The clinical phenotype of familial and sporadic late onset Alzheimer's disease

BACKGROUND: Familial factors are clearly associated with an increased risk of developing late onset Alzheimer's disease (LOAD). However, there is emerging evidence to suggest that familial factors may also influence clinical phenotype. To date, most studies have focussed on familial influences upon age of onset or duration of illness and few studies have compared the frequency of non-cognitive symptoms between familial and sporadic LOAD. OBJECTIVE: To describe the clinical phenotype, with an emphasis on non-cognitive symptoms, of patients with LOAD and to explore familial differences. METHOD: 374 patients with LOAD were recruited from the community based Camberwell Dementia Case Register and a comparison made of the clinical phenotype of patients with and without a first degree family history of dementia. RESULTS: A first degree family history of dementia was found in 27% of fully ascertained cases. An earlier age of onset was found in familial cases (77.2 years compared to 78.3 years, p<0.05). However, no other differences in clinical phenotype, including the rate of cognitive decline, duration or the frequency of non-cognitive symptoms, were found between familial and sporadic cases. CONCLUSIONS: Apart from an earlier age of onset, patients with familial LOAD, as a group, do not have major differences in their clinical phenotype compared to patients with sporadic LOAD.     

A gender difference in the association between APOE genotype and age-related cognitive decline.

OBJECTIVE: To determine whether the APOE epsilon4 allele is associated with age-related intellectual decline in a community-dwelling sample of Danes. METHODS: A sample of 189 subjects who did not have dementia was tested with the Wechsler Adult Intelligence Scale (WAIS) at the ages of 50 and 80 years. Of these subjects, 163 (84 women and 79 men) completed all WAIS subtests at both assessments and 139 completed the digit symbol and block design subtests at the ages of 50, 60, 70, and 80 years. RESULTS: Cognitive decline from the age of 50 to the age of 80 years was substantial and larger for the performance subtests than for the verbal subtests (the declines were 18.40 for the performance IQ and 8.39 for the verbal IQ). APOE genotype was unrelated to the observed WAIS results of the 80-year assessment, but there was a significant interaction between APOE genotype and sex for decline scores in the performance IQ and three performance subtests (digit symbol, block design, and object assembly). In women, 26 epsilon4 carriers showed larger decline than 58 noncarriers, whereas there was no significant relation between APOE genotype and cognitive decline in men. The association in women between APOE genotype and cognitive decline was significant only for decline in the decade from age 70 to age 80 years. The interaction between sex and APOE genotype remained significant when education was included as a covariate. CONCLUSION: The APOE epsilon4 allele is associated with normal age-related decline in cognitive functions in women only. This finding may be supportive of recent evidence suggesting sex differences in APOE-associated risk for AD. Thus, the sex difference in the risk of sporadic AD may partly be explained by a sex-specific impact of the APOE epsilon4 allele on age-related cognitive decline.     

家族性与散发性难治性精神分裂症的对照研究

目的 探讨家族性与散发性难治性分裂症患者的临床特点。方法 在533例住院分裂症患者中有113例符合难治性分裂症的标准，其中根据有无精神病家族史分为家族性分裂症组(研究组)和散发性分裂症组(对照组)，对研究组与对照组的临床资料进行比较。结果 研究组与对照组相比，在首次发病年龄上差异有显著性意义；而在性别、病前性格、文化程度、有无诱因、起病形式、治疗前病程、总病程、病程特点、住院次数、服药依从性、社会支持、家庭经济水平、症状特点及诊断分型等方面差异均无显著性意义。结论 首次发病年龄对于分裂症遗传学研究具有重要意义。     

Comparison of sporadic and familial disease amongst 580 cases of motor neuron disease.

A review of 580 hospital case notes of patients with motor neuron disease (MND) revealed 20 families in which more than one case had been reported. For 27 of the cases in these families full medical records were available, and a history of a further 37 affected family members were obtained. The cases in these 20 families are termed familial and the remainder sporadic. Parent to child transmission occurred in 16 of the 20 families of the familial cases, suggesting autosomal dominant inheritance. In three families there was involvement of siblings only, and in one family two cousins were affected. The sex ratio for the documented familial case records seen was 0.8:1 (M/F = 12:15), for the total (documented and historical) it was 1.06:1 (33:31), but in sporadic cases it was 1.6:1 (341:212) and more frequent occurrence of sensory features at presentation was reported in the familial cases (15% in the familial cases and 5% in the sporadic cases). However, none of these differences reached statistical significance. Familial cases also differed from sporadic cases in having a younger age of onset (a mean of 52 years in the familial cases compared with 56 years in the sporadic) and in the shorter median reported duration of illness (1.1 year in the familial cases; 2.6 years in the sporadic). However, in only one fifth of sporadic cases was the age at onset and death known, although this was known for 22 of the 27 familial cases, so that the data on survival and age of onset are too incomplete to test formally.     

Age of onset in familial and sporadic schizoph4.4.renia

We have studied the gender and family history differences with regard to age of onset of schizophrenia. These differences have often been viewed as an important clue to the aetiology of the illness. Patients from three centres in Europe and Canada were included in the study. A sample of 1089 subjects was categorized according to the subject's sex, family history of schizophrenia, and the centre. The principal statistical method was analysis of variance. Patients with no family history of schizophrenia had a consistently higher average age of onset. This effect was seen in both male and female subjects across all three groups. These results support the relationship between familial risk and early onset, but no interaction of gender and family history was found.     

Familial (genetic) subtypes of pure depressive disease.

The author reviewed data from five studies and found that depressed patients with a history of depression in a parent or child have more sibships containing depression than depressed patients without this family history. Thus, there is a clustering of depressions in certain families. Sporadic pure depressive disease (PDD), where no depressive illness exists in a first-degree family member of a depressed proband, is associated with a later age of onset than familial PDD, where depressive illness does exist in a first-degree relationship. The possibility exists that familial PDD and sporadic PDD are autonomous illnesses. The presence of a family history of depression may be predictive to some extent of a good response to adequate tricyclic medication or ECT.     

Family history of affective illness in schizophrenia patients: Symptoms and cognition

This study examined the relationship between having a family history of affective disorder and neuropsychological functioning and PANSS symptoms in schizophrenia patients falling into four exclusive family history groups (affective spectrum disorders, schizophrenia spectrum disorders, both, or neither). Schizophrenia patients with a family history of affective illness had the best performance on IQ tests and executive function measures. Symptoms showed fewer family history group differences. Schizophrenia patients with a family history of affective disorder may be a distinct subtype in the group of schizophrenias and may be biologically more similar to patients with serious affective disorder.     

Comparative study of neuropsychological correlates in schizophrenia with onset in childhood, adolescence and adulthood

Childhood onset schizophrenia (COS) patients have marked neuropsychological deficits in areas of attention, working memory and executive functions. Similar deficits have been found in studies on Adolescent onset (AdOS) and Adult onset schizophrenia (AOS). In this study we compared the neuropsychological profile of COS with AdOS and AOS to test the hypothesis that earlier the onset greater is the severity of illness and greater are the neuropsychological deficits. A sample of 15 patients of COS was compared with 20 patients each of AdOS and AOS group. Assessment of neuropsychological profile was done using standard neuropsychological battery for Indian population. Nahor Benson Test and Bender Visual Motor Gestalt Test were used to assess perceptuomotor functioning. COS patients showed significantly greater deficits on scales of IQ, memory and perceptuomotor skills as compared to AdOS that in turn had greater deficits than AOS. The persistence of differences across the three groups inspite of controlling for education and age suggest that these deficits may have been present even before the onset of illness and was not the result of poor academic achievements. These findings also point towards a brain damage in schizophrenia that occurs on a continuum of severity with COS being the most virulent, AOS being the least and AdOS falling in between these two extremes.     

The impact of familial loading on gender differences in age at onset of schizophrenia

To evaluate the impact of familial loading and gender on age at onset, 197 schizophrenic patients were investigated. Patients with familial loading had an earlier age at onset without gender differences. In contrast, an earlier age at onset for men was found in sporadic cases. These data support that both gender and familial loading contribute to the heterogeneity of schizophrenia.     

Clusters in a cohort of untreated schizophrenia: prognostic importance, atypical cases and the familial versus sporadic distinction.

In search of features of prognostic importance, a cohort of patients admitted to a mental hospital in 1925 was investigated by means of multivariate clustering techniques. Using K-means cluster analysis or Q-factor analysis, a group containing cases with unfavourable prognosis was isolated. Other groups derived were prognostically heterogeneous. One group of patients, in early phases similar to good prognosis schizoaffective psychoses, could be distinguished and characterized by non-symptom items. There was initial periodicity and onset was acute. They were, on average, younger than the other subjects and there was no personality deviation or emotional disturbance before onset of disease. A family history of mental illness was rare. Two of the factors were positively and negatively characterized by items covering familial history of mental illness, thus seemingly confirming the familial vs sporadic distinction in the subclassification of schizophrenia. Though the clinical pictures were distinctively different at the time when the ratings underlying the analysis were made, approximately the same proportion of cases in the two groups had independently been diagnosed as paranoid schizophrenia--also taking the course of illness into account. It could furthermore be shown that the population at risk--siblings and children of subjects--as well as the observed number of years at risk in these groups were significantly smaller in the sporadic group than in the familial group. This was a combined effect of a lower fertility in subjects and parents in the sporadic group and a higher rate of drop out due to mortality and other reasons among siblings of these subjects. The same tendency was indicated when subjects with and without family history irrespective of factor belongingness were compared. It cannot be concluded that the familial vs sporadic distinction is without relevance in the research on schizophrenia, but its essence may easily be obscured, if the population at risk is not taken into account.     

Neuropsychological impairment and psychopathology in first-episode schizophrenic patients related to the early course of illness

The objective of the present study was to explore whether the early course of illness including first onset of psychotic symptoms influences neuropsychological functioning and psychopathology in first-episode schizophrenics. Patients with a short prodromal period (n = 20) and patients with a long prodromal period (n = 20) and controls matched with regard to age, gender and education (n = 40) were administered a battery of standardized neuropsychological tests and psychopathological rating scales. The results indicate an overall difference in neuropsychological performance with the schizophrenic patients scoring lower than controls. Schizophrenic patients scored significantly lower in all subtests except in visual memory and abstraction/flexibility than controls. No significant difference between neuropsychological performance between patient samples was found. Psychopathology was more pronounced in the long prodromal period group rating higher on negative and affective symptoms compared with the short prodromal period group. The data suggests that neuropsychological deficits in first-episode schizophrenia are independent of the early course of schizophrenia, and although negative symptoms are associated with the length of the prodromal period, they do not imply greater neuropsychological impairment. Received: 30 May 1997 / Accepted: 10 October 1997     

Cognition in Late-Onset Friedreich Ataxia

Friedreich ataxia (FRDA) is the most common hereditary ataxia. Since the discovery of the genetic cause of this disease, the phenotypic spectrum seems to be wider, including late-onset forms such as late-onset Friedreich ataxia—LOFA (25–39 years at onset). The neuropathological and clinical patterns in patients with LOFA are similar to those in patients with typical FRDA, but LOFA patients tend to have an overall milder, slowly evolving disease. Given the lack of data about cognitive performance of LOFA, we aimed to investigate whether differences in age at disease onset may be related also to differences at a cognitive level. Twenty-nine typical FRDA and seven LOFA patients were administered a comprehensive neuropsychological battery measuring multiple domains: processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions, and language. There were no significant differences in disease duration between the two groups of patients. Every patient group was matched in gender, age, years of education, and estimated IQ with a healthy-participant control group. Results indicate that both patient groups shared slowed motor processing speed and impaired conceptual thinking and verbal fluency. However, only typical FRDA patients showed a diminished cognitive processing speed and impaired visuoperceptive and visuoconstructive abilities. This pattern indicates that a later disease onset is associated to a milder cognitive impairment. Thus, our findings are in concordance with those related to clinical differences between typical FRDA and LOFA.     

Do women without a family history of schizophrenia have a later onset of schizophrenia?

The relation among age at onset of schizophrenia, sex and the presence or absence of first-degree relatives with schizophrenia was investigated in 2,417 inpatients meeting the DSM-III criteria for schizophrenia. The mean age at onset of female schizophrenic patients without a family history of this illness was slightly later than that of any of the other three groups (male familial, female familial and male nonfamilial groups). The female nonfamilial group developed schizophrenia after the age of 25 and 30 more frequently than the male familial group and female familial or male nonfamilial group, respectively.     

Clinical and neuropsychological correlates of cerebral ventricular enlargement in schizophrenia

A comprehensive assessment of computed tomography (CT) with respect to clinical, historical and neuropsychological variables has been carried out in a sample of DSM III schizophrenics fairly heterogenous with respect to duration and severity of illness and in a normal control group matched for sex, age and educational level.

The mean value of ventricular brain ratio (VBR) was significantly higher in schizophrenics than controls. Seven patients (21.2%) who had VBRs exceeding 2 SD of the control mean showed a significantly longer duration of illness than the other schizophrenics with significantly higher scores on the subscales alogia, effective flattening and attentional impairment of SANS, on the scales self-care and behaviour in crises and emergencies of DAS, on the scales rhythm, tactile, visual, reading, arithmetic, memory and left hemisphere of LNNB, and on the subtests arithmetic, digit span, digit symbol and block design of WAIS.

These results confirm earlier reports of an enlargement of lateral cerebral ventricles in a subset of schizophrenics, and its association with a higher degree of cognitive and neuropsychological impairment, social maladjustment and defectual symptomatology. Moreover, they suggest that the neuropathological process likely to underlie the increase of cerebral ventricular size progresses during the course of the illness rather than predating its onset.     

Do Women without a Family History of Schizophrenia Have a Later Onset of Schizophrenia ?

Abstract: The relation among age at onset of schizophrenia, sex and the presence or absence of first-degree relatives with schizophrenia was investigated in 2,417 inpatients meeting the DSM-111 criteria for schizophrenia. The mean age at onset of female schizophrenic patients without a family history of this illness was slightly later than that of any of the other three groups (male familial, female familial and male nonfamilial groups). The female nonfamilial group developed schizophrenia after the age of 25 and 30 more frequently than the male familial group and female familial or male nonfamilial group, respectively.     

Neuropsychological functioning in MRI-derived subgroups of schizophrenia

This study examined neuropsychological functioning in two subgroups of patients with familial schizophrenia. Those who showed evidence of progressive ventricular enlargement observed across serial MRI scans (n=6) were compared with subjects whose ventricular volume remained static (n=10) over an average of 28 months. No differences were found in terms of age, education, ethnicity, level of psychotic symptomatology, DSM-IV subtype, age of onset, or duration of illness. Neurocognitively, the static ventricle group was impaired across more cognitive domains and had a larger percentage of subjects falling into the impaired range on a majority of measures, with the greatest differences on measures of attention (p<0.02) and nonverbal memory (p<0.07). These results suggest that clinically meaningful differences between these two MRI-derived subgroups of patients with schizophrenia may exist, and further underscore the heterogeneity of the illness.     

Epidemiological and clinical correlates of familial and sporadic schizophrenia

We studied 68 schizophrenic cases with a schizophrenic first-degree relative (familial group) and 62 cases without such a family history (sporadic group). We compared them on: (i) clinical variables, including premorbid adjustment, age of onset and severity of symptoms; (ii) neural abnormalities, including abnormal involuntary movements, neural “soft” and “hard signs”; (iii) neuropsychological tests, including the Wechsler Adult Intelligence Scale and the Continuous Performance Test and (iv) environmental risk factors, including winter birth and obstetrical complications. Sporadic cases were more likely to be born in winter and had more severe psychotic symptoms, but most analyses yielded no difference between the groups. Our results offer some support that sporadic schizophrenia is a more environmental subtype, but they also suggest that the familial vs sporadic distinction of schizophrenia has limited power to identify distinct subgroups.     

Clinical characteristics of familial versus sporadic alcoholism in a sample of male and female patients.

Presence of a family history of alcoholism may predict clinical characteristics in affected subjects, such as an earlier age at onset. More frequent and severe social maladjustment and somatic complications are also regularly cited for familial alcoholism, although subject to many other confusing factors. We analysed the clinical specificities of 79 alcohol-dependent inpatients according to the absence versus presence of family history of alcoholism. Patients were evaluated for lifetime psychiatric morbidity with the Diagnostic Interview for Genetic Studies (DIGS), for somatic complications with a systematic screening list, and first-degree relatives (N = 428) were assessed with the Family Inventory Schedule and Criteria (FISC). Age at onset and social complications were predicting familial versus sporadic alcoholism, even when considering censored data and/or interaction between variables. But differences became non-significant when excluding patients with antisocial personality. If age at onset effectively appears to be the most informative characteristic for predicting familial versus sporadic alcoholism, it seems that it may be necessary in future studies to systematically take into account antisocial personality diagnosis, because of a probable contamination.     

Level and pattern of neuropsychological functioning in early-onset psychoses

The present study aimed to compare the level and pattern of cognitive deficits in patients with early-onset psychoses with an age, gender and IQ matched control group. In order to ensure a representative sample of patients with psychoses, participants with an IQ of less than 70 were included. Forty-eight patients with an onset of psychoses before the age of 16, and 47 age, gender and IQ matched controls without psychoses were recruited. Psychotic symptomatology was assessed using the Schedules for Clinical Assessment to obtain DSM-IV and ICD-10 diagnoses. Positive and negative symptoms were assessed using the Positive and Negative Symptoms Scale. Levels of cognitive function were measured using a comprehensive neuropsychological battery. A pattern of specific impairments was not found, with few significant differences between the two cohorts. However both cohort groups performed lower than age derived norms. Therefore it appears that there are global cognitive deficits rather than specific deficits in early-onset psychoses when compared to normative data, in-line with conclusions of early-onset schizophrenia research, but patients did not have greater deficit than controls when matched on IQ, gender and age, even after excluding participants with IQ less than 70.     

At issue: Sex and gender in schizophrenia

Using data collected in a study of sex differences in schizophrenia, I undertook this study to show the utility of distinguishing between sex and gender in the study of schizophrenia. Schizophrenia and schizoaffective disorder were combined to yield 213 patients (141 men, 72 women). There were 98 healthy controls (41 men, 57 women). The relative contributions of sex and gender to the prediction of age of first hospitalization and neuropsychological functioning were examined in linear regression analyses. Sex, but not gender, was a significant predictor of age at first hospitalization, even when controlling for illness severity. Among patients, sex and gender significantly contributed to the prediction of neuropsychological performance, beyond the contributions of education, age, and illness severity. Comparable results were found among healthy controls, although gender was significant only for women. For both healthy subjects and patients, more frequent endorsement of female typical social roles predicted better neuropsychological functioning. Being female also predicted higher neuropsychological scores in patients. The findings suggest that some aspects of schizophrenia study, such as the disorder's onset, may be best pursued from a more biological (sex difference) perspective, while a sociocultural (gender difference) perspective may best serve other aspects of study, such as neuropsychological functioning.