The search for disease-modifying treatments for Alzheimer's disease is a global research priority.1 Despite promising findings in mouse models2 and encouraging early phase human studies, successive ...large clinical trials of anti-amyloid immunotherapies failed to translate into clinical benefit, questioning the wisdom of such a strategy. ...the recent publication of the phase 3 trial of lecanemab in early Alzheimer's disease3 is likely to be seen as an historic moment in the field—the beginning of a new era of disease-modifying therapies for Alzheimer's disease.4 This trial represents more than 20-years of research efforts that build on clinical, laboratory, and trial observations.2,4 Lecanemab is a humanised monoclonal antibody with particular affinity for large (75–300 kDa) amyloid-β assemblies called protofibrils, which are intermediary structures between monomers and fibrillary amyloid plaques. The phase 3 trial, which involved fortnightly intravenous infusions of lecanemab(10 mg/kg) or placebo in people with early Alzheimer's disease, achieved its primary endpoint, with significant slowing of decline by 27% on the Clinical Dementia Rating Sum of Boxes (CDR-SB) score following lecanemab treatment.3 Differences appeared after6 months of treatment, and at the end of the 18-month double-blind treatment period, the CDR-SB score in the lecanemab group had increased (worsened) by 1·21 points, compared with an increase of 1·66 points in the placebo group (difference –0·45, 95% CI −0·67 to −0·23; p<0·001). There will be legitimate questions about equity of access within and between countries, with the risk that treatments are only available to the privileged few. ...with only symptomatic therapies for Alzheimer's disease to offer, time was not of the essence in terms of diagnosis and starting treatment.10 Now time will be of the essence.
Dementia is arguably the most pressing public health challenge of our age. Since dementia does not have a cure, identifying risk factors that can be controlled has become paramount to reduce the ...personal, societal and economic burden of dementia. The relationship between exposure to air pollution and effects on cognitive function, cognitive decline and dementia has stimulated increasing scientific interest in the past few years. This review of the literature critically examines the available epidemiological evidence of associations between exposure to ambient air pollutants, cognitive performance, acceleration of cognitive decline, risk of developing dementia, neuroimaging and neurological biomarker studies, following Bradford Hill guidelines for causality.
The evidence reviewed has been consistent in reporting associations between chronic exposure to air pollution and reduced global cognition, as well as impairment in specific cognitive domains including visuo-spatial abilities. Cognitive decline and dementia incidence have also been consistently associated with exposure to air pollution. The neuro-imaging studies reviewed report associations between exposure to air pollution and white matter volume reduction. Other reported effects include reduction in gray matter, larger ventricular volume, and smaller corpus callosum. Findings relating to ischemic (white matter hyperintensities/silent cerebral infarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease have been heterogeneous, as have observations on hippocampal volume and air pollution. The few studies available on neuro-inflammation tend to report associations with exposure to air pollution.
Several effect modifiers have been suggested in the literature, but more replication studies are required. Traditional confounding factors have been controlled or adjusted for in most of the reviewed studies. Additional confounding factors have also been considered, but the inclusion of these has varied among the different studies. Despite all the efforts to adjust for confounding factors, residual confounding cannot be completely ruled out, especially since the factors affecting cognition and dementia are not yet fully understood.
The available evidence meets many of the Bradford Hill guidelines for causality. The reported associations between a range of air pollutants and effects on cognitive function in older people, including the acceleration of cognitive decline and the induction of dementia, are likely to be causal in nature.
However, the diversity of study designs, air pollutants and endpoints examined precludes the attribution of these adverse effects to a single class of pollutant and makes meta-analysis inappropriate.
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•Epidemiological evidence suggests air pollution adversely affects cognitive function.•Evidence suggests air pollution is causally associated with cognitive impairment.•Evidence suggests air pollution is causally associated with increased risk of dementia.•Residual confounding cannot be completely ruled out.•Diversity of study designs, air pollutants and endpoints precludes meta-analysis.
Summary In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging–Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's ...disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
Summary Background The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and ...genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD). Methods We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. Findings Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years SD 7·2 vs 50·4 years SD 5·2, respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1's first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 47% with PSEN1 mutations and 12 33% with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP ), which affected around a quarter of the patients in each group (20 24% and nine 25%, respectively). A number of patients with PSEN1 mutations had pyramidal (21 25%), extrapyramidal (12 14%), or cerebellar (three 4%) signs. Interpretation ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. Funding Medical Research Council and National Institute for Health Research.
Summary Background TRACK-HD is a prospective observational study of Huntington's disease (HD) that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with ...early stage disease. We report 12-month longitudinal changes, building on baseline findings. Methods We did a 12-month follow-up of patients recruited from the four TRACK-HD study sites in Canada, France, the Netherlands, and the UK. Participants were premanifest individuals (preHD) carrying the mutant HTT gene, patients with early HD, and controls matched by age and sex with the combined preHD and early HD groups. Data were collected by use of 3T MRI and clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Statistical analysis assessed annualised change with the use of linear regression models to estimate differences between groups. Findings 116 preHD individuals, 114 early HD patients, and 115 people in the control group completed follow-up. Four preHD individuals, nine early HD patients, and eight people in the control group did not complete the follow-up. A further nine participants, who completed follow-up assessments, were unable to undergo MRI. After adjustment for demographics, annualised rates of generalised and regional brain atrophy were higher in preHD and early HD groups than in controls. Whole-brain atrophy rates were 0·20% (95% CI 0·05–0·34; p=0·0071) per year higher in preHD participants and 0·60% (0·44–0·76; p<0·0001) in early HD patients, and caudate atrophy rates were 1·37% (0·99–1·75; p<0·0001) per year higher in preHD and 2·86% (2·34–3·39; p<0·0001) in early HD. Voxel-based morphometry revealed grey-matter and white-matter atrophy, even in subjects furthest from predicted disease onset. Quantitative imaging showed statistically significant associations with disease burden, an indicator of disease pathology, and total functional capacity, a widely-used clinical measure of disease severity. Relative to controls, decline in cognition and quantitative motor function was detectable in both pre- and early HD, as was deterioration in oculomotor function in early HD. Interpretation Quantitative imaging showed the greatest differentiation across the spectrum of disease and functional measures of decline were sensitive in early HD, with cognitive and quantitative motor impairment also detectable in preHD. We show longitudinal change over 12 months in generalised and regional brain volume, cognition, and quantitative motor tasks in individuals many years from predicted disease onset and show the feasibility of obtaining quantifiable endpoints for future trials. Funding CHDI/HighQ Foundation Inc.
Visual rating scales, developed to assess atrophy in patients with cognitive impairment, offer a cost-effective diagnostic tool that is ideally suited for implementation in clinical practice. By ...focusing attention on brain regions susceptible to change in dementia and enforcing structured reporting of these findings, visual rating can improve the sensitivity, reliability and diagnostic value of radiological image interpretation. Brain imaging is recommended in all current diagnostic guidelines relating to dementia, and recent guidelines have also recommended the application of medial temporal lobe atrophy rating. Despite these recommendations, and the ease with which rating scales can be applied, there is still relatively low uptake in routine clinical assessments. Careful consideration of atrophy rating scales is needed to verify their diagnostic potential and encourage uptake among clinicians. Determining the added value of combining scores from visual rating in different brain regions may also increase the diagnostic value of these tools.
To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease.
Serum samples were collected ...from 74 participants (34 with behavioral variant FTD bvFTD, 3 with FTD and motor neuron disease and 37 with primary progressive aphasia PPA) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume.
Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL SD 51.3 pg/mL) than controls (19.6 pg/mL SD 8.2 pg/mL; p < 0.001). Concentrations were also significantly higher in bvFTD (57.8 pg/mL SD 33.1 pg/mL) and both the semantic and nonfluent variants of PPA (95.9 and 82.5 pg/mL SD 33.0 and 33.8 pg/mL, respectively) compared with controls and in semantic variant PPA compared with logopenic variant PPA. Concentrations were significantly higher than controls in both the C9orf72 and MAPT subgroups (79.2 and 40.5 pg/mL SD 48.2 and 20.9 pg/mL, respectively) with a trend to a higher level in the GRN subgroup (138.5 pg/mL SD 103.3 pg/mL). However, there was variability within all groups. Serum concentrations correlated particularly with frontal lobe atrophy rate (r = 0.53, p = 0.003).
Increased serum NfL concentrations are seen in FTD but show wide variability within each clinical and genetic group. Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes.
Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget’s disease of the bone, and ...frontotemporal dementia (IBMPFD) and they account for 1%–2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.
► VCP deficiency is associated with mitochondrial depolarization ► VCP deficiency leads to increased mitochondrial respiration and uncoupling ► ATP levels are decreased in VCP-deficient cells due to lower ATP production
In this study, Bartolome et al. show that three independent pathogenic VCP mutations induce mitochondrial uncoupling, resulting in low cellular ATP production, rendering the cells more susceptible to cell death under stress-induced ischemic conditions.
Abstract The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer’s disease (AD), ...referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.
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