Brain abnormalities in bipolar disorder detected by quantitative T1ρ mapping.

Abnormal metabolism has been reported in bipolar disorder, however, these studies have been limited to specific regions of the brain. To investigate whole-brain changes potentially associated with these processes, we applied a magnetic resonance imaging technique novel to psychiatric research, quantitative mapping of T1 relaxation in the rotating frame (T1ρ). This method is sensitive to proton chemical exchange, which is affected by pH, metabolite concentrations and cellular density with high spatial resolution relative to alternative techniques such as magnetic resonance spectroscopy and positron emission tomography. Study participants included 15 patients with bipolar I disorder in the euthymic state and 25 normal controls balanced for age and gender. T1ρ maps were generated and compared between the bipolar and control groups using voxel-wise and regional analyses. T1ρ values were found to be elevated in the cerebral white matter and cerebellum in the bipolar group. However, volumes of these areas were normal as measured by high-resolution T1- and T2-weighted magnetic resonance imaging. Interestingly, the cerebellar T1ρ abnormalities were normalized in participants receiving lithium treatment. These findings are consistent with metabolic or microstructural abnormalities in bipolar disorder and draw attention to roles of the cerebral white matter and cerebellum. This study highlights the potential utility of high-resolution T1ρ mapping in psychiatric research.

Age transitions in the course of bipolar I disorder.

BACKGROUND: This analysis aimed to show whether symptoms of either pole change in their persistence as individuals move through two decades, whether such changes differ by age grouping, and whether age of onset plays an independent role in symptom persistence. METHOD: Participants in the National Institute of Mental Health (NIMH) Collaborative Depression Study (CDS) who completed at least 20 years of follow-up and who met study criteria for bipolar I or schizo-affective manic disorder, before intake or during follow-up, were divided by age at intake into youngest (18-29 years, n=56), middle (30-44 years, n=68) and oldest (>44 years, n=24) groups. RESULTS: The persistence of depressive symptoms increased significantly in the two younger groups. Earlier ages of onset were associated with higher depressive morbidity throughout the 20 years of follow-up but did not predict changes in symptom persistence. The proportions of weeks spent in episodes of either pole correlated across follow-up periods in all age groupings, although correlations were stronger for depressive symptoms and for shorter intervals. CONCLUSIONS: Regardless of age at onset, the passage of decades in bipolar illness seems to bring an increase in the predominance of depressive symptoms in individuals in their third, fourth and fifth decades and an earlier age of onset portends a persistently greater depressive symptom burden. The degree to which either depression or manic/hypomanic symptoms persist has significant stability over lengthy periods and seems to reflect traits that manifest early in an individual's illness.

Does major depressive disorder change with age?

BACKGROUND: The authors used results from a 20-year, high-intensity follow-up to measure the influence of ageing, and of age at onset, on the long-term persistence of symptoms in major depressive disorder (MDD). METHOD: Subjects who completed a 20-year series of semi-annual and then annual assessments with a stable diagnosis of MDD or schizo-affective disorder other than mainly schizophrenic (n=220) were divided according to their ages at intake into youngest (18-29 years), middle (30-44 years) and oldest (>45 years) groups. Depressive morbidity was quantified as the proportion of weeks spent in major depressive or schizo-affective episodes. General linear models then tested for effects of time and time x group interactions on these measures. Regression analyses compared the influence of age of onset and of current age. RESULTS: Analyses revealed no significant time or group x time effects on the proportions of weeks in major depressive episodes in any of the three age groups. Earlier ages of onset were associated with greater symptom persistence, particularly in the youngest group. The proportions of weeks ill showed intra-individual stability over time that was most evident in the oldest group. CONCLUSIONS: These results indicate that the persistence of depressive symptoms in MDD does not change as individuals move from their third to their fifth decade, from their fourth to their sixth decade, or from their sixth to their eighth decade. An early age of onset, rather than youth per se, is associated with greater morbidity over two decades.

Novel homozygous and compound heterozygous COL17A1 mutations associated with junctional epidermolysis bullosa.

Junctional epidermolysis bullosa is a heritable, heterogeneous blistering skin disease with mechanically induced dermal-epidermal separation, mild skin atrophy, nail dystrophy, and alopecia. Four unrelated junctional epidermolysis bullosa families with different phenotypes were investigated here and four novel mutations associated with the disease were identified. Patients 1, 2, and 3 had generalized atrophic benign epidermolysis bullosa, with nonscarring blistering and varying degree of alopecia. Patient 4 had the localisata variant of junctional epidermolysis bullosa, with predominantly acral blistering and normal hair. All patients had mutations in the COL17A1 gene encoding collagen XVII, a hemidesmosomal transmembrane protein. Patients 1 and 2 carried homozygous deletions 520delAG and 2965delG, respectively. Patient 3 was compound heterozygous for a missense and a deletion mutation (G539E and 2666delTT), and patient 4 was heterozygous for a known mutation R1226X. The deletions led to premature termination codons and to drastically reduced collagen XVII mRNA and protein levels, consistent with the absence of the collagen in generalized atrophic benign epidermolysis bullosa skin. The missense mutation G539E allowed synthesis of immunoreactive collagen XVII in keratinocytes, but prevented its secretion, thus causing lack of the protein in the skin. The data suggest that different COL17A1 mutations and their combinations can result in a spectrum of biologic and clinical phenotypes of not only generalized atrophic benign epidermolysis bullosa, but also localized junctional epidermolysis bullosa.

Increased risk of breast cancer in relatives of malignant melanoma patients from families with strong cancer familial aggregation.

The aim of this study was to evaluate the risk of occurrence of malignancies of different site of origin in patients with malignant melanoma (MM) of the skin and their first-degree relatives from families with cancer familial aggregations with unknown pathogenetic background (CFA). We analysed tumour spectrum and age at diagnosis of malignancies in 51 families with MM/CFA. In addition, we evaluated observed frequency (OF); expected frequency (EF); and relative risk (RR) of occurrence of malignancies in these families. In all cases peripheral blood examination of common Polish founder BRCA1 mutations was performed. In 25 families, we analysed loss of heterozygosity of BRCA1 and BRCA2 genes. We identified two subgroups of cases: 22 MM/CFA families with MM diagnosed before 55 years (< or =55 MM/CFA) and 29 MM/CFA families with MM diagnosed after 55 (>55 MM/CFA). In these families we observed increased proportion of breast cancers: 17.52% in the first subgroup (mean age of diagnosis 48.5) and 12.15% in the second subgroup. The odds ratio for breast tumours occurring before 50 in < or =55 MM/CFA families was 3.71. We also observed increased numbers of liver cancers, CSU and leukaemias. OF and EF analyses revealed increased risk of occurrence of cancers of breast (OF 10.4%, EF 4.5%) and liver (OF 1.9%, EF 0.8%) in women from MM/CFA families, RR for breast tumours was approximately 3.3 in < or =55 MM/CFA families. Molecular examination of MM/CFA families revealed no alterations within the BRCA2 gene and one germline mutation of the BRCA1 gene. In conclusion, it seems to be justified to consider systematic breast surveillance beginning at the age around 35-40 years as an option in women from < or =55 MM/CFA families.

[20-year cooperation between the I Department of Internal medicine of the District Hospital and the Department of Pathological Anatomy, Medical Academy, in Bialystok (analysis of diagnostic consistency)]. / 20 Lat wspólpracy i Oddzialu Chorób Wewnetrznych Wojewódzkiego Szpitala Zespolonego z Zakladem Anatomii Patalogicznej am w Bialymstoku (analiza zgodnosci rozpoznan).

Statistical analysis of 1421 deaths (98% of all who had died at the Ward) of patients during 1965-1984 was performed. The material was divided into 3 groups according to the age: up to 59 years, from 60 to 69 and over 70 years. Among those who had died men prevailed (55.1%), but both among women and men the age was over 70 years. In the 2nd decade of the analysed period the authors found gradual increase of death percentage among elderly people, that can be ascribed to "geriatrization" of the Ward and higher accessibility to the hospital for this group of patients. Statistical analysis which included a 10-year period (1975-1984) dealt with the causes of deaths according to the clinical and pathological recognition. There dominated deaths of cardiovascular diseases (59.4%), twice increased the percent of deaths due to neoplasia and diabetes complications. On the other hand, the proportion of decreased of heart infarction fell (from 33% to 16.9%) as did of cardiac defects (from 9.5% to 5.9%). This decrease was the effect of hospital structure changes, i.e.a creation of the Ward of Cardiology and Intensive Cardiological Care in 1981. During 1981-1984 the proportion of deaths of complications of arterial hypertension, mainly in the persons at very old age, increased threefold. In this group of age there dominated deaths of cardiac infarction and circulatory insufficiency. The authors made an analysis of the conformability of clinical diagnosis and the results of autopsy. Out of 1421 deaths in 1149 cases (80.8%) the results of autopsy fully agreed with clinical diagnosis. As partially conformable the clinical diagnosis was in 15.5%, and divergent in 3.7% of cases. The latter, according to the authors, resulted from an incomplete or unproper interpretation of diseases symptoms influenced by several objective factors. As could be expected, the highest proportion of divergent diagnosis was found in the group of the eldest patients afflicted with cardiovascular and malignant diseases.

Do risk factors for suicidal behavior differ by affective disorder polarity?

BACKGROUND: Suicide is a leading cause of death and has been strongly associated with affective disorders. The influence of affective disorder polarity on subsequent suicide attempts or completions and any differential effect of suicide risk factors by polarity were assessed in a prospective cohort. METHOD: Participants with major affective disorders in the National Institute of Mental Health (NIMH) Collaborative Depression Study (CDS) were followed prospectively for up to 25 years. A total of 909 participants meeting prospective diagnostic criteria for major depressive and bipolar disorders were followed through 4204 mood cycles. Suicidal behavior was defined as suicide attempts or completions. Mixed-effects, grouped-time survival analysis assessed risk of suicidal behavior and differential effects of risk factors for suicidal behavior by polarity. In addition to polarity, the main effects of age, gender, hopelessness, married status, prior suicide attempts and active substance abuse were modeled, with mood cycle as the unit of analysis. RESULTS: After controlling for age of onset, there were no differences in prior suicide attempts by polarity although bipolar participants had more prior severe attempts. During follow-up, 40 cycles ended in suicide and 384 cycles contained at least one suicide attempt. Age, hopelessness and active substance abuse but not polarity predicted suicidal behavior. The effects of risk factors did not differ by polarity. CONCLUSIONS: Bipolarity does not independently influence risk of suicidal behavior or alter the influence of well-established suicide risk factors within affective disorders. Suicide risk assessment strategies may continue to appraise these common risk factors without regard to mood polarity.