Karen M. Doherty

Parkin disease: A clinicopathologic entity?

IMPORTANCE Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. OBJECTIVE To investigate whether parkin-linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). DESIGN, SETTING, AND PARTICIPANTS We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. RESULTS Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). CONCLUSIONS AND RELEVANCE These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

Decision making, impulsivity, and addictions: do Parkinson's disease patients jump to conclusions?

Links between impulsive‐compulsive behaviors (ICBs) in treated Parkinsons disease (PD), behavioral addictions, and substance abuse have been postulated, but no direct comparisons have been carried out so far. We directly compared patients with PD with and without ICBs with illicit drug abusers, pathological gamblers, and age‐matched healthy controls using the beads task, a test of reflection impulsivity, and a working memory task. We found that all patients with PD made more impulsive and irrational choices than the control group. PD patients who had an ICB showed similar behavior to illicit substance abusers, whereas patients without ICBs more closely resembled pathological gamblers. In contrast, we found no difference in working memory performance within the PD groups. However, PD patients without ICBs remembered distractors significantly less than all other patients during working memory tests. We were able to correctly classify 96% of the PD patients with respect to whether or not they had an ICB by analyzing three trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3%, and we propose that this task may prove to be a powerful screening tool to detect an ICB in PD. Our results also suggest that intact cortical processing and less distractibility in PD patients without ICBs may protect them from developing behavioral addictions.

Bone health in Parkinson's disease: a systematic review and meta-analysis

Objective Parkinsons disease (PD) and osteoporosis are chronic diseases associated with increasing age. Single studies have reported associations between them and the major consequence, namely, increased risk of fractures. The aim of this systematic review and meta-analysis was to evaluate the relationship of PD with osteoporosis, bone mineral density (BMD) and fracture risk. Methods A literature search was undertaken on 4 September 2012 using multiple indexing databases and relevant search terms. Articles were screened for suitability and data extracted where studies met inclusion criteria and were of sufficient quality. Data were combined using standard meta-analysis methods. Results 23 studies were used in the final analysis. PD patients were at higher risk of osteoporosis (OR 2.61; 95% CI 1.69 to 4.03) compared with healthy controls. Male patients had a lower risk for osteoporosis and osteopenia than female patients (OR 0.45; 95% CI 0.29 to 0.68). PD patients had lower hip, lumbar spine and femoral neck BMD levels compared with healthy controls; mean difference, −0.08, 95% CI −0.13 to −0.02 for femoral neck; −0.09, 95% CI −0.15 to −0.03 for lumbar spine; and −0.05, 95% CI −0.07 to −0.03 for total hip. PD patients were also at increased risk of fractures (OR 2.28; 95% CI 1.83 to 2.83). Conclusions This systematic review and meta-analysis demonstrate that PD patients are at higher risk for both osteoporosis and osteopenia compared with healthy controls, and that female patients are at greater risk than male patients. Patients with PD also have lower BMD and are at increased risk of fractures.

Pisa syndrome in Parkinson's disease: a mobile or fixed deformity?

Background Although Pisa syndrome and scoliosis are sometimes used interchangeably to describe a laterally flexed postural deviation in Parkinsons disease (PD), the imaging findings of Pisa syndrome in PD have not been previously studied in detail. Methods Patients with PD and Pisa syndrome (lateral flexion >10° in the standing position) were examined clinically and underwent radiological assessment using standing radiograph and supine CT scan of the whole spine. Results Fifteen patients were included in this observational study. All patients had scoliosis on standing radiographs, and 12 had scoliosis persisting in the supine position. Scoliotic curves improved by a mean of 44% when patients moved from standing to supine. Only a quarter of patients with structural scoliosis had evidence of bony fusion on the side of their lateral deviation rendering their deformity fixed. Conclusions Pisa syndrome describes a patient who lists to the side whereas scoliosis is defined by spinal curvature and rotation and may not be associated with lateral flexion. The finding of ‘structural scoliosis’ in Pisa syndrome should not preclude intervening to improve posture as most patients had little or no evidence of structural bony changes even when the deformity had been present for a number of years.

Parkin disease and the Lewy body conundrum.

A clear pathologic hallmark like that identified in sporadic Parkinson’s disease (PD) is lacking in many of the monogenic causes of PD. In leucine-rich repeat kinase 2 (LRRK2) mutations (PARK8), alpha-synuclein pathology in the form of Lewy bodies (LBs) is frequently, but not consistently, observed. Other pathologies reported in LRRK2 cases include tau inclusions of the Alzheimer, progressive supranuclear palsy, and frontotemporal lobar degeneration types, and TAR DNA-binding protein 43 (TDP-43) inclusions. 1 There has been only a single report of a compound heterozygous, phosphatase and tensin homolog (PTEN)-induced, putative kinase 1 (PINK1; PARK6) patient coming to autopsy. 2 That patient presented with asymmetrical rigidity at age 31 years and had a good motor response to dopaminergic therapy, but died at age 39 years. Pathologic study revealed nigral neuronal loss and gliosis, with a few LBs and Lewy neurites identified in the substantia nigra (SN), nucleus basalis of Meynert (NBM), and reticular formation of the brainstem, but not in the locus coeruleus (LC),

Late onset ataxia: MSA‐C or SCA 17? A gene penetrance dilemma

Spinocerebellar ataxia 17 (SCA 17) is a rare cause of ataxia and maybe underdiagnosed in late-onset cases without a family history. The phenotype can vary greatly with recognized clinical features including chorea, dementia, parkinsonism, dystonia, and psychiatric disturbance. We present a patient with a late onset ataxia mimicking Multiple System Atrophy — Cerebellar type (MSA-C) attributed to an intermediate range expansion of the CAG/CAA repeat of the TATA-binding protein (TBP) gene following thorough exclusion of other possible causes.

Altruistic punishment in patients with Parkinson's disease with and without impulsive behaviour.

Punishing violators of social norms when there is personal cost is known as altruistic punishment. We tested patients with Parkinsons disease (PD) with and without impulsive-compulsive behaviours (ICBs) and matched control subjects, on and off their regular dopamine replacement therapy on a task, in which the patients decided whether or not to invest a sum of money with a trustee. The sum was then quadrupled and the trustee could decide whether or not to return a portion of the investment. Participants could punish the trustee after they were informed of the trustees decision. We found that PD patients without ICBs on or off medication punished more often than controls, whereas PD patients with ICBs punished more than controls on medication, but similar to controls off medication. These results suggest a role for dopamine in altruistic punishment decisions in PD patients with impulsive compulsive behaviour.

Concomitant fragile X-associated tremor ataxia syndrome and Parkinson's disease: a clinicopathological report of two cases

Parkinsonism is common in fragile X-associated tremor/ataxia syndrome (FXTAS) but its underlying pathophysiology remains unknown. Our group reported a patient with FXTAS and parkinsonism, and in vivo evidence of presynaptic and postsynaptic nigrostriatal dysfunction.1 We report the histological findings of this case (case 1) and another case with dual pathologies of FXTAS and Lewy body Parkinsons disease (PD). Genetic testing for FXTAS was requested in seven cases from the Queen Square Brain Bank for Neurological Disorders (QSBB) based on the characteristic radiological ‘middle cerebellar peduncle’ (MCP) sign (case 1, diagnosis confirmed in life) and histological findings of round, eosinophilic p62-positive neuronal intranuclear inclusions in the hippocampus or unexplained cerebellar degeneration (6 postmortem cases were tested). Two cases were positive for FMR1 premutation and both showed histological features of FXTAS and PD. The QSBB brain donor programme was approved by a Research Ethics Committee and written consent for research was obtained from all cases. ### Case 1 A 68-year-old man presented with a 10-year history of slowly progressive right-hand tremor. There was no family history of neurological disorders or mental retardation. Examination showed hypomimia, asymmetric rest and kinetic tremor, rigidity, mild bradykinesia and inability to tandem walk. The patient was diagnosed with tremor-predominant PD but did not respond to L-dopa (600 mg/day). Over the next few years he developed mild cognitive impairment, gait ataxia and intention tremor. Brain MRI demonstrated the MCP sign and diffuse atrophy. Genetic analysis confirmed FMR1 premutation with 87 CGG expansion. 123I-FP-CIT SPECT revealed …

Camptocormia: don't forget muscle disease in the movement disorder clinic.

The cause of isolated camptocormia or ‘bent spine syndrome’ is various and often difficult to establish [1]. Patients may present to neurologists or musculoskeletal specialists but many remain without diagnosis. We recently reported a patient with camptocormia due to facioscapulohumeral dystrophy (FSHD) that had been initially diagnosed as idiopathic axial dystonia in a movement disorder clinic [2]. A second case of muscle disease masquerading as dystonia has now come to light. In this report we provide helpful diagnostic pointers that may help neurologists to pick up these cases and avoid inappropriate treatment. The patient was of non-consanguineous Ashkenazi Jewish descent. She first presented to a neurologist at the age of 66 with a 9-year history of involuntary bending of her spine when walking. Any attempt to overcome the forward flexion led to shortness of breath and increased difficulty walking. Pushing a shopping trolley caused significant improvement in her posture. She also complained of a tight band sensation around her upper abdomen. She had a past history of rheumatic fever at 8 years of age (no history of chorea) with subsequent mitral valve disease necessitating replacement with a prosthetic metal valve at the age of 46. Six years before presentation she had an episode of presumed polymyalgia rheumatica (based on symptoms of pain and stiffness around her neck, shoulders and upper arms and an elevated ESR—between 40–50 mm/h), which settled with a short course of steroids. She also had an 8-year history of deafness in the left ear. Her medications included warfarin, digoxin, bisoprolol, losartan, furosemide, spironolactone and quinine sulphate. She had never been exposed to dopamine blocking drugs. Her mother had a similar posture in her later years. On examination she had spontaneous flexion of the trunk, which worsened the further she walked. Using a rollator or placing her hands on her thighs enabled her to straighten her trunk (video). There was no fixed deformity when lying supine, and spinal imaging revealed multi-level degenerative changes but no spinal cord compression or radiculopathy. She was diagnosed with camptocormia due to idiopathic axial dystonia. DYT1 testing was negative. Focal myopathy was considered a possible cause but electromyography was felt to be contraindicated due to her treatment with warfarin. L-dopa (150 mg/day), anticholinergic drugs (trihexyphenidyl 6 mg/day and tetrabenazine 12.5 mg/day) Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6448-z) contains supplementary material, which is available to authorized users.

Decades of delayed diagnosis in 4 levodopa-responsive young-onset monogenetic parkinsonism patients

We report 4 patients with young‐onset monogenetic parkinsonism, each of whom was misdiagnosed with either a psychogenic movement disorder or chronic fatigue syndrome for 10 to 23 years after the onset of their first symptoms.