Resolution of lobe collapse in a child with cystic fibrosis with Mycobacterium abscessus using serial intrabronchial rhDNase.

An eight-year-old girl with cysticfibrosis (CF) developed a left upper lobe collapse failing to resolve withinitial conventional antibiotic treatment, mucolytics and intensifiedphysiotherapy. Mycobacterium abscessus was isolated from her sputum. Bronchoscopy revealed thick viscousmucus plugging of the left upper lobe bronchus with complete obliteration.Three bronchoscopies with saline lavage and Dornase alfa, a rhDNase, at the endof each procedure resulted in removal of this mucus plug and the re-inflationof the affected lobe, with clinical and radiological resolution. The use of flexible bronchoscopy as a 'secondary' treatment with 0.9% saline lavage and instillation of rhDNase isdescribed sparsely in the literature. This is the first reported successfultherapeutic resolution of a lung collapse in a CF patient with Mycobacteriumabscessus, with sequential therapeutic bronchoscopies with instillation ofDornase alfa. This should be considered for lobar collapse in CF not respondingto the standard therapeutic regime.

Significant Reduction in Pediatric, Population-Based Hospital Admissions Due To COVID-19 in Malta.

OBJECTIVE: This population-based, retrospective study aimed to determine whether there was a drop in pediatric admissions during the first year of COVID-19 in Malta, as reported in other centers worldwide, as well as to determine any differences in patient characteristics when compared to the previous year. MATERIALS AND METHODS: All unplanned pediatric medical admissions to Mater Dei Hospital from March 1, 2020 (a few days before the first case of COVID-19 in Malta) till February 28, 2021 (study period) and the corresponding period in 2019/20 (control period) and characteristics of patients admitted during the first 10 weeks (first wave of COVID-19) were analyzed. RESULTS: Pediatric admissions dropped by 57.7% during the first year of COVID-19 (1601 vs. 3789 in 2019). During the first wave of COVID-19, a higher percentage of neonates were admitted in 2020 when compared to all other ages. There was a lower prevalence of respiratory illnesses during the first wave of COVID-19 (31.6% vs. 47.5% in 2019, P < .001), with a higher prevalence of cases related to child abuse or adverse socio-economic circumstances (2020, 9 [3.4%] vs 1 [0.1%] in 2019, P < .001). Following school closures, a drop in communicable disease admissions was recorded (68 [42.2%] vs. 421 [70.3%] in 2019, P < .001). A negative correlation between daily pediatric admissions and active COVID-19 cases in Malta was noted (r (68) = -0.33, P = .005). CONCLUSION: The drop in admissions likely represents fear of contracting COVID-19 in hospital environments, together with a decline in communicable diseases due to school closures. Guardians' concerns must be alleviated as best as possible by effective public health measures.

WITHDRAWN: COVID-19 related acute decline in paediatric admissions in Malta, a population-based study.

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Neuropathology training worldwide-evolution and comparisons.

Training of neuropathologists varies worldwide. Systems range from highly organized specialist and subspecialist education with national certification, to regulated training with diploma recognition, to informal apprenticeships in neurological hospitals and no formal recognition. This overview compiles and summarizes the history of regulated training systems, the status of neuropathology within various countries' medical systems and the manner in which neuropathologists are trained. Anecdotal evidence suggests that countries with regulated systems of neuropathology training and an active professional organization are more likely to have an adequate supply of diagnostic specialists and a vibrant research community. The different training systems reflect the style of medical services delivery in the respective countries. In general, the existence of formal neuropathology training systems occurs only in countries with relatively high levels of per capita health expenditures, reflecting the development of medical specialization overall. Evolving diagnostic technologies and major international research endeavors, whose goals are to understand structure and function of the human brain, demand that neuropathology training is more than simply diagnostic histopathology.

White matter perivascular spaces: an MRI marker in pathology-proven cerebral amyloid angiopathy?

OBJECTIVE: We investigated whether severe, MRI-visible perivascular spaces (PVS) in the cerebral hemisphere white matter (centrum semiovale) are more common in patients with pathology-proven cerebral amyloid angiopathy (CAA) than in those with pathology-proven non-CAA-related intracerebral hemorrhage (ICH). METHODS: Using a validated 4-point scale on axial T2-weighted MRI, we compared PVS in patients with pathology-proven CAA to PVS in those with spontaneous ICH but no histopathologic evidence of CAA. In a preliminary analysis restricted to patients with T2*-weighted gradient-recalled echo MRI, we also investigated whether including severe centrum semiovale PVS increases the sensitivity of existing diagnostic criteria for probable CAA. RESULTS: Fourteen patients with CAA and 10 patients with non-CAA-related ICH were included. Eight of the patients with CAA were admitted for symptomatic, spontaneous lobar ICH, 1 because of ischemic stroke, 1 with transient focal neurologic episodes, and 4 due to cognitive decline. Severe (>20) centrum semiovale PVS were more frequent in patients with CAA compared to controls (12/14 [85.7%; 95% confidence interval (CI): 57.2%-98.2%] vs 0/10 [1-sided 95% CI: 0%-30.8%], p < 0.0005); this was robust to adjustment for age. The original Boston criteria for probable CAA showed a sensitivity of 76.9% (95% CI: 46.2%-95%), which increased to 92.3% (95% CI: 64%-99.8%), without loss of specificity, after including severe centrum semiovale PVS. CONCLUSIONS: Severe centrum semiovale PVS on MRI may be a promising new neuroimaging marker for the in vivo diagnosis of CAA. However, our findings are preliminary and require confirmation and external validation in larger cohorts of pathology-proven CAA.

Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease.

Mutations in the mitochondrial genome, and in particular the mt-tRNAs, are an important cause of human disease. Accurate classification of the pathogenicity of novel variants is vital to allow accurate genetic counseling for patients and their families. The use of weighted criteria based on functional studies-outlined in a validated pathogenicity scoring system--is therefore invaluable in determining whether novel or rare mt-tRNA variants are pathogenic. Here, we describe the identification of nine novel mt--tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, isolated progressive external ophthalmoplegia, epilepsy, deafness and diabetes. Each of the variants identified (m.4289T>C, MT-TI; m.5541C>T, MT-TW; m.5690A>G, MT-TN; m.7451A>T, MT-TS1; m.7554G>A, MT-TD; m.8304G>A, MT-TK; m.12206C>T, MT-TH; m.12317T>C, MT-TL2; m.16023G>A, MT-TP) was present in a different tRNA, with evidence in support of pathogenicity, and where possible, details of mutation transmission documented. Through the application of the pathogenicity scoring system, we have classified six of these variants as "definitely pathogenic" mutations (m.5541C>T, m.5690A>G, m.7451A>T, m.12206C>T, m.12317T>C, and m.16023G>A), whereas the remaining three currently lack sufficient evidence and are therefore classed as 'possibly pathogenic' (m.4289T>C, m.7554G>A, and m.8304G>A).

Neuropathological correlates of falling in the CC75C population-based sample of the older old.

BACKGROUND: Previous imaging studies have suggested links between brain pathologies and factors that are associated with falls such as gait, balance and daily function. Possible neuropathological correlates of older people's falls have been suggested based on brain imaging studies, but to date none have been examined in brain tissue. METHODS: Falls data collected from repeated surveys of a population-based cohort of individuals aged at least 75 years old at baseline were related to neuropathological data collected from post-mortem examination of the study's associated brain donor collection (n=212). RESULTS: Amongst people without dementia, most cerebrovascular neuropathological features examined, particularly white matter pallor, microinfarcts and microscopic atherosclerosis, were increasingly common across the subgroups categorised by no reports of falling, only one or at least two reports of falling. The overall burden of pathology was greater in those with dementia, but only microinfarcts showed a similar increase with respect to reported falling status. CONCLUSIONS: Subclinical pathologies sharing a common vascular origin are associated with increased falling amongst people with no dementia, as are microinfarcts in those with dementia. Although further research is needed to address the mechanisms of falls and their neuropathological correlates, the findings from the current study would suggest that if cerebrovascular disease prevention reduces vascular neuropathology changes this may have direct benefits in reducing falls amongst older people with or without dementia.

The relationship between clinical and pathological variables in Richardson's syndrome.

In order to determine the relationship between regional neuropathology and severity of clinical features in Richardson's syndrome (PSP-RS), the following hypotheses were tested: (1) executive dysfunction relates to prefrontal pathology; (2) language difficulties to pathology in Broca's area and/or the perirhinal cortex; and (3) visuospatial impairment to pathology in the supramarginal region. A prospectively studied case series of brain donors at a specialist clinic in Addenbrooke's Hospital Cambridge, UK, were examined. All those fulfilling postmortem criteria for PSP-RS and their last cognitive assessment within 24 months of death (N = 11/25) were included. The degree of regional neuronal loss and neuronal tau deposition across a number of cortical brain regions was performed and compared to 10 age- and sex-matched controls from the Sydney Brain Bank. Stepwise multiple linear regressions were used to determine the neuropathological correlates to cognitive scores and revealed the following. Executive dysfunction, as indexed by letter fluency, related to the degree of tau deposition in the superior frontal gyrus and supramarginal cortices (p < 0.020), language deficits related to neuron loss in the perirhinal gyrus (p < 0.001) and tau deposition in Broca's area (p = 0.020), while visuospatial dysfunction and global cognitive impairment related to tau deposition in the supramarginal gyrus (p < 0.007). The severity of cognitive deficits relate to regional cortical tau deposition in PSP-RS, although language impairment related to neuronal loss in the perirhinal region. Global cognitive dysfunction related most to the severity of tau deposition in the supramarginal gyrus warranting further research on the role of this brain region in PSP-RS.

Altered levels of glutamatergic receptors and Na+/K+ ATPase-α1 in the prefrontal cortex of subjects with schizophrenia.

Evidence has accumulated over the past years that dysregulation of glutamatergic neurotransmission maybe implicated in the pathophysiology of schizophrenia. Glutamate acts on two major classes of receptors: ionotropic receptors, which are ligand-gated ion channels, and metabotropic receptors (mGluRs), coupled to heterotrimeric G-proteins. Although several pharmacological evidences point to abnormal glutamatergic transmission in schizophrenia, changes in the expression of glutamatergic receptors in the prefrontal cortex of patients with schizophrenia remains equivocal. In the present work, we have investigated glutamatergic neurotransmission in schizophrenia by assessing the expression in Brodmann Area 10 of mGluR5, the AMPA receptor subunits GluR1 and GluR2, and Na(+)/K(+) ATPase-α1, a potential modulator of glutamate uptake in the brain. Semiquantitative analysis of the expression of these proteins from postmortem brains revealed a particularly prominent reduction of GluR1 and GluR2 expression in patients with schizophrenia vs the control group. Conversely, we observed an up-regulation in the levels of Na(+)/K(+) ATPase-α1 expression. Finally, no change in the protein levels of mGluR5 was observed in schizophrenia. Our findings support and expand the hypothesis of glutamatergic dysfunction in prefrontal cortex in the pathophysiology of schizophrenia.

Clinical comparison of progressive aphasia associated with Alzheimer versus FTD-spectrum pathology.

OBJECTIVE: Recent post-mortem studies indicate that 30-40% of patients with clinically diagnosed progressive aphasia (PA) have Alzheimer's disease pathology, while the remainder have pathology in the FTD spectrum. This study aimed to compare the clinical features of patients from these two groups. MATERIALS AND METHODS: A retrospective chart review was conducted on 33 pathologically verified PA patients: n=13 AD and n=20 FTD-spectrum pathology. Demographics, global cognitive function, non-verbal memory, neuropsychiatric symptoms and structural imaging were compared between the two pathology-confirmed groups. RESULTS: The median survival was 6.3 years in the FTD group versus 8.1 years in the AD group, in spite of the fact that onset for AD was on average 2.0 years older than FTD. Features highly specific in predicting FTD-spectrum pathology were age of onset before 60 years, preference for sweet food, disinhibition and focal knife-edge frontotemporal atrophy, although the sensitivity for each of these was remarkably low (highest sensitivity was 45% for disinhibition). Some clinical features hypothesised to distinguish AD from FTD-spectrum pathology, such as global functional impairment within 2 years of onset and poor non-verbal memory ability, were not useful in separating the two groups. CONCLUSIONS: If present, certain clinical and imaging features can help to identify PA with FTD-spectrum pathology, notably the presence of the neuropsychiatric features seen with behavioural presentations of FTD and knife-edge atrophy on structural imaging. The profile of non-linguistic cognitive deficits does not appear to be discriminatory, though prospective studies are needed to evaluate this issue further.

Semantic dementia: demography, familial factors and survival in a consecutive series of 100 cases.

A great deal has been written about cognitive aspects of semantic dementia but little is known about the demography or prognosis. We describe these features in a consecutive series of 100 patients seen over a 17-year period; all cases were assessed and followed up in a specialist clinic. The mean age at diagnosis was 64.2 (+/-7.1) range 40-79 years, but 46 presented after age 65 and 7 after 75; a higher proportion than the existing literature might predict. Fifteen had a first-degree relative with dementia, but in seven this was almost certainly unrelated. Only two had relatives with young-onset dementia. There were no families with more than two affected members. The familial rate was estimated at between 2% and 7% (95% confidence interval 0-12%). Kaplan-Meier analyses indicated a 50% survival of 12.8 years (95% confidence interval 11.9-13.7); a more benign course than suggested by neuropathologically based studies. We were unable to identify any factors influencing survival. Of the 100, 34 have died, with pathological confirmation in 24; 18 had frontotemporal lobar degeneration with ubiquitin-positive inclusions (13 of 13 confirmed TAR DNA binding protein-43 positive), and 3 had classic tau-positive Pick bodies and 3 had Alzheimer's pathology. The age at diagnosis or death across the pathological subgroups was equivalent. Although semantic dementia has a strong statistical association with ubiquitin-positive pathology, it does not have the signature of familial frontotemporal lobar degeneration with ubiquitin-positive inclusions, notably the presence of intranuclear lentiform TAR DNA binding protein-43 inclusions. The age of onset is older than predicted and the course more slowly progressive than suggested by earlier studies of small groups of subjects.

Lewy body variant of Alzheimer's disease: selective neocortical loss of t-SNARE proteins and loss of MAP2 and alpha-synuclein in medial temporal lobe.

Lewy bodies (LBs) appear in the brains of nondemented individuals and also occur in a range of neurodegenerative disorders, such as dementia with Lewy bodies (DLB) and Parkinson's disease. A number of people with a definite diagnosis of Alzheimer's disease (AD) also exhibit these intraneuronal inclusions in allo- and/or neocortical areas. The latter, referred to as Lewy body variant of AD (LBV), bears a clinical resemblance to AD in terms of age at onset, duration of illness, cognitive impairment, and illness severity. Since the presence of LBs is accompanied by neuronal cytoskeleton changes, it is possible that the latter may influence neuronal connectivity via alterations to the synaptic network. To address this, we examined the expression of synaptic proteins (synaptophysin, syntaxin, SNAP-25, and alpha-synuclein) and two cytoskeletal proteins (tau and MAP2) in the brain tissue of subjects enrolled in a population-based autopsy study (n = 47). They were divided into groups with no memory problems (control group, n = 15), LBV (n = 5), AD devoid of LBs (n = 17), cerebrovascular dementia (n = 3), and mixed dementia (n = 7). The LBV and AD groups had a similar degree of cognitive impairment and neuropathological staging in terms of Braak staging and CERAD score. In comparison with the control group and the dementia groups without LBs, the LBV group had significantly lower levels of syntaxin and SNAP-25 (23%) in the neocortex, and depletion of MAP2 (64%), SNAP-25 (34%), and alpha-synuclein (44%) proteins in the medial temporal lobes. These findings suggest that the t-SNARE complex deficit present in LBV may be associated with the presence of LB-related pathology and may explain the more profound cholinergic loss seen in these patients.

Neuropathological correlates of dementia in over-80-year-old brain donors from the population-based Cambridge city over-75s cohort (CC75C) study.

Key neuropathological changes associated with late-onset dementia are not fully understood. Population-based longitudinal studies offer an opportunity to step back and examine which pathological indices best link to clinical state. CC75C is a longitudinal study of the population aged 75 and over at baseline in Cambridge, UK. We report on the first 213 participants coming to autopsy with sufficient information for an end of life dementia diagnosis. Clinical diagnosis was ascertained by examining retrospective informant interviews, survey responses, and death certificates according to DSM-IV criteria. The neuropathological protocol was based on the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Clinical dementia was present in 113 participants (53%): 67% with Alzheimer's disease, 4% vascular dementia, 22% mixed dementia, and 1% dementia with Lewy bodies. As Alzheimer-type pathology was common, the mutually blinded clinical and neuropathological diagnoses were not strongly related. Multivariable analysis identified associations between dementia during life and entorhinal cortex neuritic plaques, hippocampal diffuse plaques, neocortical neurofibrillary tangles, white matter pallor, Lewy bodies, and hippocampal atrophy. These results were consistent in those with clinical Alzheimer's disease. Vascular pathologies, especially microinfarcts, were more common in those with clinical diagnoses including vascular dementia. Alzheimer-type and cerebrovascular pathology are both common in the very old. A greater burden of these pathologies, Lewy bodies, and hippocampal atrophy, are associated with a higher risk of, but do not define, clinical dementia in old age.

Phosphorylation of soluble tau differs in Pick's disease and Alzheimer's disease brains.

Frontotemporal lobar degeneration (FTLD) is a common cause of presenile dementia characterised by behavioural and language disturbances. Pick's disease (PiD) is a subtype of FTLD, which presents with intraneuronal inclusions consisting of hyperphosphorylated tau protein aggregates. Although Alzheimer's disease (AD) is also characterised by tau lesions, these are both histologically and biochemically distinct from the tau aggregates found in PiD. What determines the distinct characteristics of these tau lesions is unknown. As phosphorylated, soluble tau has been suggested to be the precursor of tau aggregates, we compared both the level and phosphorylation profile of tau in tissue extracts of AD and PiD brains to determine whether the differences in the tau lesions are reflected by differences in soluble tau. Levels of soluble tau were decreased in AD but not PiD. In addition, soluble tau was phosphorylated to a greater extent in AD than in PiD and displayed a different phosphorylation profile in the two disorders. Consistently, tau kinases were activated to different degrees in AD compared with PiD. Such differences in solubility and phosphorylation may contribute, at least in part, to the formation of distinct tau deposits, but may also have implications for the clinical differences between AD and PiD.

Is the pathology of corticobasal syndrome predictable in life?

Corticobasal syndrome (CBS) has been associated with a heterogeneous spectrum of pathologies with an increasing number of reports of Alzheimer's type pathology. There is, however, no means of predicting pathology of CBS in vivo at present. We compared the clinical features of patients presenting with CBS who have either pathologic changes of classic corticobasal degeneration (CBD) or Alzheimer's disease (AD) at post-mortem to identify predictors of the specific pathological processes in life. Twelve patients with CBS were followed prospectively; six had AD and six had classic CBD neuropathology. After review of the presenting clinical features, we identified nine potential predictor variables, compared their frequency in the two groups, and performed a discriminant function analysis. Initial episodic memory complaints and poor performance on the combined orientation-memory subtest of the Addenbrooke's Cognitive Examination (ACE) reliably predicted AD pathology while varying combinations of early frontal-lobe type behavioral symptoms, nonfluent language disturbance, orobuccal apraxia, and utilization behavior predicted CBD pathology ante-mortem. CBS is frequently associated with Alzheimer's disease pathology. Early episodic memory impairment versus early behavioral symptomatology appears to best predict AD or CBD pathology in life.

The neural basis of semantic memory: evidence from semantic dementia.

Semantic dementia (SD) is a syndrome of progressive impairment in semantic memory. Fifty-eight brain regions were measured in seven post mortem SD cases, ten normal controls and two disease controls (diagnosis frontotemporal dementia and motor neuron disease, FTD-MND). Manual segmentation of the whole brain has not previously been undertaken in a series of SD cases, either post mortem or during life. Widespread volume loss relative to controls was found in SD, with anterior temporal lobe regions bearing the brunt (>60% atrophy of temporopolar and perirhinal cortices bilaterally). Comparison of regional volumes in SD and FTD-MND found greater atrophy in SD only in temporopolar and perirhinal volumes. The sole region showing atrophy relative to controls in FTD-MND but not SD was motor cortex. Posterior temporal and frontal regions were not consistently affected and no significant asymmetry of atrophy was found. In summary, whole-brain regional evaluation in SD, in comparison with normal controls and FTD-MND, found anterior temporal atrophy encompassing the perirhinal cortex with relative sparing of adjacent posterior temporal regions.

High grade glioma: imaging combined with pathological grade defines management and predicts prognosis.

INTRODUCTION: There is ambiguity in pathological grading of high grade gliomas within the WHO 2000 classification, especially those with predominant oligodendroglial differentiation. PATIENTS AND METHODS: All adult high grade gliomas treated radically, 1996-2005, were assessed. Cases in which pathology was grade III but radiology suggested glioblastoma (GBM) were classified as 'grade III/IV'; their pathology was reviewed. RESULTS: Data from 245 patients (52 grade III, 18 grade III/IV, 175 GBM) were analysed using a Cox Proportional Hazards model. On pathology review, features suggestive of more aggressive behaviour were found in all 18 grade III/IV tumours. Oligodendroglial components with both necrosis and microvascular proliferation were present in 7. MIB-1 counts for the last 8 were all above 14%, mean 27%. Median survivals were: grade III 34 months, grade III/IV 10 months, GBM 11 months. Survival was not significantly different between grade III/IV and GBM. Patients with grade III/IV tumours had significantly worse outcome than grade III, with a hazard of death 3.7 times higher. CONCLUSIONS: The results highlight the current inconsistency in pathological grading of high grade tumours, especially those with oligodendroglial elements. Patients with histological grade III tumours but radiological appearances suggestive of GBM should be managed as glioblastoma.

Altered dimerization of metabotropic glutamate receptor 3 in schizophrenia.

BACKGROUND: Metabotropic glutamate receptors (mGlus) may be involved in the pathophysiology of schizophrenia. Group II mGlus (mGlu2 and mGlu3) have attracted considerable interest since the development of potent specific agonists that exhibit atypical antipsychotic-like activity and reports of a genetic association between the mGlu3 gene and schizophrenia. METHODS: In this postmortem study, mGlu3 protein levels in Brodmann area 10 of prefrontal cortex from schizophrenic (n = 20) and control (n = 35) subjects were analyzed by western immunoblotting using a novel specific mGlu3 antibody and an antibody for the vesicular glutamate transporter 1 (VGluT1). RESULTS: We report a significant decrease in the dimeric/oligomeric forms of mGlu3 in schizophrenic patients compared with control subjects, whereas total mGlu3 and VGluT1 levels were not altered significantly. CONCLUSIONS: This is the first experimental evidence that mGlu3 receptor levels are altered in schizophrenia and supports the hypothesis that neurotransmission involving this particular excitatory amino acid receptor is impaired in schizophrenia.

Clinical and pathological characterization of progressive aphasia.

OBJECTIVE: The clinical and neuropathological categorization of patients presenting with progressive aphasia is an area of controversy. This study aimed to characterize a large group of progressive aphasic patients from a single center (n = 38), first clinically by case note review, and then pathologically. METHODS: Hierarchical cluster analysis of the cases according to their clinical language deficits was used to establish an unbiased, data-driven classification. RESULTS: This analysis revealed two groups of cases corresponding to the syndromes of progressive nonfluent aphasia (n = 23) and semantic dementia (n = 15). Postmortem analysis showed a majority in both groups of pathologies from the spectrum of frontotemporal lobar degeneration: the most frequent were non-Alzheimer's disease (AD) tauopathy in the nonfluent cases (10 of 23) and frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions in the fluent cases (8 of 15). Despite rigorous exclusion of cases with clinically significant memory deficits or other cognitive impairments, the pathology of AD was present in approximately one third of each group (overall 12 of 38), although often with an atypical neuroanatomical distribution. INTERPRETATION: Progressive aphasia is best seen as a composite of two conditions, on both clinical and pathological levels: progressive nonfluent aphasia and semantic dementia.