Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Neuropathological and biochemical investigation of Hereditary Ferritinopathy cases with ferritin light chain mutation: Prominent protein aggregation in the absence of major mitochondrial or oxidative stress.

AIMS: Neuroferritinopathy (NF) or hereditary ferritinopathy (HF) is an autosomal dominant movement disorder due to mutation in the light chain of the iron storage protein ferritin (FTL). HF is the only late-onset neurodegeneration with brain iron accumulation disorder and study of HF offers a unique opportunity to understand the role of iron in more common neurodegenerative syndromes. METHODS: We carried out pathological and biochemical studies of six individuals with the same pathogenic FTL mutation. RESULTS: CNS pathological changes were most prominent in the basal ganglia and cerebellar dentate, echoing the normal pattern of brain iron accumulation. Accumulation of ferritin and iron was conspicuous in cells with a phenotype suggesting oligodendrocytes, with accompanying neuronal pathology and neuronal loss. Neurons still survived, however, despite extensive adjacent glial iron deposition, suggesting neuronal loss is a downstream event. Typical age-related neurodegenerative pathology was not normally present. Uniquely, the extensive aggregates of ubiquitinated ferritin identified indicate that abnormal FTL can aggregate, reflecting the intrinsic ability of FTL to self-assemble. Ferritin aggregates were seen in neuronal and glial nuclei showing parallels with Huntington's disease. There was neither evidence of oxidative stress activation nor any significant mitochondrial pathology in the affected basal ganglia. CONCLUSIONS: HF shows hallmarks of a protein aggregation disorder, in addition to iron accumulation. Degeneration in HF is not accompanied by age-related neurodegenerative pathology and the lack of evidence of oxidative stress and mitochondrial damage suggests that these are not key mediators of neurodegeneration in HF, casting light on other neurodegenerative diseases characterized by iron deposition.

Inheritance of mitochondrial DNA in humans: implications for rare and common diseases.

The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ-specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late-onset common human diseases including Parkinson's disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age-related diseases. Thus, mtDNA contributes to a wide range of human pathologies. For many decades, it has generally been accepted that mtDNA is inherited exclusively down the maternal line in humans. Although recent evidence has challenged this dogma, whole-genome sequencing has identified nuclear-encoded mitochondrial sequences (NUMTs) that can give the false impression of paternally inherited mtDNA. This provides a more likely explanation for recent reports of 'bi-parental inheritance', where the paternal alleles are actually transmitted through the nuclear genome. The presence of both mutated and wild-type variant alleles within the same individual (heteroplasmy) and rapid shifts in allele frequency can lead to offspring with variable severity of disease. In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far-reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.

Correction: Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

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The pattern of retinal ganglion cell dysfunction in Leber hereditary optic neuropathy.

Leber inherited optic neuropathy (LHON) is characterized by subacute bilateral loss of central vision due to dysfunction and loss of retinal ganglion cells (RGCs). Comprehensive visual electrophysiological investigations (including pattern reversal visual evoked potentials, pattern electroretinography and the photopic negative response) performed on 13 patients with acute and chronic LHON indicate early impairment of RGC cell body function and severe axonal dysfunction. Temporal, spatial and chromatic psychophysical tests performed on 7 patients with acute LHON and 4 patients with chronic LHON suggest severe involvement or loss of the midget, parasol and bistratified RGCs associated with all three principal visual pathways.

Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy.

OBJECTIVE: To identify the cause of isolated distal weakness in a family with both neuropathic and myopathic features on EMG and muscle histology. METHODS: Case study with exome sequencing in 2 affected individuals, bioinformatic prioritization of genetic variants, and segregation analysis of the likely causal mutation. Functional studies included Western blot analysis of the candidate protein before and after heat shock treatment of primary skin fibroblasts. RESULTS: A novel HSPB1 variant (c.387C>G, p.Asp129Glu) segregated with the phenotype and was predicted to alter the conserved α-crystallin domain common to small heat shock proteins. At baseline, there was no difference in HSPB1 protein levels nor its binding partner αB-crystallin. Heat shock treatment increased HSPB1 protein levels in both patient-derived and control fibroblasts, but the associated increase in αB-crystallin expression was greater in patient-derived than control fibroblasts. CONCLUSIONS: The HSPB1 variant (c.387C>G, p.Asp129Glu) is the likely cause of distal neuromyopathy in this pedigree with pathogenic effects mediated through binding to its partner heat shock protein αB-crystallin. Mutations in HSBP1 classically cause a motor axonopathy, but this family shows that the distal weakness can be both myopathic and neuropathic. The traditional clinical classification of distal weakness into "myopathic" or "neuropathic" forms may be misleading in some instances, and future treatments need to address the pathology in both tissues.

Exome sequencing in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.

Voxel-based analysis in neuroferritinopathy expands the phenotype and determines radiological correlates of disease severity.

Neuroferritinopathy is an autosomal dominant adult-onset movement disorder which occurs due to mutations in the ferritin light chain gene (FTL). Extensive iron deposition and cavitation are observed post-mortem in the basal ganglia, but whether more widespread pathological changes occur, and whether they correlate with disease severity is unknown. 3D-T1w and quantitative T2 whole brain MRI scans were performed in 10 clinically symptomatic patients with the 460InsA FTL mutation and 10 age-matched controls. Voxel-based morphometry (VBM) and voxel-based relaxometry (VBR) were subsequently performed. Clinical assessment using the Unified Dystonia Rating Scale (UDRS) and Unified Huntington's Disease Rating Scale (UHDRS) was undertaken in all patients. VBM detected significant tissue changes within the substantia nigra, midbrain and dentate together with significant cerebellar atrophy in patients (FWE, p < 0.05). Iron deposition in the caudate head and cavitation in the lateral globus pallidus correlated with UDRS score (p < 0.001). There were no differences between groups with VBR. Our data show that progressive iron accumulation in the caudate nucleus, and cavitation of the globus pallidus correlate with disease severity in neuroferritinopathy. We also confirm sub-clinical cerebellar atrophy as a feature of the disease. We suggest that VBM is an effective technique to detect regions of iron deposition and cavitation, with potential wider utility to determine radiological markers of disease severity for all NBIA disorders.

Frequency of rare recessive mutations in unexplained late onset cerebellar ataxia.

Sporadic late onset cerebellar ataxia is a well-described clinical presentation with a broad differential diagnosis that adult neurologists should be familiar with. However, despite extensive clinical investigations, an acquired cause is identified in only a minority of cases. Thereafter, an underlying genetic basis is often considered, even in those without a family history. Here we apply whole exome sequencing to a cohort of 12 patients with late onset cerebellar ataxia. We show that 33% of 'idiopathic' cases harbor compound heterozygous mutations in known ataxia genes, including genes not included on multi-gene panels, or primarily associated with an ataxic presentation.

Treatment strategies for inherited optic neuropathies: past, present and future.

Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain. The majority of patients with DOA harbour pathogenic mutations within OPA1, a nuclear gene that codes for a multifunctional inner mitochondrial membrane protein. Despite their contrasting genetic basis, LHON and DOA share overlapping pathological and clinical features that serve to highlight the striking tissue-specific vulnerability of the retinal ganglion cell (RGC) layer to disturbed mitochondrial function. In addition to severe visual loss secondary to progressive optic nerve degeneration, a subgroup of patients will also develop a more aggressive syndromic phenotype marked by significant neurological deficits. The management of LHON and DOA remains largely supportive, but major advances in our understanding of the mechanisms underpinning RGC loss in these two disorders are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. In addition to neuroprotective strategies for rescuing RGCs from irreversible cell death, innovative in vitro fertilisation techniques are providing the tantalising prospect of preventing the germline transmission of pathogenic mtDNA mutations, eradicating in so doing the risk of disease in future generations.

An under-recognised cause of spastic paraparesis in middle-aged women.

Having excluded common structural, inflammatory and vascular causes of a spastic paraparesis, the diagnostic yield of further clinical investigations is low. Here, we show that testing for rare metabolic and genetic causes can have important implications for both the patient and their family.

A multi-center comparison of diagnostic methods for the biochemical evaluation of suspected mitochondrial disorders.

A multicenter comparison of mitochondrial respiratory chain and complex V enzyme activity tests was performed. The average reproducibility of the enzyme assays is 16% in human muscle samples. In a blinded diagnostic accuracy test in patient fibroblasts and SURF1 knock-out mouse muscle, each lab made the correct diagnosis except for two complex I results. We recommend that enzyme activities be evaluated based on ratios, e.g. with complex IV or citrate synthase activity. In spite of large variations in observed enzyme activities, we show that inter-laboratory comparison of patient sample test results is possible by using normalization against a control sample.

Next generation sequencing for neurological diseases: new hope or new hype?

Over the past year huge advances have been made in our ability to determine the genetic aetiology of many neurological diseases through the utilisation of next generation sequencing platforms. This technology is, on a daily basis, providing new breakthroughs in neurological disease. The aim of this article is to clearly describe the technological platforms, methods of data analysis, established breakthroughs, and potential future clinical and research applications of this innovative and exciting technique which has relevance to all those working within clinical neuroscience.

Progressive brain iron accumulation in neuroferritinopathy measured by the thalamic T2* relaxation rate.

Neuroferritinopathy is an autosomal dominant extrapyramidal movement disorder, caused by FTL gene mutations. Iron decreases the MR T2* decay time, therefore increasing the R2* (R2* = 1 /T2*), which correlates with brain tissue iron content. 3T structural and quantitative MR imaging assessment of R2* in 10 patients with neuroferritinopathy demonstrated a unique pattern of basal ganglia cavitation involving the substantia nigra in older patients and increasing thalamic R2* signal intensity detectable during 6 months. Increasing R2* signal intensity in the thalamus correlated with progression on a clinical rating scale measuring dystonia severity. Thalamic R2* signal intensity is a clinically useful method of objectively tracking disease progression in this form of neurodegeneration with brain iron accumulation.

PGD and heteroplasmic mitochondrial DNA point mutations: a systematic review estimating the chance of healthy offspring.

BACKGROUND: Mitochondrial disorders are often fatal multisystem disorders, partially caused by heteroplasmic mitochondrial DNA (mtDNA) point mutations. Prenatal diagnosis is generally not possible for these maternally inherited mutations because of extensive variation in mutation load among embryos and the inability to accurately predict the clinical expression. The aim of this study is to investigate if PGD could be a better alternative, by investigating the existence of a minimal mutation level below which the chance of an embryo being affected is acceptably low, irrespective of the mtDNA mutation. METHODS: We performed a systematic review of muscle mutation levels, evaluating 159 different heteroplasmic mtDNA point mutations derived from 327 unrelated patients or pedigrees, and reviewed three overrepresented mtDNA mutations (m.3243A>G, m.8344A>G and m.8993T>C/G) separately. RESULTS: Mutation levels were included for familial mtDNA point mutations only, covering all affected (n = 195) and unaffected maternal relatives (n = 19) from 137 pedigrees. Mean muscle mutation levels were comparable between probands and affected maternal relatives, and between affected individuals with tRNA- versus protein-coding mutations. Using an estimated a priori prevalence of being affected in pedigrees of 0.477, we calculated that a 95% or higher chance of being unaffected was associated with a muscle mutation level of 18% or less. At a mutation level of 18%, the predicted probability of being affected is 0.00744. The chance of being unaffected was lower only for the m.3243A>G mutation (P < 0.001). Most carriers of mtDNA mutations will have oocytes with mutation levels below this threshold. CONCLUSIONS: Our data show, for the first time, that carriers of heteroplasmic mtDNA mutations will have a fair chance of having healthy offspring, by applying PGD. Nevertheless, our conclusions are partly based on estimations and, as indicated, do not provide absolute certainty. Carriers of mtDNA should be informed about these constraints.

No consistent evidence for association between mtDNA variants and Alzheimer disease.

OBJECTIVE: Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain. METHODS: We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis. RESULTS: In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD. CONCLUSION: The current evidence linking common mtDNA variations with AD is not compelling.