Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognized for its association with dementia. AIMS: This study investigated clinical and neuropathological differences between DLB and PDD. METHODS: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. RESULTS: CAA was more common in DLB than in PDD (P = 0.003). The severity of CAA was greater in DLB than in PDD (P = 0.009), with significantly higher CAA scores in the parietal lobe (P = 0.043), and the occipital lobe (P = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. CONCLUSIONS: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

Developmental stages and estimated prevalence of coexisting mental health and neurodevelopmental conditions and service use in youth with intellectual disabilities, 2011-2012.

BACKGROUND: Few studies exist on mental health and neurodevelopmental conditions and service use among youth with intellectual disabilities (IDs), which makes it difficult to develop interventions for this population. The objective of the study is to (1) estimate and compare the prevalence of mental health and neurodevelopmental conditions in youth with and without ID across three developmental stages and (2) estimate and compare mental health service use in youth with and without ID across three developmental stages. METHODS: We conducted secondary data analysis using cross-sectional data collected from caregivers completing the 2011-2012 National Survey of Children's Health. The data set represents a nationally representative sample of youth (0-17 years) in the USA with one child from each household being randomly selected. Data were collected from caregivers in 50 states, Washington D.C. and the US Virgin Islands. We restricted the sample to parents of youth between 3-17 years (N = 81 510). RESULTS: Compared with youth without ID, youth ages 3-17 with ID had a statistically significantly higher prevalence of (1) mental health and neurodevelopmental conditions and (2) mental health care use and medication use for mental health and neurodevelopmental issues (other than attention deficit disorder/attention deficit hyperactivity disorder). Clinically significant differences in coexisting conditions and service use were also found across developmental stages. CONCLUSIONS: Youth with ID are at greater risk of having coexisting mental health and neurodevelopmental conditions than youth without ID and are more likely to receive treatment. Therefore, clinicians should consider mental health and neurodevelopmental conditions and the unique needs of youth by developmental stage when tailoring interventions for youth with ID.

Review: Clinical, neuropathological and genetic features of Lewy body dementias.

Lewy body dementias are the second most common neurodegenerative dementias after Alzheimer's disease and include dementia with Lewy bodies and Parkinson's disease dementia. They share similar clinical and neuropathological features but differ in the time of dementia and parkinsonism onset. Although Lewy bodies are their main pathological hallmark, several studies have shown the emerging importance of Alzheimer's disease pathology. Clinical amyloid-ß imaging using Pittsburgh Compound B (PiB) supports neuropathological studies which found that amyloid-ß pathology is more common in dementia with Lewy bodies than in Parkinson's disease dementia. Nevertheless, other co-occurring pathologies, such as cerebral amyloid angiopathy, TDP-43 pathology and synaptic pathology may also influence the development of neurodegeneration and dementia. Recent genetic studies demonstrated an important role of APOE genotype and other genes such as GBA and SNCA which seem to be involved in the pathophysiology of Lewy body dementias. The aim of this article is to review the main clinical, neuropathological and genetic aspects of dementia with Lewy bodies and Parkinson's disease dementia. This is particularly relevant as future management for these two conditions may differ.

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations.

OBJECTIVE: The histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases. METHODS: We performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987-2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible. RESULTS: Through the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants. CONCLUSIONS: Patients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.

Exploring the putative role of kallikrein-6, calpain-1 and cathepsin-D in the proteolytic degradation of α-synuclein in multiple system atrophy.

AIMS: There is evidence that accumulation of α-synuclein (α-syn) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) results from impaired removal of α-syn rather than its overproduction. Kallikrein-6 (KLK6), calpain-1 (CAPN1) and cathepsin-D (CTSD) are among a small number of proteases that cleave α-syn and are dysregulated in PD and DLB. Our aim in this study was to determine whether protease activity is altered in another α-synucleinopathy, multiple system atrophy (MSA), and might thereby modulate the regional distribution of α-syn accumulation. METHODS: mRNA and protein level and/or activity of KLK6, CAPN1 and CTSD were measured and assessed in relation to α-syn load in multiple brain regions (posterior frontal cortex, caudate nucleus, putamen, occipital cortex, pontine base and cerebellar white matter), in MSA (n = 20) and age-matched postmortem control tissue (n = 20). RESULTS: CTSD activity was elevated in MSA in the pontine base and cerebellar white matter. KLK6 and CAPN1 levels were elevated in MSA in the putamen and cerebellar white matter. However, the activity or level of these proteolytic enzymes did not correlate with the regional distribution of α-syn. CONCLUSIONS: Accumulation of α-syn in MSA is not due to reduced activity of the proteases we have studied. We suggest that their upregulation is likely to be a compensatory response to increased α-syn in MSA.

Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features.

AIM: Juvenile idiopathic inflammatory myopathies have been recently reclassified into clinico-serological subgroups. Myopathological correlates of the subgroups are incompletely understood. METHODS: We studied muscle biopsies from 101 children with clinically and serologically defined juvenile idiopathic inflammatory myopathies from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review and C5b-9 complement analysis. RESULTS: Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti-TIF1γ, 15/90 anti-NXP2, 11/90 anti-MDA5, 5/90 anti-Mi2 and 6/90 anti-PmScl. JDM biopsy severity scores were consistently low in the anti-MDA5 group, high in the anti-Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage-rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101) and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b-9-deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b-9 deposition. CONCLUSION: We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes.

A rare case of Paget's disease affecting the cervical spine.

We present the case of a 75-year-old man with a rapidly progressive cervical myelopathy on a background of a 3-year history of neck pain and a severely degenerative cervical spine. The patient developed progressive myelopathy over a six-month period and suffered from worsening kyphosis. Suspicion of an underlying oncological process prompted transfer to our tertiary referral unit. Biopsy was consistent for Paget's disease, an extremely rare diagnosis of the cervical spine. Magnetic resonance imaging revealed cord compression between C4 and C6 with associated cord signal change indicative of myelopathy. A three-level corpectomy and posterior instrumented fusion was performed. There was significant blood loss (3.5l) intraoperatively, consistent with a diagnosis of Paget's disease of the bone. Cell salvage was used, as was neuromonitoring for both the anterior and posterior part of the procedure. Postoperatively, neurological function improved slightly and the patient required community neurorehabilitation to allow independent living.

9.4 T MR microscopy of the substantia nigra with pathological validation in controls and disease.

BACKGROUND: The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinson's disease and progressive supranuclear palsy. METHODS: 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinson's disease) and imaged using high field 9.4 Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images. RESULTS: The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinson's disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinson's disease and controls, but reduced in progressive supranuclear palsy. CONCLUSIONS: We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinson's disease whereas in progressive supranuclear palsy there was microarchitectural destruction.

Past and projected temporal trends in arthroscopic hip surgery in England between 2002 and 2013.

INTRODUCTION: Hip arthroscopy is increasingly adopted for the treatment of intra-articular and extra-articular pathologies. Studies from USA demonstrate a 365% increase in the number of procedures performed between 2004 and 2009 and 250% increase between 2007 and 2011. There is limited evidence of long-term efficacy for this procedure and hip arthroscopy is not universally funded across England. The aim of this study is to describe temporal trends in the adoption of hip arthroscopy in England between 2002 and 2013 and to forecast trends for the next 10 years. METHODS: A search of the Hospital Episodes Database was performed for all codes describing arthroscopic hip procedures with patient age, sex and area of residence. RESULTS: 11 329 hip arthroscopies were performed in National Health Service hospitals in England between 2002 and 2013. The number of hip arthroscopies performed increased by 727% (p<0.0001) during this period and is forecast to increase by 1388% in 2023. Females represent 60% of all patients undergoing hip arthroscopy (p<0.001). Median age category is 40-44 for females and 35-39 for males and average age decreased during the study period (p<0.0001). There is significant regional variation in procedure incidence. In the final year of this study the highest incidence was in the Southwest (8.63/100 000 population) and lowest in East Midlands (1.29/100 000 population). CONCLUSIONS: The increase in number of hip arthroscopies performed in England reflects trends in USA and continued increases are forecast. Evidence from robust clinical trials is required to justify the increasing number of procedures performed and regional variation suggests potential inequality in the provision of this intervention.

Neuropathology of Beta-propeller protein associated neurodegeneration (BPAN): a new tauopathy.

INTRODUCTION: Beta-propeller protein associated neurodegeneration (BPAN) is associated with mutations in the WD repeat domain 45 (WDR45) gene on chromosome Xp11 resulting in reduced autophagic flux. This study describes the clinical and neuropathological features of a female 51 year old BPAN case. The clinical history includes learning disability and progressive gait abnormalities since childhood followed by progressive dystonic features in young adulthood. Brain imaging revealed generalised brain atrophy and bilateral mineralisation of the globus pallidus and substantia nigra. RESULTS: The major pathological findings were observed in the substantia nigra with excess iron deposition, gliosis, axonal swellings and severe neuronal loss. Iron deposition was also observed in the globus pallidus. There was extensive hyperphosphorylated-tau deposition in the form of neurofibrillary tangles, pre-tangles and neuropil threads. Furthermore, histological studies and immunoblotting confirmed a mixed Alzheimer type 3-and 4-repeat tau pathology. Microtubule-associated protein 1A/1B-light chain 3 (LC3) immunoblotting of brain homogenates indicated autophagic activity and may support the role of WDR45 in autophagy. CONCLUSIONS: The widespread Alzheimer-type tau pathology in this disease indicates that this should be considered as a tauopathy and adds further support to the proposal that impaired autophagy may have a role in tauopathies.

Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy.

Hereditary transthyretin amyloidosis (ATTR) is a genetically and clinically heterogeneous disease manifesting with predominant peripheral and autonomic neuropathy; cardiomyopathy, or both. ATTR V122I is the most common variant associated with non-neuropathic familial amyloid cardiomyopathy. We present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment.

Zebra body myopathy is caused by a mutation in the skeletal muscle actin gene (ACTA1).

We present follow up data on the original case of 'zebra body myopathy' published by Lake and Wilson in 1975. Pathological features in a second biopsy performed at the age of 29 years included a wide variation in fibre size, multiple split fibres, excess internal nuclei and endomysial connective tissue, rimmed vacuoles, accumulation of myofibrillar material and large 'wiped out' areas lacking stain for oxidative enzymes. The presence of nemaline rods and actin-like filaments in addition to small zebra bodies suggested ACTA1 as a candidate gene. This has been confirmed by the identification of a novel c.1043T.p.Leu348Gln mutation, which probably occurred de novo. This case illustrates that the myopathy associated with zebra bodies is part of the spectrum of myopathies associated with the ACTA1 gene. It also highlights that accumulation of actin filaments is not confined to severe neonatal ACTA1 cases and that progression of weakness can occur in congenital myopathies, as the patient is now wheelchair bound and can only stand with the aid of a walking frame.

Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient.

Oculoleptomeningeal amyloidosis is a rare manifestation of hereditary transthyretin (TTR) amyloidosis. Here, we present the first case of leptomeningeal amyloidosis associated with the TTR variant Leu12Pro mutation in an African patient. A 43-year-old right-handed Nigerian man was referred to our centre with rapidly progressive neurological decline. He presented initially with weight loss, confusion, fatigue, and urinary and erectile dysfunction. He then suffered recurrent episodes of slurred speech with right-sided weakness. He went on to develop hearing difficulties and painless paraesthesia. Neurological examination revealed horizontal gaze-evoked nystagmus, brisk jaw jerk, increased tone, brisk reflexes throughout and bilateral heel-shin ataxia. Magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid analysis showed a raised protein of 6.4 g/dl. Nerve conduction studies showed an axonal neuropathy. Echocardiography was characteristic of cardiac amyloid. TTR gene sequencing showed that he was heterozygous for the leucine 12 proline mutation. Meningeal and brain biopsy confirmed widespread amyloid angiopathy. TTR amyloidosis is a rare cause of leptomeningeal enhancement, but should be considered if there is evidence of peripheral or autonomic neuropathy with cardiac or ocular involvement. The relationship between different TTR mutations and clinical phenotype, disease course, and response to treatment remains unclear.

Necrotising myositis, the deadly impersonator.

We report two cases of patients with necrotising myositis who presented initially with limb pain and swelling on a background of respiratory complaints. Patient 1, a previously well 38-year-old female, underwent various investigations in the emergency department for excessive lower limb pain and a skin rash. Patient 2, a 61-year-old female with a background of rheumatoid arthritis and hypertension, presented to accident and emergency feeling generally unwell and was treated for presumed respiratory sepsis. Both deteriorated rapidly and were referred to the plastic surgery team with soft tissue necrosis, impending multiorgan failure and toxaemia. Large areas of necrotic muscle and skin were debrided, which grew group A streptococci, Streptococcus pyogenes. Patient 1 had a high above knee amputation of the left leg with extensive debridement of the right. Despite aggressive surgical intervention and microbiological input with intensive care support, patient 2 died. These two cases highlight the importance of early diagnosis and prompt surgical and pharmacological intervention in managing this life-threatening disease. Pain is the primary symptom with skin changes being a late and subtle sign in a septic patient. The Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC) may be of use if there is concern to aid diagnosis of this life-threatening disease.

Neuropathological features of multiple system atrophy with cognitive impairment.

Cognitive impairment (CI) is an exclusion criterion for the diagnosis of multiple system atrophy (MSA), according to the second consensus statement. This view was recently challenged by patients with pathologically confirmed MSA who were reported to have dementia. With an aim to investigate the pathological substrate of CI in MSA, quantitative assessment of the glial and neuronal cytoplasmic inclusions and semiquantitative assessment of neuronal loss in the cortical and limbic regions was performed. No differences in the severity of these MSA-related pathological findings were identified between nine MSA cases with CI and nine MSA cases with normal cognition. Alzheimer's-related pathological changes, cerebral amyloid angiopathy, and cerebrovascular disease did not differ between the two MSA groups. MSA-specific α-synuclein and secondary pathological conditions were not more severe in MSA cases with CI, suggesting that although CI may be intrinsic to the MSA disease process, further investigation into the pathological basis of cognitive impairment in MSA is warranted.

Characteristics of progressive supranuclear palsy presenting with corticobasal syndrome: a cortical variant.

AIMS: Since the first description of the classical presentation of progressive supranuclear palsy (PSP) in 1963, now known as Richardson's syndrome (PSP-RS), several distinct clinical syndromes have been associated with PSP-tau pathology. Like other neurodegenerative disorders, the severity and distribution of phosphorylated tau pathology are closely associated with the clinical heterogeneity of PSP variants. PSP with corticobasal syndrome presentation (PSP-CBS) was reported to have more tau load in the mid-frontal and inferior-parietal cortices than in PSP-RS. However, it is uncertain if differences exist in the distribution of tau pathology in other brain regions or if the overall tau load is increased in the brains of PSP-CBS. METHODS: We sought to compare the clinical and pathological features of PSP-CBS and PSP-RS including quantitative assessment of tau load in 15 cortical, basal ganglia and cerebellar regions. RESULTS: In addition to the similar age of onset and disease duration, we demonstrated that the overall severity of tau pathology was the same between PSP-CBS and PSP-RS. We identified that there was a shift of tau burden towards the cortical regions away from the basal ganglia; supporting the notion that PSP-CBS is a 'cortical' PSP variant. PSP-CBS also had less severe neuronal loss in the dorsolateral and ventrolateral subregions of the substantia nigra and more severe microglial response in the corticospinal tract than in PSP-RS; however, neuronal loss in subthalamic nucleus was equally severe in both groups. CONCLUSIONS: A better understanding of the factors that influence the selective pathological vulnerability in different PSP variants will provide further insights into the neurodegenerative process underlying tauopathies.