Frontotemporal dementia and parkinsonism linked to chromosome 17 with the N279K tau mutation

We present a case of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) harboring the N279K mutation in the MAPT gene from the family known as pallido‐ponto‐nigral degeneration (PPND). This 49‐year‐old man was followed for 17 years. He presented at age 41 years with left leg stiffness and en‐bloc turning. During the course of his illness he developed a constellation of symptoms including parkinsonism, pyramidal signs, vertical gaze palsy, dysphagia, dystonia, personality and cognitive dysfunction, weight loss and mutism. Gross neuropathological examination showed mild atrophy of the cerebral cortex, hippocampal formation, amygdala, thalamus, subthalamic nucleus and depigmentation of the substantia nigra. Microscopy revealed neuronal loss and gliosis in the same regions. Tau immunohistochemistry showed pretangles, numerous threads, grain‐like structures and oligodendroglial tau‐positive inclusions (“coiled bodies”). In the spinal cord the tau pathology was more abundant in gray than white matter. Pretangles and threads were present in the anterior and, to a lesser extent, in the posterior horns. FTDP‐17 should be suspected in patients with a history of familial parkinsonism combined with behavioral and cognitive changes, onset before age 65 years and an aggressive clinical course.     

Identifying incident cases of parkinsonism among veterans using a tertiary medical center.

To better understand the impact of incident Parkinson's disease (PD) on the Veteran's Health Administration (VHA) and to develop methods applicable to future epidemiological research, we performed a medical record review study at a tertiary referral VHA medical center. Searching the local data base, we identified 782 veterans with diagnostic codes for PD or secondary parkinsonism (SP) between 1998 and 2000. Based on structured medical record review, a movement disorders specialist confirmed diagnoses for incident parkinsonism cases. Among the 782, 191 incident parkinsonism cases were identified (100 PD, 75 SP, and 16 Parkinson's Plus). Incident PD cases were older at diagnosis (74.5 vs. 70.4 yr; P < 0.05) and more likely to be white (81% vs. 62; P < 0.07) than incident SP cases. Diagnostic codes were insufficient to distinguish between incident PD and SP (positive predictive value, 57% and 39%, respectively), and VHA sources failed to identify 21% of confirmed deaths among the incident PD cohort by November 2004. Although the large number of incident cases identified suggests PD is an important cause of disability among elderly VHA users, observed limitations of VHA sources for identifying incident PD cases and determining their vital status should be considered when designing future studies.     

Synthesis of 14C‐labeled piperidines and application to synthesis of [14C]SCH 351125, a CCR5 receptor antagonist

1‐Benzyl‐4‐hydroxy[2‐¹⁴C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [¹⁴C]formaldehyde in high yield. The distribution pattern of ¹⁴C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza‐Cope rearrangement. These steps precede the rate‐determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [¹⁴C]SCH 351125, required for metabolism studies, was prepared from 1‐benzyl‐4‐hydroxy[2‐¹⁴C]piperidine in six steps. [¹⁴C]SCH 351125 is a mixture of four atropisomers. Preparation of [¹⁴C]SCH 351125 besylate salt of the desired atropisomer pair is also described. Copyright © 2007 John Wiley & Sons, Ltd.     

Gd-DTPA-enhanced MR in thoracic disc herniations

Summary The Gd-DTPA-enhanced magnetic resonance findings in two patients with herniated thoracic intervertebral discs are reported. The first patient was a 56-year-old woman with a small subligamentous T6-7 disc herniation, slightly lateralized to the right. The second patient was a 51-year-old man with a central and right posterolateral disc herniation, including a large calcified fragment, at the T8-9 level. The nonenhanced MR examination revealed the presence of an extradural mass lesion in both patients, impinging upon the dural sac and compressing and displacing the spinal cord posteriorly. The lesion was slightly hypointense on both T1- and T2-weighted spin echo sequences. Following intravenous injection of Gd-DTPA in a dosage of 0.1 mmol/kg body weight, enhancement of the posterior longitudinal ligament was noted and triangular areas of contrast uptake were seen to occur in the epidural space above and below the herniated disc. At surgery, they were found to correspond to dilated and congested epidural veins.     

Novel antiepileptic drug levetiracetam decreases dyskinesia elicited by L-dopa and ropinirole in the MPTP-lesioned marmoset.

Long-term dopamine replacement therapy of Parkinson's disease leads to the occurrence of dyskinesias. Altered firing patterns of neurons of the internal globus pallidus, involving a pathological synchronization/desynchronization process, may contribute significantly to the genesis of dyskinesia. Levetiracetam, an antiepileptic drug that counteracts neuronal (hyper)synchronization in animal models of epilepsy, was assessed in the MPTP-lesioned marmoset model of Parkinson's disease, after coadministration with (1) levodopa (L-dopa) or (2) ropinirole/L-dopa combination. Oral administration of levetiracetam (13-60 mg/kg) in combination with either L-dopa (12 mg/kg) alone or L-dopa (8 mg/kg)/ropinirole (1.25 mg/kg) treatments was associated with significantly less dyskinesia, in comparison to L-dopa monotherapy during the first hour after administration. Thus, new nondopaminergic treatment strategies targeting normalization of abnormal firing patterns in basal ganglia structures may prove useful as an adjunct to reduce dyskinesia induced by dopamine replacement therapy without affecting its antiparkinsonian action.     

Paraneoplastic movement disorder in a patient with non-Hodgkin's lymphoma and CRMP-5 autoantibody.

The paraneoplastic autoantibody, collapsin response-mediator protein (CRMP)-5 immunoglobulin G (IgG), is specific for neuronal cytoplasmic CRMP-5, and is usually associated with small-cell lung carcinoma or thymoma. We report on details of a movement disorder that followed anti-B-cell therapy in a patient with lymphoma, and was accompanied by CRMP-5 IgG.     

Failure of intramuscular antivenom in Red‐back spider envenoming

Four cases of Red‐back spider envenoming are reported in which there was minimal response to intramuscular antivenom. Intravenous antivenom was then administered in each case with almost complete resolution of symptoms. All cases were followed up to confirm the effect of treatment. This failure of intramuscular Red‐back antivenom raises the question of its efficacy. There has been no controlled trial to prove that intramuscular Red‐back antivenom is effective and animal work with other antivenoms has demonstrated the intramuscular formulation to have delayed and incomplete effects. Controlled studies should be undertaken to establish the effectiveness of intravenous and intramuscular Red‐back antivenom.     

Bent knees and tiptoeing: late manifestations of end-stage Parkinson's disease.

We describe a unique gait phenomenon of bent knees in 9 patients with idiopathic Parkinson disease (mean age, 73.1 +/- 11.1 years), 3 of whom also manifested tiptoeing. The bent-knee posture appeared only during ambulation; in the recumbent position, full or nearly full extension was possible in all patients. The abnormality emerged after long-standing disease (6-23 years from onset) and failed to respond to dopaminergic treatment. Most of the patients also had bent spine (camptocormia). The pathogenesis of these phenomena are unknown, but they might represent a rare type of dystonia.     

Off-resonance effects in the transient response of SSFP sequences.

A previously developed eigenvector formalism is adapted to off-resonance in the transient response of quasiperiodic steady-state free precession (SSFP) sequences, including TrueFISP as a special case. The effective relaxation rates for essentially parallel and perpendicular deviations from the steady state are determined analytically in leading order perturbation theory. The latter are a known cause of oscillatory artifacts and therefore constitute the main target of a variety of preparation techniques. In addition, the former also play a dominating role in applications such as inversion recovery (IR) TrueFISP, which intentionally measure far away from the equilibrium. For both components, the approach toward equilibrium turns out to depend sensitively on field inhomogeneities, especially for smaller ratios of T2/T1. For the perpendicular deviations, the calculations show that--except very close to banding artifacts, where the steady-state signal is almost zero--field inhomogeneities additionally increase their effective relaxation rate almost as much as in the free induction decay (FID). The analytical results are tested against numerical simulation and MR measurements.