Late-onset Probands Research Articles

Early‐onset obsessive‐compulsive disorder: a subgroup with a specific clinical and familial pattern?

The familial nature of obsessive-compulsive disorder (OCD) has been previously demonstrated. The identification of candidate symptoms such as age at onset may help to disentangle the clinical and genetic heterogeneity of the disorder. In this study, the specificity of early-onset OCD was investigated, focusing on the effect of gender, comorbid conditions and familial risk of tics and OCD by studying a population consisting exclusively of patients with early-onset OCD. One hundred and forty-four patients having OCD were recruited in the study (108 early-onset probands and 36 late-onset probands). The early-onset probands and 199 of their first-degree relatives were investigated using structured interviews and questionnaires. This sample of early onset was mainly composed of children and adolescents (74 children and adolescents and 34 adults). The average age of onset of OCD is 9.98+/-3.2 years. Forty-four per cent of the probands have a comorbid tic disorder. The age-corrected morbid risk among the first-degree relatives is 17% for OCD and 12% for tics. Morbid risk for OCD and tics was independent of the presence of tics in probands. Only 32.6% of the probands have a positive family history of OCD. These findings are consistent with other reports in the literature that the morbid risk of OCD is elevated in relatives of probands with early-onset OCD. However, the majority of cases do not have a positive family history of OCD. This result suggests that early onset is not the only specific clinical marker for familial risk in OCD. Thus more work is needed to clearly elucidate other factors related to increased genetic vulnerability for OCD.

Role of familial factors in late-onset Alzheimer disease as a function of age.

Whereas early-onset Alzheimer disease (AD; usually onset at age < 50 years) has been defined with genetic mutation on chromosomes 1, 14, and 21, the degree of familial contribution to late-onset AD is unclear. Further, it is uncertain if subgroups of late-onset AD exist. To examine the influence of familial factors as a function of age in late-onset AD we investigated lifetime risks and age-specific hazard rates of AD-like illness among late-onset AD probands' and controls' first-degree relatives, using questionnaires and medical records. As part of a longitudinal study on aging and AD, we studied 78 AD probands with age of onset > or =50 years (28 "definite" and 50 "probable" AD according to NINCDS/ADRDA criteria) and 101 healthy old controls seen since 1981. Both probands and controls were screened rigorously with medical tests and brain imaging and seen regularly until autopsy. Multiple informants and medical records were used for first-degree relatives. Among first-degree relatives, 49 secondary cases of AD-like illness were found for the AD probands' relatives (391 relatives 40 years old or older) compared with 20 cases among controls' relatives (456 relatives 40 years old or older). Relatives of AD probands had a significantly increased lifetime risk of AD-like illness of 52.8+/-11.4% by age 94 years compared with a lifetime risk in relatives of controls of 22.1+/-5.8% by age 90 years. Age-specific hazard rates in relatives of AD probands increased until the 75-79-year age interval and then decreased; in contrast the age-specific hazard rates increased in relatives of controls after the 80-84-year age interval. To determine if a dividing line exist among late-onset AD, several cutoff ages were used in our study to compare cumulative risk curves of AD-like illness between relatives of late-onset probands and relatives of late-late-onset probands. Differences in the pattern of cumulative incidence of AD in relatives showed that 67-71 years is the range for a dividing line between late- and late-late-onset AD. Age-specific hazard rates of AD in relatives supported a difference between late- and late-late-onset. Whereas these rates increased until the 75-79-year age interval and then decreased in late-onset AD, the rates began increasing after the 65-69-year age interval and through the oldest age interval in both late-late-onset AD and control groups. Our results support the concept that familial factors exist in late-onset AD and that different familial factors may exist in late-onset AD subgroups.

Family history in recurrent depression

The authors report morbid risks found for depression, alcoholism, and bipolar disorder in first-degree relatives of 179 probands with recurrent depression. Comparisons were made for relatives' gender, probands' gender, and probands' age at onset. Results showed overall morbid risks of 20.7% for non-bipolar depression, 15.4% for alcoholism, and 1.1% for bipolar disorder. Female relatives were found to be at greater risk for depression than males, while the reverse was true for alcoholism. Sex of proband had no effect. Risk to relatives of early-onset probands was significantly elevated compared to late-onset probands. Various cutoffs for ages at onset were examined, and the effect became more marked as the cutoff age was decreased to 20.

Age-of-onset and genetic transmission in affective disorders.

Age-of-onset data were gathered on first-degree relatives of 252 probands with bipolar and unipolar affective disorders. Early onset probands (younger than 40 at onset) had more early onset relatives and a greater risk for affective disorder among their relatives than late onset probands (40 or older). This indicates that age-of-onset is a familial factor correlated with the liability to affective illness. Multiple threshold models of inheritance were applied to the data using age-of-onset as a liability-threshold determinant. The hypothesis of autosomal single-major locus was ruled out. Multifactorial-polygenic inheritance provided a better fit to the data. The data suggest that early and late onset affective disorders can be placed at different thresholds on a genetic environmental continuum and that the early onset form is more deviant genetically than the late onset type. The implications for genetic research in affective disorder are discussed.

Morbidity risks in subtypes of unipolar depressive illness: differences between early and late onset forms.

Despite the high prevalence of unipolar depression in the general population, few genetic studies are available on subtypes of unipolar illness. We evaluated morbid risks for depression, alcoholism and/or sociopathy in the relatives of early onset (before age 40) and late onset (after age 40) unipolar patients in a sample of 106 probands consecutively admitted to the New York State Psychiatric Institute. unipolar patients with an early onset disease have a greater familial morbidity for depression, alcoholism and sociopathy than unipolar patients with a late onset disease. There is an excess of unipolar depression in female relatives of early onset unipolars when compared to late onset probands, regardless of the proband's sex. Alcoholism and sociopathy are also more prevalent in the relatives of early onset unipolars versus late onset probands. Our morbidity risk data show familial genetic differences between early and late onset forms of unipolar illness and partially confirm Winokur's concept of two subtypes of unipolar depression.

Early- and Late-Onset Bipolar Illness

We categorized a sample of 134 bipolar probands into early- and late-onset groups; age 30 years was the cutting point. Early-onset probands had three times the morbidity risk /MR) for affective disorder in first-degree relatives as late-onset probands and a greater proportion of relatives with the more severe, bipolar form. Early-onset patients also exhibited more neuropsychological dysfunction, less frequently had a unipolar manic course, and had a greater MR for alcoholism in first-degree relatives. The two groups did not differ in other clinical or historical characteristics or in the proportion of EEG abnormalities. Age at illness onset is useful in clarifying the genetic basis of affective disorder. The data are consistent with a polygenic or multifactorial model of illness in which the more severe genotype is expressed earlier in life and through the course of illness.

Types of depressive illness.

A major problem in the affective disorders is what constitutes an homogeneous illness. A recent study enabled us to separate depressive illnesses into two types (1). The first we have called ‘depression spectrum disease’; its prototype is a female with an onset of a depressive illness before the age of 40, in whose family more depression is seen in female relatives than in male relatives, the deficit in males being made up by alcoholism and sociopathy. The second illness we have called ‘pure depressive disease’, the prototype of which is a male whose depression starts after age 40 and in whom there are equal amounts of depression in both male and female relatives and no large amount of alcoholism or sociopathy in the males. First degree relatives of depression spectrum disease are more likely to be psychiatrically ill (depression, sociopathy or alcoholism) than first degree relatives of pure depressive disease probands. Data of Hopkinson and Ley support this concept in part (2); they found that early-onset affective probands (&lt; 40) had higher morbid risks for affective illness in relatives than late-onset probands (onset after 40). Further confirmation comes from a study of 259 alcoholics and their first degree relatives (3). Most of the psychiatrically ill male relatives had alcoholism; most of the psychiatrically ill female relatives had depression. As of the present the differentiation of the two kinds of depressive illness is made on the basis of a specific familial predisposition. Major clinical differences in the two groups have eluded us.