Karen Shaw

A common LRRK2 mutation in idiopathic Parkinson's disease

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant Parkinsons disease. Few mutations in this gene have been identified. We investigated the frequency of a common heterozygous mutation, 2877510 g-->A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019 ser), in idiopathic Parkinsons disease. We assessed 482 patients with the disorder, of whom 263 had pathologically confirmed disease, by direct sequencing for mutations in exon 41 of LRRK2. The mutation was present in eight (1.6%) patients. We have shown that a common single Mendelian mutation is implicated in sporadic Parkinsons disease. We suggest that testing for this mutation will be important in the management and genetic counselling of patients with Parkinsons disease.

Hyposmia in G2019S LRRK2-related parkinsonism Clinical and pathologic data

Background: Mutations in PARK8 (LRRK2) are associated with autosomal dominant parkinsonism and Parkinson disease (PD). Hyposmia is present in at least 80% of patients with PD and an accumulation of α-synuclein (α-syn) is seen in the olfactory pathways. In this study we have clinically examined olfaction and pathologically examined the rhinencephalon in individuals carrying the G2019S LRRK2 mutation. Methods: The University of Pennsylvania Smell Test (UPSIT) was used to evaluate the sense of smell in 19 parkinsonian and two asymptomatic carriers of the G2019S mutation and compared with groups of patients with PD and healthy controls. Postmortem examination of α-syn accumulation in the rhinencephalon was also carried out in four parkinsonian carriers of the G2019S mutation. Results: The mean UPSIT score in G2019S parkinsonian carriers was lower than that in healthy controls (p < 0.001) and similar to that found in patients with PD (p > 0.999). Smell tests in two asymptomatic carriers of the G2019S mutation were in the normal range. Postmortem studies of the olfactory pathways in one of the patients who had been clinically tested, and found to have hyposmia, and three other cases with the G2019S mutation, revealed α-syn deposition in the olfactory pathways in all cases. Conclusions: Odor identification is diminished in LRRK2 G2019S mutation parkinsonism but the asymptomatic carriers of the mutation had normal olfaction. We found α-syn accumulation with Lewy bodies in the rhinencephalon in all four cases examined pathologically.

The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features.

Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinsons disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.

The alpha-synuclein gene in multiple system atrophy

Background: The formation of α-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. Method: The linkage disequilibrium (LD) structure of the α-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. Results and conclusion: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases

population with or without NDDs which is currently not known. The most recent consecutive cases with the primary pathological diagnosis of PSP (N = 50), Parkinson’s disease (N = 50), AD (N = 20), corticobasal degeneration (CBD, N = 27), FTLD (N = 24) and multiple system atrophy (MSA, N = 50) and controls (>60 years old, N = 47) in the archives of the Queen Square Brain Bank for Neurological Disorders (QSBB) were included in this study. The QSBB brain donor programme is approved by a London Multi-Centre Research Ethics Committee and tissue is stored for research under a license from the Human Tissue Authority. Immunohistochemistry with antibodies to phosphorylated tau (AT8), Aβ, α-synuclein, TDP-43 was performed. Histological slides stained with the AT8 (frontal and temporal cortices, hippocampal formation, midbrain, pons and medulla) and Aβ antibodies (frontal cortex and hippocampal formation) were reviewed by one neuropathologist (TR). Cases considered to have positive CTE histology were then reviewed by a second neuropathologist (JH) and a consensus was achieved by a joint review of the cases. The interpretation of CTE histological changes can be challenging in co-existing tauopathies. A case is determined to have positive CTE pathology when the following distinctive features are present [11]: (1) perivascular foci of taupositive lesions in the neurons, astrocytes and neurites in the neocortex; (2) irregular distribution of these tau-positive lesions at the sulcal depths; (3) clusters of subpial ATs. The medical records of the positive cases were reviewed; family members were interviewed by a QSBB research nurse to screen for past history and risk factors for TBIs. Of the 268 screened NDDs and control cases, 32 cases (11.9 %, M:F = 19:13) had histological evidence of CTE (Table 1). The prevalence of CTE was highest in PSP Chronic traumatic encephalopathy (CTE) is a long-term neurodegenerative consequence of repetitive traumatic brain injury (rTBI). The histological features of CTE are characterised by neurofibrillary tangles (NFTs) composed of both 3-repeat and 4-repeat tau isoforms and astrocytic tau pathology (ATs) commonly in the frontal and temporal cortices and are distinct from other tauopathies [9]. The recent classification delineates 4 pathological stages with progression of tau pathology from multifocal (I and II) to widespread disease (III and IV) [12]. Of 68 CTE cases in the McKee series with history of rTBIs, only 43 had pure CTE pathology, the other 25 cases (37 %) had co-morbid neurodegenerative disorders (NDDs) including Lewy body disease, motor neuron disease, Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), Pick’s disease and progressive supranuclear palsy (PSP) [12]. TDP43 pathology was found in 85 % of CTE cases across all disease stages [12]. Our group reported an ex-professional boxer with dual pathologies of CTE and PSP [10]. It is possible that rTBIs or the existence of chronic CTE-tau pathology play a role in triggering the deposition of other abnormal proteins in the brain [17, 18]. The existing literature mainly focused on high-risk individuals especially contact sport athletes. This study aimed to investigate the prevalence of histological evidence of CTE in the general

Salivary cortisol levels in Parkinson's disease and its correlation to risk behaviour

Objective To investigate salivary cortisol samples in patients with Parkinsons disease (PD) with and without impulsive compulsive behaviours (ICB) during a risk task. Methods Salivary cortisol levels were measured in 13 PD patients without ICB (PD−ICB) and in 15 PD patients with ICB (PD+ICB) before, after medication and throughout the day, and were compared with results with 14 healthy controls. All participants also performed a gambling task to assess risk taking behaviour. Results Significantly higher diurnal cortisol levels were found in the PD−ICB group compared with healthy controls but no differences were seen between the PD+ICB and the control group. Increased cortisol levels were significantly correlated with increased risk taking in PD+ICB patients but no interaction was found in the PD−ICB group. Conclusions The findings are in keeping with previous studies which have linked low cortisol levels with antisocial behaviour. The higher cortisol levels during the risk task in the PD+ICB group are consistent with reports in pathological gamblers during gambling and addicts during drug abuse. The results support the hypothesis that cortisol plays an important role in risk taking in ICBs.

Banking on brains: insights of brain donor relatives and friends from an experiential perspective.

Brain donation is critical to understand the pathological causes of neurodegenerative diseases. Increasing levels of donation requires an understanding of those factors that both encourage and deter donation. At present, there are few studies of how people understand, feel and decide about brain donation for scientific research. This qualitative experiential study contributes to the growing literature on brain donation through its specific focus on how the donation process is experienced from the perspectives of family members and friends. Nineteen semi-structured interviews were analysed using a phenomenologically informed thematic analysis. Four themes were derived from the analysis, three of which are described in detail: Making the decision to donate; a personal perspective on the donation process; the significance of the brain; beliefs about brain donation. In particular, the thematic analysis highlights the variation of individual decision making and the emotions and reasons underpinning such decisions. Key conclusions include the importance of integrated practice amongst relevant healthcare professionals as well as the need for supportive and informed communication. Also, in light of the finding that the brain assumed no special significance for most participants, the value of the distinction between brain donation for research purposes and organ transplantation is questioned.