Pawel Tacik

[18F]AV-1451 tau-PET uptake does correlate with quantitatively measured 4R-tau burden in autopsy-confirmed corticobasal degeneration

We assessed the relationship between [18F]AV-1451 uptake on PET with tau burden at autopsy, and with measures of neurodegeneration from [18F]fluorodeoxyglucose (FDG) PET and MRI, in a patient with autopsy-confirmed CBD as well as performed correlative autoradiography, as previously described [6]. The male patient died aged 59 after a 10-year history of progressive neurological decline. He first presented with difficulty getting his words out and was diagnosed with primary progressive apraxia of speech [5]. Over time, he developed difficulty with language, swallowing difficulties, ideomotor apraxia, marked parkinsonism, and balance and gait problems (Online resource 1), hence his clinical diagnosis was later changed to corticobasal syndrome [1]. He tested negative for microtubuleassociated protein tau mutations. Autopsy revealed 4R tau-positive, but 3R tau-negative threads in grey and white matter of cortex, basal ganglia, thalamus and brainstem, as well as pretangles, astrocytic plaques and coiled bodies (oligodendroglial inclusions) consistent with a diagnosis of CBD [3] (Fig. 1a, Online Resource 1). Fourteen months prior to death, he underwent [18F]AV-1451 PET, as well as Pittsburgh-compound B (PiB) PET, FDG-PET and a 3T volumetric MRI. In addition, he had undergone MRI scans 9 and 22 months before death. We abstracted tau burden at autopsy, tau-PET uptake, FDG-PET uptake, grey matter volumes and grey matter rates of atrophy for the identical set of ten regions-of-interest (ROIs) in the left hemisphere (middle frontal, supplementary motor area, primary motor, Broca’s area, orbitofrontal cortex, inferior parietal, superior temporal, parahippocampal gyrus, visual cortex and striatum). Tau burden at autopsy was determined quantitatively. All ten ROIs were scanned at ultra-resolution on the ScanScopeXT from which large areas of interest were annotated using ImageScope-11.2 (Aperio Technologies, Vista, CA). Annotated regions were Corticobasal degeneration (CBD) is a neurodegenerative disease characterized by the deposition of abnormally hyperphosphorylated 4-repeat (4R) tau in the brain [3]. Recent advances in molecular neuroimaging include the production of positron emission tomography (PET) ligands that bind to abnormal tau in the brain. One such ligand, [18F]AV-1451, has been shown to bind to abnormal 3R + 4R tau in diseases such as Alzheimer’s disease [2]. In addition, one case report found an association between antemortem [18F]AV-1451 and tau burden in an autopsied case with a mutation in the microtubule-associated protein tau gene with 3R + 4R tau [9]. Autoradiographic studies however have found very little, if any, binding in diseases characterized by 4R-tau including CBD [6–8], and no PETautopsy studies have been published for a 4R-tau disease.

Update on novel familial forms of Parkinson’s disease and multiple system atrophy

Parkinsons disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders classified as synucleinopathies, which are defined by the presence of α-synuclein protein pathology. Genetic studies have identified a total of 18 PARK loci that are associated with PD. The SNCA gene encodes the α-synuclein protein. The first pathogenic α-synuclein p.A53T substitution was discovered in 1997; this was followed by the identification of p.A30P and p.E46K pathogenic substitutions in 1998 and 2004, respectively. In the last year, two possible α-synuclein pathogenic substitutions, p.A18T and p.A29S, and two probable pathogenic substitutions, p.H50Q and p.G51D have been nominated. Next-generation sequencing approaches in familial PD have identified mutations in the VPS35 gene. A VPS35 p.D620N substitution remains the only confirmed pathogenic substitution. A second synucleinopathy, MSA, originally was considered a sporadic condition with little or no familial aggregation. However, recessive COQ2 mutations recently were nominated to be the genetic cause in a subset of familial and sporadic MSA cases. Further studies on the clinicogenetics and pathology of parkinsonian disorders will facilitate clarification of the molecular characteristics and pathomechanisms underlying these disorders.

Three sib-pairs of autopsy-confirmed progressive supranuclear palsy

OBJECTIVE To describe the clinical, pathological, and genetic features of three sib-pairs of pathologically-confirmed progressive supranuclear palsy (PSP). METHODS We searched the Mayo Clinic neurodegenerative diseases brain bank for cases of PSP in which more than one family member had pathologically-confirmed PSP. Clinical and pathological data were reviewed and all individuals were screened for mutations in MAPT, by sequencing exons 1, 7, and 9-13. RESULTS We identified three sib-pairs of pathologically-confirmed PSP. Sufficient information was available to suggest an autosomal dominant inheritance in two. The mean age at symptom onset was 41 years in one pair, and 76 years in the other two. The young onset pair had a p.S285R mutation in MAPT, but no mutations were detected in the other two. CONCLUSIONS All sib-pairs had typical pathological features of PSP; however, the age at onset of the sib-pair with MAPT mutation was significantly younger than sporadic PSP. Future studies are warranted to identify a possible genetic basis for PSP associated with late onset and typical PSP pathology.

Three families with Perry syndrome from distinct parts of the world

OBJECTIVES Perry syndrome consists of autosomal dominant Parkinsonism, depression, weight loss, and central hypoventilation. Eight mutations in 16 families have been reported: p.F52L, p.G67D, p.G71R, p.G71E, p.G71A, p.T72P, p.Q74P, and p.Y78C located in exon 2 of the dynactin 1 (DCTN1) gene on chromosome 2p13.1. METHODS Genealogical, clinical, genetic, and functional studies were performed in three kindreds from New Zealand, the United States, and Colombia. A diaphragmatic pacemaker was implanted in the proband from the Colombian family to treat her respiratory insufficiency. Dopaminergic therapy was initiated in probands from two families. RESULTS Besides the probands, 17 symptomatic relatives from all families were identified. The cardinal signs of Perry syndrome were present in all three probands with symptomatic disease onset in their fifth or sixth decade of life. Parkinsonism was moderate with a partial response to dopaminergic treatment. All affected persons but two died of respiratory insufficiency. The proband from the Colombian family is alive most likely due to early diagnosis and implantation of a diaphragmatic pacemaker. Two-and-a-half-year follow-up examination has revealed that the diaphragmatic pacemaker is optimally functioning without any major complications. In the Colombian and US families, the DCTN1 p.G71R and in the New Zealand family the DCTN1 p.Y78C mutations were identified. In functional assays, both mutations altered microtubule binding consistent with a pathogenic role. CONCLUSIONS Perry syndrome is a rare condition, but new cases are expected to be diagnosed worldwide. Early diagnosis prevents life-threatening acute respiratory failure. Diaphragmatic pacemakers should be considered as an effective symptomatic treatment option.

Clinicopathologic heterogeneity in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) due to microtubule-associated protein tau (MAPT) p.P301L mutation, including a patient with globular glial tauopathy

The p.P301L mutation in microtubule‐associated protein tau (MAPT) is a common cause of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17). We compare clinicopathologic features of five unrelated and three related (brother, sister and cousin) patients with FTDP‐17 due to p.P301L mutation.

A Novel Tau Mutation in Exon 12, p.Q336H, Causes Hereditary Pick Disease

Abstract Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c.1008G>C, p.Q336H) in 1 patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared with sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism, and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p.Q336H mutation formed filaments faster than wild-type tau, especially with 3R tau. It also promoted more microtubule assembly than wild-type tau. We conclude that mutations in MAPT, including p.Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p.Q336H, and another previously reported variant at the same codon (p.Q336R), seems to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau–dependent manner.

Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG)

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.

Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration

Mutations in the leucine‐rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinsons disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers.

Latin America's first case of Perry syndrome and a new treatment option for respiratory insufficiency

Dear Sirs, Perry syndrome is an autosomal dominant disorder characterized by rapidly progressive Parkinsonism, depression, weight loss, and central hypoventilation [1]. Since the original publication in 1975, only 52 patients from ten families have been found, but no case had been reported from Latin America. The mean age of symptom onset is 48 years, and the mean disease duration is 5 years. Patients usually die of respiratory complications. Genome-wide linkage analysis identified disease-segregating mutations located in exon 2 of the dynactin 1 (DCTN1) gene on chromosome 2p13 [4]. A 56-year-old Colombian female was admitted to the Hospital Universitario San Ignacio, in Bogota, Colombia, with acute deterioration of her respiration. On clinical examination, the patient displayed generalized anxiety and a severe depressive episode. She reported a weight loss of 15 kg in 6 months. The patient had a 2-year history of Parkinsonism, which comprised hypomimia, cogwheel rigidity in all extremities, and low-frequency postural and intention tremor of the upper extremities that was more pronounced on the left side. Levodopa at a maximum daily dosage of 1,000 mg combined with 100 mg of carbidopa slightly improved the tremor. Brain MRI, EEG, and muscle biopsy did not show any relevant abnormalities. A gas blood analysis on admission showed the following values: FiO2 21 %, pH 7.32, pCO2 60 mmHg, PO2 20 mmHg, HCO3 31 mmol/l, SatO2 88 % with a supply of 2 l of O2 per minute via nasal cannula. This demonstrated severe respiratory acidosis with acidemia. There was no history of chronic obstructive pulmonary disease. The patients body max index was 16.6. Diagnostic procedures to clarify the etiology of the respiratory insufficiency included diaphragm electromyography (EMG), the mouth pressure generated 100 ms after the onset of an occluded inspiratory effort (P0.1), and the transdiaphragmatic pressure (Pdi) measured with a transesophageal probe. Their results were as follows: normal EMG, 9 cm H2O (P0.1), and 5 cm H2O (Pdi), which suggested a central etiology. Due to unstable and deteriorating respiratory conditions, no polysomnography could be performed. Instead, the patient was placed on mechanical ventilation following tracheostomy. Numerous attempts to treat her with noninvasive respiratory support over a period of 2 months prior to the hospital admission had been unsuccessful. Efforts to wean the patient off a ventilator during other 2 months following the admission failed. Thus, the patient was fitted with a bilateral diaphragmatic pacemaker with direct stimulation of the phrenic nerve (Mark IV Breathing Pacemaker System, Avery Biomedical Devices, Inc.) following a bilateral anterior thoracotomy with a 6-cm transverse incision over the third intercostal space. The surgery was complicated by a mild right hematothorax and subcutaneous emphysema. The patient was stimulated with a pulse train of 20 Hz. The most common pacemaker settings were an amplitude of 1.6 mA and a respiratory frequency of 15 breaths per minute. Two-year-follow-up examinations have displayed a good function of the diaphragmatic pacemaker. The patient became independent in her everyday life. There have been no episodes of acute respiratory failure, albeit the patient has occasionally developed pneumonia. This has successfully been treated with antibiotics. Implantation of a diaphragmatic pacemaker also enabled to avoid the very high costs of permanent ventilatory support. Family history revealed the same symptoms in her mother and another nine relatives on her mothers side, including four uncles, two sisters, and three cousins. All died of respiratory insufficiency. Molecular genetic testing for Perry syndrome confirmed this diagnosis revealing the c.211 G > A (p.G71R) mutation in exon 2 of the DCTN1 gene on chromosome 2p13.1. Our patient is Latin Americas first genetically confirmed case of Perry syndrome. Contrary to other cases, our patient presented with mild extrapyramidal symptoms and pronounced respiratory insufficiency as the main complaint. However, the latter has successfully been treated with the use of a diaphragmatic pacemaker. Our case is the first successful attempt to apply a diaphragmatic pacemaker in a patient with Perry syndrome, although diaphragmatic pacemakers in the form of direct phrenic nerve pacing (Diaphragmatic/Phrenic Nerve Stimulator) have already been applied in the symptomatic treatment of different conditions such as congenital central hypoventilation syndrome [5] or medullary trauma [6]. Diaphragmatic pacemakers with the direct stimulation of the diaphragm (Diaphragm Pacing Systems) have been approved by the US Food and Drug Administration in the treatment of ventilator failure in amyotrophic lateral sclerosis [7], spinal cord injuries, and congenital central hypoventilation syndrome. We conclude that implantation of a diaphragmatic pacemaker should be considered as a safe, effective, and cost-reducing treatment option for respiratory insufficiency in patients with Perry syndrome. Early diagnosis significantly improves the patients quality of life and prevents life-threatening acute respiratory failure. Parkinsonian features, although always present in Perry syndrome, may not be disabling in some cases. Perry syndrome is not geographically constrained. New cases from South America are expected to be diagnosed.

Occurrence of Crohn's disease with Parkinson’s disease

We retrospectively investigated the co-occurrence of Crohns disease in a cohort of 876 patients with Parkinsons disease, based on the observation that LRRK2 is a shared genetic risk factor. We identified 2 patients with Crohns disease; this number was consistent with the number of cases expected in the general population.