First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation.

The c.4309A>C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.

Fulfilment of patients' goals after thalamic deep brain stimulation: a follow-up study.

Deep brain stimulation (DBS) in the ventrolateral thalamus (VIM) is shown to reduce tremor in essential tremor (ET) and Parkinson's disease (PD). Our aim was to evaluate the results of VIM DBS from the patients' perspective. Sixteen consecutively included patients (8 ET and 8 PD) described their own outcome goals preoperatively and evaluated the fulfillment 1, 6 and 12 months postoperatively. We conclude that the patients could do specific activities that are of importance to them such as eating, drinking and socializing, and perceived either partial or total fulfillment of their goals.

Effects of different electrical parameter settings on the intelligibility of speech in patients with Parkinson's disease treated with subthalamic deep brain stimulation.

We evaluated the effects of different electrical parameter settings on the intelligibility of speech in patients with Parkinson's disease (PD) bilaterally treated with deep brain stimulation (DBS) in the subthalamic nucleus (STN). Ten patients treated with DBS for 15 +/- 5 months (mean, SD) with significant (P < 0.01) symptom reduction (Unified Parkinson's Disease Rating Scale III) were included. In the medication off condition, video laryngostroboscopy was performed and then, in random order, 11 DBS parameter settings were tested. Amplitude was increased and decreased by 25%, frequency was varied in the range 70 to 185 pps, and each of the contacts was tested separately as a cathode. The patients read a standard running text and five nonsense sentences per setting. A listener panel transcribed the nonsense sentences as perceived and valued the quality of speech on a visual analogue scale. With the patients' normally used settings, there was no significant (P = 0.058) group difference between DBS OFF and ON, but in four patients the intelligibility deteriorated with DBS ON. The higher frequencies or increased amplitude caused significant (P < 0.02) impairments of intelligibility, whereas changing the polarity between the separate contacts did not. The settings of amplitude and frequency have a major influence on the intelligibility of speech, emphasizing the importance of meticulous parameter adjustments when programming DBS to minimize side effects related to speech.

Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments.

Thalamic deep brain stimulation (DBS) is proven to suppress tremor in Parkinson's disease (PD) and essential tremor (ET). However, there are few reports on its long-term efficacy. We studied the efficacy of DBS at 2 years and 6-7 years after electrode implantations in the ventrointermediate nucleus of the thalamus in 39 patients (20 PD, 19 ET) with severe tremor. Twenty-five of the patients completed the study. Evaluations were done in a double-blind manner with the Unified Parkinson's Disease Rating Scale (UPDRS) and Essential Tremor Rating Scale (ETRS). DBS decreased tremor sum scores in PD (P < 0.025) compared to the preoperative baseline (median, 7; Q25-75, 6-9) both at 2 years (median, 2; Q25-75, 2-3.5; n = 16) and at 6 to 7 years (median, 2.5; Q25-75, 0.5-3; n = 12). Stimulation on improved tremor sum as well as sub scores (P < 0.025) compared to stimulation off conditions. In ET, thalamic stimulation improved (P < 0.025) kinetic and positional tremor at both follow-up periods (n = 18 and n = 13, respectively) with significant improvements (P < 0.025) in hand-function tests. PD but not ET patients showed a general disease progression. Stimulation parameters were remarkably stable over time. We conclude that high-frequency electric thalamic stimulation can efficiently suppress severe tremor in PD and ET more than 6 years after permanent implantation of brain electrodes.