The objective of this study is to describe the neuropathologic findings in three
LRRK2
G2019S carriers with Parkinson's disease (PD). We cross-referenced a list of 956 PD individuals that had been ...previously genotyped in clinical studies at Columbia University, with 282 subjects with a parkinsonian syndrome who came to autopsy in our brain bank since 1991. We found three autopsies of G2019S mutation carriers. Pathological analyses of the samples were blind to the genetic findings. We retrospectively reviewed the clinical records of the three patients. All three had a clinical and pathological diagnosis of PD. Cognitive impairment was a late feature in two out of three patients. Cortical involvement varied significantly: one had diffuse Lewy body (LB) pathology, tau inclusions, and amyloid pathology consistent with advanced Alzheimer's disease; one had diffuse cortical LB; and one had only brainstem predominant LB pathology. Cognitive impairment may be a long-term complication in G2019S mutation carriers. However, the extent of cortical involvement is variable. Larger longitudinal follow-up of
LRRK2
G2019S mutation carriers is required to assess for risk factors for cortical involvement and dementia.
BACKGROUNDIn genetic research on essential tremor (ET), certain individuals may be particularly challenging to categorize diagnostically. METHODSIn the Family Study of Essential Tremor (>200 ...enrollees), 28 participants with borderline clinical findings who did not meet strict criteria for ET were assigned final diagnoses of ET. We scrutinized the clinical features of these cases and the sensitivity/specificity of certain features that best separated them from 19 unaffected individuals. RESULTSBORDERLINE ET CASES DIFFERED FROM UNAFFECTED INDIVIDUALS IN EIGHT FEATURES: total tremor score, at least one kinetic tremor rating ≥1.5, at least one kinetic tremor rating ≥1.5 in the dominant arm, tremor rating during spiral drawing ≥1.5, higher spiral axis score, head tremor, complaint of tremor, and comment on tremor by others. The combination of at least one kinetic tremor rating ≥1.5 in the dominant arm and the presence of at least three of the remaining seven features predicted the clinician-assigned diagnosis in 88.6% of borderline ET vs. unaffected individuals (sensitivity 84.6%, specificity 94.4%). DISCUSSIONIn a family study, a small number of clinical features characterized borderline ET, and a particular combination of these separated the majority of these borderline cases from normals. These analyses may help researchers minimize diagnostic misclassification.
Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have ...facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
Essential tremor (ET) is often familial and phenotypic features may be shared within families. Cranial (neck, voice, and jaw) tremor is an important feature of ET. We examined whether cranial tremor ...aggregates in ET families, after controlling for other factors (age, tremor severity, and duration).
Among ET probands and relatives enrolled in a genetic study at Columbia University (95 subjects in 28 families), we assessed the degree to which occurrence of cranial tremor in the proband predicted occurrence of cranial tremor in affected relatives.
Forty-five (47.4%) subjects had cranial tremor on neurological examination (probands 66.7%, relatives 39.7%). Among 28 families, 23 (82.1%) contained individuals with and individuals without cranial tremor, indicating a high degree of within-family heterogeneity. In comparison to subjects without cranial tremor, those with cranial tremor had higher total tremor scores (p < 0.001), were older (p = 0.003), and had tremor of longer duration (p = 0.01). In logistic regression models, the odds of cranial tremor in a relative were not related to occurrence of cranial tremor in the proband (p > 0.24).
Cranial tremor did not aggregate in families with ET; the major predictor of this disease feature was tremor severity rather than presence of cranial tremor in another family member.
BACKGROUNDClassically, the onset of head tremor in essential tremor (ET) patients follows that of hand tremor, such that there is a somatotopic spread of involved areas. Here we present a series of ...seven self-reportedly "unaffected" relatives of ET cases. These seven were clinically asymptomatic and had normal levels of arm tremor on examination, yet each evidenced a transient head wobble on examination. We estimate the prevalence of this phenotype within the two studies from which cases were ascertained. METHODSET cases and their self-reportedly affected and unaffected relatives, enrolled in two family studies, underwent a medical history and videotaped neurological examination. RESULTSIn seven self-reportedly "unaffected" relatives, a transient and subtle head wobble was seen, always during sustained phonation, speech, or reading aloud. Total tremor score (a measure of arm tremor) ranged from 5 to 12 (i.e., mild tremor within the range of normal). The prevalence of this phenotype of early head tremor was 3.7% in one study and 23.1% in the other. DISCUSSIONWe present a series of seven individuals who had early head tremor in an evolving transition state from normal to ET. These cases raise a number of broad clinical, phenotypic, and pathophysiological issues about ET.
Chemoradiation for the treatment of anal cancer is known to cause significant hematologic toxicity (HT). We sought to investigate if radiation dose to specific pelvic subsites is associated with ...increased HT risk.
Forty-five patients with nonmetastatic anal cancer who received definitive chemoradiation with intensity modulated radiation therapy and concurrent mitomycin-C and 5-fluorouracil were studied. Total pelvic bone marrow (TBM) was divided into 3 subsites: lumbosacral bone marrow (LSBM), including the entire sacrum and L5 vertebral body; iliac bone marrow (IBM) extending from the iliac crests to the superior border of the femoral head; and lower pelvic bone marrow, including the pubic bones, ischia, acetabula, and proximal femurs. The primary endpoint was absolute neutrophil count (ANC) nadir during or within 2 weeks of treatment completion. Generalized linear modeling was used to analyze the correlation between the equivalent uniform dose (with an "a" value of 0.5) to the individual pelvic subsites and the various hematologic endpoints. Age, body mass index, sex, baseline blood counts, and immunosuppression were analyzed as potential covariates.
Mean ± standard deviation ANC nadir was 0.77 × 10
/L (±0.66 × 10
/L). Grades 3+ and 4+ neutropenia occurred in 71.1% and 44.4% of patients, respectively. In addition to radiation dose to pelvic bone marrow, baseline ANC was the only significant predictor of hematologic toxicity on multivariable analysis and was included in all models. The equivalent uniform doses of TBM, LSBM, and IBM were each significantly associated with neutropenia. The model performance of TBM (adjusted R
= 0.226) was similar to both LSBM (adjusted R
= 0.206) and IBM (adjusted R
= 0.249).
Radiation doses to TBM, LSBM, and IBM were individually associated with HT, suggesting that sparing just a portion of pelvic bone marrow is insufficient to decrease rates of clinically significant bone marrow suppression.
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