Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study of 198 serial magnetic resonance images.

BACKGROUND AND PURPOSE: The aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD. METHODS: In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n = 21), GRN mutations (n = 11), C9ORF72 repeat expansions (n = 11) or sporadic FTD (n = 15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor-based morphometry. Sample size estimates were calculated. RESULTS: Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD. CONCLUSION: These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.

Mapping, monitoring, and surveillance of neglected tropical diseases: towards a policy framework.

As national programmes respond to the new opportunities presented for scaling up preventive chemotherapy programmes for the coadministration of drugs to target lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiasis, and trachoma, possible synergies between existing disease-specific policies and protocols need to be examined. In this report we compare present policies for mapping, monitoring, and surveillance for these diseases, drawing attention to both the challenges and opportunities for integration. Although full integration of all elements of mapping, monitoring, and surveillance strategies might not be feasible for the diseases targeted through the preventive chemotherapy approach, there are opportunities for integration, and we present examples of integrated strategies. Finally, if advantage is to be taken of scaled up interventions to address neglected tropical diseases, efforts to develop rapid, inexpensive, and easy-to-use methods, whether disease-specific or integrated, should be increased. We present a framework for development of an integrated monitoring and evaluation system that combines both integrated and disease-specific strategies.

Early experience determines song dialect responsiveness of female sparrows.

In a laboratory experiment, female white-crowned sparrows responded almost exclusively to male songs taken from their home dialect region and usually not to songs taken from an alien dialect region. Song dialect populations may represent a level of genetic population structure below that of the subspecies and may play an important role in songbird evolution.

Clinical and genetic features of families with frontotemporal dementia and parkinsonism linked to chromosome 17 with a P301S tau mutation.

In 9 patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with a P301S tau mutation, the predominant phenotype was frontotemporal dementia in 3 and parkinsonism in 6. Comparison of the tau genotype/haplotype carrying the mutation and the initial clinical sign showed association between H1/H1 and parkinsonism and between H1/H2 and personality change. Thus, the tau haplotype carrying the mutation and the tau genotype may be related to the clinical phenotype throughout the disease course.

Chromosome abnormalities as primary events in human malignant disease: evidence from marker chromosomes.

Observations on the chromosomes of cells from 5 human malignant tumors are reported. Each tumor had one or more distinctive marker chromosomes. Marker chromosomes were present in a total of 700 of 711 metaphases from these tumors, which included an early malignant lesion of the cervix showing minimal invasion. Two tumors (a Stage 4 carcinoma of the cervix and a reticulum cell sarcoma, both untreated) yielded preparations of high quality. The 7 best-spread metaphases from the former with the modal number of chromosomes (60) had identical karyotypes, as did 16 from the latter with the modal number of 49. Less extensive data on 13 other tumors, 8 of which had marker chromosomes, are also presented. The data presented here, together with the published data on the chromosomes of cells from human tumors, support the view that human malignant tumors frequently but not invariably arise from a single cell in which chromosome changes have occurred. A carcinoma of the corpus uteri, to which brief reference is made, is a possible exception: Most metaphases had apparently normal karyotypes. The role of chromosome abnormalities (particularly structural changes) in the malignant transformation is discussed. Possible parallels between the chromosome findings in the cells of malignant tumors and those in chronic myeloid leukemia are considered. It is suggested that in tumors there may be both specific changes (perhaps involving chromosomes structurally changed) and coincidental changes. Variation in the coincidental changes might largely account for the wide differences between the karyotypes of different tumors.

Degradation of oil by fungi isolated from Gulf of Mexico beaches.

Fungi of the Ascomycota phylum were isolated from oil-soaked sand patties collected from beaches following the Deepwater Horizon oil spill. To examine their ability to degrade oil, fungal isolates were grown on oiled quartz at 20°C, 30°C and 40°C. Consistent trends in oil degradation were not related to fungal species or temperature and all isolates degraded variable quantities of oil (32-65%). Fungal isolates preferentially degraded short (

Radiation damage in patients treated by total-body irradiation, bone marrow grafting, and cyclosporin.

The bone marrow (BM) and peripheral blood (PB) from 63 patients were assessed for the presence of chromosomal aberrations after bone marrow transplantation (BMT) following total body irradiation (TBI) for leukemia. Forty-one patients showed no abnormalities in either BM or PB, and 22 had aberrations in either BM or PB or both. Only stable aberrations were found in the BM, but both stable and unstable abnormalities were present in the PB, the majority showing only unstable aberrations. Among the 25 patients who had a leukemic relapse, clonal chromosomal abnormalities were found in the BM of 12 out of the 16 cases for whom marrow was studied at the time of the relapse. A statistically significant negative correlation between leukemic relapse and graft versus host disease (GvHD) was found, but the relationships between chromosome damage and leukemic relapse, GvHD, and the pretransplant radiation dose and between the radiation dose and both leukemic relapse and GvHD were not significant.

Derivative chromosome, der(17;22)(q10;q10), in two carcinomas of the cervix uteri and one of the skin.

In a previous study, we described 17p+ chromosomes in about 40% of carcinomas of the cervix, but it was usually not possible to identify the additional material on the short arm of the chromosome 17. Here we report an apparently identical rearranged chromosome in two squamous cell carcinomas of the cervix and one of the skin, in which the whole of 17p has been replaced by the long arm of a chromosome 22: der(17;22)(q10;q10), suggesting that this rearrangement may represent a significant step in the development of carcinomas of the cervix and other sites.

Numerical chromosome changes in 165 malignant tumors. Evidence for a nonrandom distribution of normal chromosomes.

The numbers of normal copies of each of the chromosomes in representative karyotypes from 165 malignant tumors of the bladder, breast, cervix, colorectum, and testis studied in this laboratory or described in the literature were assessed to determine whether particular chromosomes were over- or underrepresented. For each chromosome, the mean number of copies was expressed as a percentage of the number expected on the basis of the total number of chromosomes in the karyotypes. The most highly represented autosomes in the tumors as a whole were, in descending order of frequency, numbers 7, 20, 12, 19, 21, and 3, while those most underrepresented were numbers 10, 1, 4, 5, 14, 17, 11, and 18. In tumors of males, the Y tended to be underrepresented. The X was highly represented in the testicular tumors (there were usually two or more copies) and in colorectal tumors of males, but not in the other tumor categories studied. For the tumors as a whole, statistically significant differences could be demonstrated between pairs of autosomes that were at opposite ends of the frequency range. Differences between tumors at the different sites studied were not demonstrable. It is suggested that the determination of the number of normal copies of chromosomes, i.e., whether there are more or fewer than expected, may usefully complement observations on structural changes by reflecting the presence of oncogenes and tumor-suppressor genes, respectively. It may also point to chromosomes that are involved in significant genic changes in which cytogenetic observations on structural changes are equivocal.

Abnormal chromosomes including small metacentrics in 14 ovarian cancers.

In direct preparations of 14 ovarian cancers including 11 primary tumors, chromosomes #1 (12 tumors), #3 (12 tumors, including 3q- chromosomes in five), #6 [eight tumors, including six with a 6q- and two with an i(6p)], #11 (11p + in seven tumors), and #14 (14q+ in at least seven tumors) were most frequently involved in structural aberrations. Also, abnormal small metacentrics were seen in 11 tumors. In ten of these the chromosome appeared to be an i(4p) or i(5p) and in one of these, a mixed Müllerian tumor, there was also an i(12p); the latter anomaly was also present (in duplicate) in a dysgerminoma.

Chromosome 7q deletions: observations on 13 malignant tumors.

Deletions of the long arm of chromosome 7, with breakpoints varying from q11 to q34, are described in 13 malignant tumors, including three carcinomas of the prostate, three colorectal carcinomas, and four testicular germ cell tumors. In two of the tumors, the chromosome also had a deletion of 7p. Review of the literature shows that 7q- chromosomes have been detected in various tumor types and are particularly common in benign and malignant mesothelial tumors, secondary leukemias, testicular cancers, and carcinomas of the ovary and prostate. Their significance may lie in loss of an unknown tumor-suppressor gene situated distally on 7q.

X-chromatin, sex chromosomes, and ploidy in 37 germ cell tumors of the testis.

X-chromatin was present in interphase cells from nine of 14 teratomas and all of three combined tumors, but only one of 20 seminomas (which tended to have higher chromosome numbers). Eight of the 37 tumors were karyotyped; seven, only one of which (a teratoma) was X-chromatin-positive, had two X chromosomes while one, the X-chromatin-positive seminoma, had three. A possible relationship between the presence of inactive, X-chromatin-forming, X chromosomes and the number of autosomes is suggested by the data on the eight karyotyped tumors; the ratio of the number of Xs to the number of autosomes was higher for the two X-chromatin-positive tumors than for the remainder. All eight had at least one Y chromosome, and eight further tumors had one to three Y-bodies in their interphase cells. It is uncertain whether retention of the Y is a characteristic of male germ cell tumors, as tumors lacking a Y have been described by other workers. Two characteristics of these tumors, however, are high ploidy (at least 55 chromosomes), perhaps signifying an origin from a triploid or tetraploid cell, and chromosome 12 aberrations, usually resulting in an i(12p).

Favorable prognosis of solid tumors with very low chromosome numbers?

In contrast to near-haploid leukemias, the rare solid cancers with very low chromosome numbers (below 34) may be characterized by a particularly favorable outcome, as was shown by three such tumors studied in this laboratory.

Chromosome 17p loss in carcinoma of the cervix uteri.

Markers derived from chromosome 17 were present in 13 (42%) of 31 carcinomas of the cervix uteri. Altogether, 14 such markers were present, ten of which were 17p+ chromosomes with a small amount of additional material, probably of variable origin, while three were i(17q)s. The significance of the chromosome 17 aberrations in cervical carcinoma may lie in the loss of recessive genes on 17p.

Ectopic nucleolar organizer regions. A common anomaly revealed by Ag-NOR staining of metaphases from nine cancers.

In view of the sparsity of reports on nucleolar organizer regions (NORs) in human tumor metaphase chromosomes, we have applied the silver (Ag-NOR) technique to a previously studied testicular germ-cell tumor that had an abnormal translocation, which involved a 13p, and to nine new sequentially studied tumors. Six of the new tumors, and the germ cell tumor, showed ectopic NORs (e.g., at the end of the long arm of acrocentrics or metacentrics, or interstitially in metacentrics): five carcinomas and a leiomyosarcoma, all of which also revealed numerous structural chromosome changes after G-banding. The three tumors that did not show ectopic NORs were lymphomas with relatively simple karyotypic changes. It seems that the presence of ectopic NORs in the majority of the tumors is a reflection of the multiplicity of structural changes in these tumors and does not signify that there is any particular propensity for acrocentrics to take part in these changes. It was interesting that several of the chromosomes showed large notably a metacentric in a squamous cell carcinoma of the skin in which the Ag-NOR-positive region was seen as an unstained gap in unbanded and G-banded chromosomes.

i(12p): specific chromosomal marker in seminoma and malignant teratoma of the testis?

A similar small marker chromosome, frequently present in duplicate, was seen in direct preparations and short-term cultures of each of ten seminomas, one combined seminoma and teratoma, and one malignant teratoma of the testis. In the four most favorable tumors (seminomas) this chromosome was identified as an i(12p). The findings may point to a chromosomal change that is specific for malignant testicular tumors.

Diffuse large cell (Kiel-1) lymphoma with a t(9;11)(p21-22;q13) and a missing Y as the only chromosome changes.

We describe a diffuse large cell (Kiel-1) lymphoma in a 76-year-old man that is noteworthy because, apart from a missing Y, the only chromosome change was a hitherto undescribed reciprocal translocation, t(9;11)(p21-22;q13). It is interesting that the breakpoints lay in the vicinity of genes that encode proteins engaged in cell cycle control: CCND1 situated at 11q13 and p15 and p16 at 9p21.

Nonrandom chromosome changes in carcinoma of the cervix uteri. II. Ten tumors in the triploid-tetraploid range.

Nonrandom chromosome changes in direct preparations of 10 cervical carcinomas with modal numbers in the range of 60-82 were similar to those found in a previous study on near-diploid tumors: Chromosomes 1 (seven tumors) and 11 (five tumors) were most often involved in structural rearrangements and a small metacentric, often present in duplicate, was seen in six tumors. The appearances of the small metacentric again suggested an origin from a chromosome #4 or #5: either a long arm deletion or a short arm isochromosome; in one tumor, Giemsa-11 banding was more compatible with a #4 than a #5. Chromosome #17 anomalies were probably present in four tumors, and two tumors had markers, probably derived from chromosome #2, containing homogeneously staining regions.

Nonrandom chromosome changes in carcinoma of the cervix uteri. I. Nine near-diploid tumors.

Chromosome analysis of G- and C-banded preparations of tumor material, processed by a direct method, from nine primary carcinomas of the cervix with modal chromosome numbers in the range 41-49 showed the nonrandom involvement of certain chromosomes in structural and numerical changes. Besides chromosome No. 1 (six tumors), structural changes involved chromosomes No. 11 (five tumors with variable breakpoints and translocation partners), No. 3 (three tumors) No. 6 (three tumors), and No. 17 (17p+ in two tumors). A small metacentric (present in duplicate in most metaphases of one tumor), which may have been a 5q- (?) (with an interstitial long arm deletion), was seen in five tumors. Additional normal chromosomes included chromosomes No. 1 (one tumor without structural changes in this chromosome showing trisomy 1) and No. 3 (four tumors showing trisomy in the absence of structural changes involving this chromosome). Losses commonly affected the B, D, and G groups, particularly chromosomes No. 13 (three tumors) and No. 21 (six tumors), as well as chromosome No. 18 (four tumors). Two X chromosomes were present in all tumors except the two with the lowest modal numbers, both of which lacked an X chromosome.

Cytogenetic study of ten carcinomas of the bladder: involvement of chromosomes 1 and 11.

In direct preparations of ten untreated transitional cell carcinomas of the bladder, chromosomes #1 and #11 were most frequently involved in structural changes (in at least seven tumors each). Three tumors had one or two 11p- chromosomes, and, in other tumors, chromosome #11 had taken part in translocations or isochromosome formation, which, except in one tumor, resulted in a loss of short arm material. Also, there was a tendency for the presence of fewer than expected normal chromosomes #11. Chromosome #1 anomalies are common in most types of tumor; however, chromosome #11 abnormalities, particularly the loss of short arm material, are not common and may thus characterize carcinoma of the bladder, a finding that is of interest in view of the location of an oncogene, c-Ha-ras1, on 11p. Translocations probably involved chromosome #17 in four tumors. Structurally changed chromosomes #3 were seen in four tumors, including one or two 3q- chromosomes in two or possibly three tumors.