Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy.

About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.

GSK-3ß orchestrates the inhibitory innervation of adult-born dentate granule cells in vivo.

Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3ß) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3ß-overexpressing newborn neurons show an increased number and altered size of Gephyrin+ postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3ß overexpression triggers a depletion of Parvalbumin+ interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3ß is dysregulated.

Selective disruption of synaptic NMDA receptors of the hippocampal trisynaptic circuit in Aß pathology.

Synaptic dysfunction is an early feature in Alzheimer's disease (AD) pathogenesis and a major morphological correlate of memory deficits. Given the main synaptic location of N-methyl-D-aspartate receptors (NMDARs), their dysregulation has been implicated in these pathological effects. Here, to detect possible alterations in the expression and synaptic localisation of the GluN1 subunit in the brain of amyloidogenic APP/PS1 mice, we employed histoblot and SDS-digested freeze-fracture replica labelling (SDS-FRL) techniques. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus in a layer-dependent manner, in the cortex and the caudate putamen of APP/PS1 transgenic mice at 12 months of age but was unaltered at 1 and 6 months. Using quantitative SDS-FRL, we unravelled the molecular organisation of GluN1 in seven excitatory synapse populations at a high spatial resolution in the CA1 and CA3 fields and the DG of the hippocampus in 12-month-old APP/PS1 mice. In the CA1 field, the labelling density for GluN1 in the excitatory synapses established on spines and interneurons, was significantly reduced in APP/PS1 mice compared to age-matched wild-type mice in the stratum lacunosum-moleculare but unaltered in the stratum radiatum. In the CA3 field, synaptic GluN1 was reduced in mossy fibre-CA3 pyramidal cell synapses but unaltered in the A/C-CA3 pyramidal cell synapses. In the DG, the density of GluN1 in granule cell-perforant pathway synapses was reduced in APP/PS1 mice. Altogether, our findings provide evidence of specific alterations of synaptic GluN1 in the trisynaptic circuit of the hippocampus in Aß pathology. This differential vulnerability in the disruption of NMDARs may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit and cognitive impairment characteristic of APP/PS1 mice.

Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients.

BACKGROUND: Synaptic and extrasynaptic distribution of N-methyl-D-aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer´s disease (AD) subjects, despite their contribution to neurodegeneration. METHODS: We have developed a protocol to isolate synaptic and extrasynaptic membranes from controls and AD frontal cortex. We characterized the distribution of the NMDAR subunits GluN2B, GluN2A, GluN1, and GluN3A, as well as post-translational modifications, such as phosphorylation and glycosylation. RESULTS: Lower levels of synaptic GluN2B and GluN2A were found in AD fractions, while extrasynaptic GluN2B and GluN1 levels were significantly higher; GluN3A distribution remained unaffected in AD. We also identified different glycoforms of GluN2B and GluN2A in extrasynaptic membranes. Synaptic Tyr1472 GluN2B phosphorylation was significantly lower in AD fractions. DISCUSSION: Reduction of synaptic NMDAR subunits, particularly for GluN2B, is likely to contribute to synaptic transmission failure in AD. Additionally, the increment of extrasynaptic NMDAR subunits could favor the activation of excitotoxicity in AD. HIGHLIGHTS: New protocol to isolate synaptic and extrasynaptic membranes from the human cortex. Low GluN2B and GluN2A levels in Alzheimer´s disease (AD) synaptic membranes. High GluN2B and GluN1 levels in AD extrasynaptic membranes. Specific glycoforms of extrasynaptic GluN2B and GluN2A. Low phosphorylation at Tyr1472 in synaptic GluN2B in AD.

Genetic testing in dementia.

There is growing public awareness and concern regarding dementia risk. In addition, genetic testing is increasingly accessible and is at the point of being integrated into routine clinical practice. As a result, there is a pressing need for treating clinicians to have the appropriate knowledge base to request and consent for diagnostic genetic testing in cognitive clinics. We outline our approach to genetic testing in patients with Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies and vascular cognitive impairment. We discuss when to consider testing, the consenting process, and the interpretation and communication of genetic test results.

Empirical and Authoritative Classification of Neuropsychiatric Syndromes in Neurocognitive Disorders.

Neuropsychiatric symptoms of neurocognitive disorders have been classified into higher-order constructs, often called neuropsychiatric syndromes. As with the general psychopathology literature, these classifications have been achieved through two approaches: empirical and authoritative. The authoritative approach relies on expert panels that condense the available evidence into operational criteria, whereas the empirical approach uses statistical methods to discover symptom patterns and possible hierarchies formed by them. In this article, the author reviews the strengths and weaknesses of both approaches using general psychopathology literature as a reference point. The authoritative approach, influenced by the DSM, has led to several sets of criteria, which could aid clinical trials, diagnostics, and communication. However, unknown reliability and the complex relationships between empirical evidence and published criteria may limit the utility of current criteria. The empirical approach has been used to explore syndrome structures on the basis of rating scales for neuropsychiatric symptoms. The structures suggested in these studies have not been replicated easily and have been limited by either small sample sizes, restricted breadth of neuropsychiatric assessment, or both. Suggestions for further development of both approaches are offered. First, neuropsychiatric symptoms and syndromes need to be studied with measures of broad scope and in large samples. These requirements are prerequisites not only for eliciting highly informative empirical classifications but also for understanding these symptoms at a more nuanced level. Second, both approaches could benefit from more transparency. Finally, the reliability of the available authoritative criteria should be examined.

The worldwide costs of dementia in 2019.

INTRODUCTION: Dementia is a leading cause of death and disability globally. Estimating total societal costs demonstrates the wide impact of dementia and its main direct and indirect economic components. METHODS: We constructed a global cost model for dementia, presenting costs as cumulated global and regional costs. RESULTS: In 2019, the annual global societal costs of dementia were estimated at US $1313.4 billion for 55.2 million people with dementia, corresponding to US $23,796 per person with dementia. Of the total, US $213.2 billion (16%) were direct medical costs, US $448.7 billion (34%) direct social sector costs (including long-term care), and US $651.4 billion (50%) costs of informal care. DISCUSSION: The huge costs of dementia worldwide place enormous strains on care systems and families alike. Although most people with dementia live in low- and middle-income countries, highest total and per-person costs are seen in high-income countries. HIGHLIGHTS: Global economic costs of dementia were estimated to reach US $1313.4 in 2019. Sixty-one percent of people with dementia live in low-and middle-income countries, whereas 74% of the costs occur in high-income countries. The impact of informal care accounts for about 50% of the global costs. The development of a long-term care infrastructure is a great challenge for low-and middle-income countries. There is a great need for more cost studies, particularly in low- and middle-income countries. Discussions of a framework for global cost comparisons are needed.

Blood ß-synuclein is related to amyloid PET positivity in memory clinic patients.

INTRODUCTION: ß-synuclein is an emerging blood biomarker to study synaptic degeneration in Alzheimer´s disease (AD), but its relation to amyloid-ß (Αß) pathology is unclear. METHODS: We investigated the association of plasma ß-synuclein levels with [18F] flutemetamol positron emission tomography (PET) in patients with AD dementia (n = 51), mild cognitive impairment (MCI-Aß+ n = 18, MCI- Aß- n = 30), non-AD dementias (n = 22), and non-demented controls (n = 5). RESULTS: Plasma ß-synuclein levels were higher in Aß+ (AD dementia, MCI-Aß+) than in Aß- subjects (non-AD dementias, MCI-Aß-) with good discrimination of Aß+ from Aß- subjects and prediction of Aß status in MCI individuals. A positive correlation between plasma ß-synuclein and Aß PET was observed in multiple cortical regions across all lobes. DISCUSSION: Plasma ß-synuclein demonstrated discriminative properties for Aß PET positive and negative subjects. Our data underline that ß-synuclein is not a direct marker of Aß pathology and suggest different longitudinal dynamics of synaptic degeneration versus amyloid deposition across the AD continuum. HIGHLIGHTS: Blood and CSF ß-synuclein levels are higher in Aß+ than in Aß- subjects. Blood ß-synuclein level correlates with amyloid PET positivity in multiple regions. Blood ß-synuclein predicts Aß status in MCI individuals.

Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice.

The dysregulation of transposable elements contributes to neurodegenerative disorders. Previous studies have reported an increase in retrotransposon transcription in Drosophila models as well as in human tauopathies. In this context, we tested the possible protective effects of a reverse transcriptase inhibitor, namely lamivudine (also known as 3TC), in P301S mice, an animal model of Alzheimer's disease based on FTDP-17-tau overexpression. Transgenic P301S mice administered lamivudine through drinking water showed a decrease in the following histopathological marks typical of tauopathies: tau phosphorylation; inflammation; neuronal death; and hippocampal atrophy. Lamivudine treatment attenuated motor deficits (Rotarod test) and improved short-term memory (Y-maze test). To evaluate the role of tau in retrotransposition, we cotransfected HeLa cells with a plasmid containing a complete LINE-1 sequence and a neomycin reporter cassette designed for retrotransposition assays, and a plasmid with the tau sequence. LINE-1 insertion increased considerably in the cotransfection compared to the transfection without tau. In addition, lamivudine inhibited the insertion of LINE-1. Our data suggest that the progression of the tauopathy can be attenuated by the administration of lamivudine upon the first symptoms of neuropathology.

Automated Medical Diagnosis of Alzheimer´s Disease Using an Efficient Net Convolutional Neural Network.

Alzheimer's disease (AD) poses an enormous challenge to modern healthcare. Since 2017, researchers have been using deep learning (DL) models for the early detection of AD using neuroimaging biomarkers. In this paper, we implement the EfficietNet-b0 convolutional neural network (CNN) with a novel approach-"fusion of end-to-end and transfer learning"-to classify different stages of AD. 245 T1W MRI scans of cognitively normal (CN) subjects, 229 scans of AD subjects, and 229 scans of subjects with stable mild cognitive impairment (sMCI) were employed. Each scan was preprocessed using a standard pipeline. The proposed models were trained and evaluated using preprocessed scans. For the sMCI vs. AD classification task we obtained 95.29% accuracy and 95.35% area under the curve (AUC) for model training and 93.10% accuracy and 93.00% AUC for model testing. For the multiclass AD vs. CN vs. sMCI classification task we obtained 85.66% accuracy and 86% AUC for model training and 87.38% accuracy and 88.00% AUC for model testing. Based on our experimental results, we conclude that CNN-based DL models can be used to analyze complicated MRI scan features in clinical settings.

Diagnostic criteria in dementing illness. What's new? / Criterios diagnósticos en la enfermedad demencial ¿Qué hay de nuevo?

The spectrum of neurodegenerative diseases that primarily affect cognition and behaviorspreads from asymptomatic preclinical disease to very mild cognitive impairment to frank dementia. Alzheimer's disease (AD) is the most common cause of a decline in cognitive ability. Also, it is a devastating condition that affects patients and their entirefamilies of caregivers, exacting tremendous financial hardships. Diagnosis may be complicated by other forms of dementia that have symptoms and pathologies similar to AD. Knowing the key features and pathology of each type of dementia can help in the accurate diagnosis of patients, so they will receive the treatment and support services appropriate for their condition and maintain the highest possible functioning in daily life and quality of life. Differentiate, based on clinical criteria, neuropathology, and biomarkers, AD and its atypical variants from other common dementias including Dementia with Lewy Bodies, Vascular Cognitive Impairment, Frontotemporal Degeneration, and less frequent cognitive disorders. The importance of getting an accurate and early diagnosis of dementiais now increasingly significant to make important decisions about treatment, support, and care. Nonpharmacological as well as pharmacological interventions should be initiated once the diagnosis is obtained. Biochemical markers to identify Alzheimer's disease play a central role in the new diagnostic criteria for the disease and in the recent biological definition of AD. This review article presents up-to-date data regarding the recent diagnostic criteria of Alzheimer´s disease and related disorders, emphasizing its usefulness in routine clinical practice.

El espectro de enfermedades neurodegenerativas que afectan principalmente a la cognición y el comportamiento abarca desde la enfermedad preclínica asintomática hasta el deterioro cognitivo muy leve y la demencia franca. La enfermedad de Alzheimer (EA) es la causa más común de deterioro de la capacidad cognitiva. Es una enfermedad devastadora que afecta a los pacientes y a toda su familia de cuidadores, lo que supone enormes dificultades socioeconómicas y psicoemocionales. El diagnóstico puede complicarse debido a otras formas de demencia que presentan síntomas y patologías similares a la EA. Los marcadores bioquímicos para identificar la enfermedad de Alzheimer desempeñan un papel central en los nuevos criterios diagnósticos de la enfermedad y en la reciente definición biológica de la EA. Conocer las características claves y la patología de cada tipo de demencia puede ayudar en el diagnóstico preciso de los pacientes, a fin de que reciban el tratamiento y los servicios de apoyo adecuados a su condición y mantengan el mayor funcionamiento posible en la vida diaria y la calidad de vida. Por lo tanto es prioritario diferenciar, basándose en criterios clínicos, neuropatología y biomarcadores, la EA y sus variantes atípicas de otras demencias comunes como el Deterioro Cognitivo Vascular, la Degeneración Fronto- temporal entre otras, y los trastornos cognitivos menos frecuentes. Este artículo de revisión presenta datos actualizados relativos a los recientes criterios diagnósticos de algunas formas de demencia haciendo hincapié en su utilidad en la práctica clínica habitual. Se exponen los criterios de EA, de Demencia Vascular (DV), de la demencia Fronto-temporal (DFT) y de una forma rara de demencia, descripta en los últimos años, que se evidencia en pacientes muy añosos con un perfil similar a la EA. Se trata de la encefalopatía predominantemente límbica por tdp- 43 relacionada a la edad (LATE).

Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism.

In Alzheimer's disease (AD), pathological forms of tau are transferred from cell to cell and "seed" aggregation of cytoplasmic tau. Phosphorylation of tau plays a key role in neurodegenerative tauopathies. In addition, apolipoprotein E (apoE), a major component of lipoproteins in the brain, is a genetic risk determinant for AD. The identification of the apoE receptor, low-density lipoprotein receptor-related protein 1 (LRP1), as an endocytic receptor for tau raises several questions about the role of LRP1 in tauopathies: is internalized tau, like other LRP1 ligands, delivered to lysosomes for degradation, and does LRP1 internalize pathological tau leading to cytosolic seeding? We found that LRP1 rapidly internalizes 125I-labeled tau, which is then efficiently degraded in lysosomal compartments. Surface plasmon resonance experiments confirm high affinity binding of tau and the tau microtubule-binding domain to LRP1. Interestingly, phosphorylated forms of recombinant tau bind weakly to LRP1 and are less efficiently internalized by LRP1. LRP1-mediated uptake of tau is inhibited by apoE, with the apoE4 isoform being the most potent inhibitor, likely because of its higher affinity for LRP1. Employing post-translationally-modified tau derived from brain lysates of human AD brain tissue, we found that LRP1-expressing cells, but not LRP1-deficient cells, promote cytosolic tau seeding in a process enhanced by apoE. These studies identify LRP1 as an endocytic receptor that binds and processes monomeric forms of tau leading to its degradation and promotes seeding by pathological forms of tau. The balance of these processes may be fundamental to the spread of neuropathology across the brain in AD.

The congruency of neuropsychological and F18-FDG brain PET/CT diagnostics of Alzheimer's Disease (AD) in routine clinical practice: insights from a mixed neurological patient cohort.

BACKGROUND: Diagnostics of Alzheimer's Disease (AD) require a multimodal approach. Neuropsychologists examine the degree and etiology of dementia syndromes and results are combined with those of cerebrospinal fluid markers and imaging data. In the diagnostic process, neuropsychologists often rely on anamnestic and clinical information, as well as cognitive tests, prior to the availability of exhaustive etiological information. The congruency of this phenomenological approach with results from FDG-PET/CT examinations remains to be explored. The latter yield highly accurate diagnostic information. METHOD: A mixed sample of N = 127 hospitalized neurological patients suspected of displaying a dementia syndrome underwent extensive neuropsychological and FDG-PET/CT examinations. Neuropsychological examinations included an anamnestic and clinical interview, and the CERAD cognitive test battery. Two decisional approaches were considered: First, routine diagnostic results were obtained, i.e. the final clinical decision of the examining neuropsychologist (ADClinical vs. non-ADClinical). Secondly, a logistic regression model was implemented, relying on CERAD profiles alone. CERAD subscales that best predicted AD based on FDG-PET/CT were identified and a nominal categorization obtained (ADTest vs. non-ADTest). Congruency of results from both approaches with those of the FDG-PET/CT (ADPET vs. non-ADPET) were estimated with Cohen's Kappa (κ) and Yule's Y coefficient of colligation. Descriptive estimates of accuracy, sensitivity and specificity of CERAD relative to FDG-PET/CT diagnostics were derived. RESULTS: ADPET patients constituted N = 33/127 (26%) of the sample. The clinical decision approach (ADClinical vs. non-ADClinical) showed substantial agreement with the FDG-PET/CT classification (κ = .69, Y = .72) involving good accuracy (84.2%), moderate sensitivity (75.8%) and excellent specificity (92.6%). In contrast, the decisional approach that relied on CERAD data alone (ADTest vs. non-ADTest) involved only moderate agreement with the FDG-PET/CT (κ = .54, Y = .62) with lower accuracy (74.8%), attributable to decreased sensitivity (56.3%) and comparable specificity (93.3%). CONCLUSIONS: It is feasible to identify AD through a comprehensive neuropsychological examination in a mixed sample of neurological patients. However, within the boundaries of methods applied here, decisions based on cognitive test results alone appear limited. One may conclude that the clinical impression based on anamnestic and clinical information obtained by the neuropsychological examiner plays a crucial role in the identification of AD patients in routine clinical practice.

A four-month home-based tDCS study on patients with Alzheimer's disease.

In the present open-label study, our first aim was to study the tolerability and feasibility of long-term treatment with transcranial direct current stimulation (tDCS) and the second aim was to measure whether the treatment led to cognitive improvement. Participants with AD used a tDCS home-treatment kit inducing a low current (2 mA) via two scalp electrodes 30 minutes daily for 4 months. A total of 8 participants were recruited. The treatment technique was manageable for the participants and their spouses, and no troublesome side effects were reported. No significant effects of treatment were found after 4 months.

Hydroxytyrosol improves mitochondrial energetics of a cellular model of Alzheimer's disease.

Mitochondrial energetic deficit is one of the hallmarks of neurodegenerative disorders, e.g. Alzheimer´s disease (AD). Adherence to a Mediterranean diet is associated with lower incidence of cognitive decline and AD and extra virgin olive oil's (poly)phenols such as oleuropein and hydroxytyrosol (HT) are being actively studied in this respect. In this study, we assessed the effects of HT on mitochondrial energetic dysfunction in the 7PA2 cells cellular model, i.e. one of the best cellular models of Aß toxicity with a well-characterized mitochondrial dysfunction typically observed in AD. We report an increase of new mitochondria at 8 h post HT-treatment, which was followed by higher mitochondrial fusion. Further, ATP concentrations were significantly increased after 24 h of treatment with HT as compared with controls. Our data suggest that HT may revert the energetic deficit of a cellular model of AD by potentiating mitochondrial activity. Because HT is being proposed as dietary supplement or component of functional foods, future studies in appropriate animal models and - eventually - humans are warranted to further investigate its potential neuroprotective actions in AD.

Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease.

Alzheimer's disease (AD) is clinically characterized by a progressive loss of cognitive functions and short-term memory. AD patients present two distinctive neuropathological lesions: neuritic plaques and neurofibrillary tangles (NFTs), constituted of beta-amyloid peptide (Aß) and phosphorylated and truncated tau proteins. Aß deposits around cerebral blood vessels (cerebral amyloid angiopathy, CAA) is a major contributor to vascular dysfunction in AD. Vascular amyloid deposits could be early events in AD due to dysfunction in the neurovascular unit (NVU) and the blood-brain barrier (BBB), deterioration of the gliovascular unit, and/or decrease of cerebral blood flow (CBF). These pathological events can lead to decreased Aß clearance, facilitate a neuroinflammatory environment as well as synaptic dysfunction and, finally, lead to neurodegeneration. Here, we review the histopathological AD hallmarks and discuss the two-hit vascular hypothesis of AD, emphasizing the role of neurovascular dysfunction as an early factor that favors vascular Aß aggregation and neurodegeneration. Addtionally, we emphasize that pericyte degeneration is a key and early element in AD that can trigger amyloid vascular accumulation and NVU/BBB dysfunction. Further research is required to better understand the early pathophysiological mechanisms associated with NVU alteration and CAA to generate early biomarkers and timely treatments for AD.

Simultaneous Inhibitory Effects of All-Trans Astaxanthin on Acetylcholinesterase and Oxidative Stress.

Alzheimer´s disease is a global neurodegenerative health concern. To prevent the disease, the simultaneous inhibition of acetylcholinesterase and oxidative stress is an efficient approach. In this study, the inhibition effect of all-trans astaxanthin mainly from marine organisms on acetylcholinesterase and oxidative stress was evaluated by a chemical-based method in vitro and cell assay model. The results show that all-trans astaxanthin was a reversible competitive inhibitor and exhibited a strong inhibition effect with half inhibitory concentration (IC50 value) of 8.64 µmol/L. Furthermore, all-trans astaxanthin inhibited oxidative stress through reducing malondialdehyde content and increasing the activity of superoxide dismutase as well as catalase. All-trans astaxanthin could induce the changes of the secondary structure to reduce acetylcholinesterase activity. Molecular-docking analysis reveals that all-trans astaxanthin prevented substrate from binding to acetylcholinesterase by occupying the space of the active pocket to cause the inhibition. Our finding suggests that all-trans astaxanthin might be a nutraceutical supplement for Alzheimer´s disease prevention.

Healthcare costs of dementia diseases before, during and after diagnosis: Longitudinal analysis of 17 years of Swedish register data.

INTRODUCTION: This study examines health-care costs attributed to dementia diseases in the 10 years prior to, during, and 6 years after diagnosis. METHODS: Using administrative register data for people diagnosed with dementia (2010-2016) in southern Sweden (n = 21,184), and a comparison group without dementia, health-care costs over 17 years were examined using longitudinal regression analysis. RESULTS: Average annual health-care costs per person were consistently higher before diagnosis in the dementia group (10 years before: Swedish krona (SEK) 2063, P < .005 and 1 year before: SEK8166, P < .005). At diagnosis, health-care costs were more than twice as high (SEK44,410, P < .005). Four to 6 years after diagnosis, there was no significant different in costs compared to comparators. DISCUSSION: Excess health-care cost arise as early as 10 years before a formal diagnosis of dementia, and while there is a spike in cost after diagnosis, health-care costs are no different 4 years after. These findings question currently accepted assumptions on costs of dementia.

Transition from mild cognitive impairment to normal cognition: Determining the predictors of reversion with multi-state Markov models.

INTRODUCTION: The theoretical framework of the Alzheimer's disease continuum considers transition between stages in a unidirectional manner. Here we examine the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) and explore a set of potential variables associated with this phenomenon. METHODS: A total of 985 Spanish community-dwelling individuals aged 70 years and over at baseline were monitored for 5 years. During this time, 173 MCI and 36 dementia cases were identified. Multi-state Markov models were performed to characterize transitions between states through the dementia continuum. RESULTS: The rate of reversion from MCI to NC was 11%. There were significant non-modifiable (age, socioeconomic status, or apolipoprotein E) and modifiable factors (cognitive training or absence of affective symptoms) associated with reversion. DISCUSSION: Overall, our results highlight that the likelihood of progression from MCI to dementia is very similar to that of reversion from MCI to NC.

Primary progressive aphasia: ReADing the clinical GRANularity.

Primary progressive aphasia remains a diagnostic challenge despite (or even because of) the increasing availability of ancillary tests and biomarkers. We present a 67-year-old man with apparently sporadic logopenic aphasia and positive Alzheimer biomarkers who was subsequently found also to have a pathogenic mutation in the progranulin gene. This was signalled by early atypical features (mild expressive agrammatism and behavioural change, rapid clinical deterioration) around the core logopenic aphasia syndrome. Each of the canonical progressive aphasia syndromes has a 'halo' of less typical variants that may herald alternative or additional pathologies. The accurate diagnosis of primary progressive aphasia depends on careful clinical analysis to direct investigations appropriately.