dementia incidence at time 2 is based on a more unambiguously dementia free time 1 cohort.

A total of 308 subjects who were not demented at time 1 had two waves of medical data (fig 1). Among those who died before time 2 or did not have a medical assessment at time 2 (n=120) an informant questionnaire42 which examined the six domains of the clinical dementia rating (CDR) was used (n=86) to identify incident dementia cases in order to achieve more complete case ascertainment (sensitivity 80%, specificity 98%). A common problem in studies on the incidence of dementia is the lack of data on subjects who die between the two waves of assessment or have incomplete testing. In removing such subjects from analyses it is presumed that they did not become cases of incident dementia. In this study a validated informant questionnaire which has been found to have moderate agreement with clinician based CDR ratings42 was used, thereby achieving more complete case ascertainment. Subjects assessed by the informant questionnaire were diagnosed as demented if they were rated as mildly, moderately, or severely demented according to the informant CDR.

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Figure 1

Flow diagram of the study population. CDR=clinical dementia rating.

STATISTICAL ANALYSIS

Non-demented subjects who participated in a medical assessment at time 1 were defined as being either preclinical or well. Using well subjects as the reference group, a logistic regression model examined whether the preclinical syndromes (both as a group and as individual syndromes) were predictive of either death or dementia.