The criteria used to rule out mild cognitive impairment impact dementia incidence rates in subjective cognitive decline.

BACKGROUND: The research criteria for subjective cognitive decline (SCD) exclude mild cognitive impairment (MCI), but do not stipulate the use of specific MCI criteria. This study compared different approaches to defining (i.e., excluding) MCI during the ascertainment of SCD, focusing on the impact on dementia incidence rates in SCD. METHODS: This cohort study utilized routine healthcare data collected in the Essex Memory Clinic from 1999 to 2023. Two different operationalizations of the SCD criteria were used to categorize the cohort into two SCD patient samples. One sample was based on local clinical practice - MCI was excluded according to the Winblad criteria (this sample was termed SCDWinblad). The other sample was created via the retrospective application of the Jak/Bondi criteria for the exclusion of MCI (termed SCDJak/Bondi). Only patients aged ≥ 55 years at baseline with ≥ 12 months follow-up were considered for inclusion. The initial clinical/demographic characteristics of the samples were compared. Rates of incident dementia were calculated for each sample, and unadjusted and Mantel-Haenszel-adjusted incidence rate ratios were calculated to compare dementia incidence between the SCD samples. RESULTS: The Essex Memory Clinic database included 2,233 patients in total. The SCD and study eligibility criteria were used to select SCDWinblad (n = 86) and SCDJak/Bondi (n = 185) samples from the database. Median follow-up (3 years) did not differ between the two samples. The SCDJak/Bondi sample was significantly older than the SCDWinblad at first assessment (median age: 74 versus 70 years) and had poorer scores on tests of global cognition, immediate and delayed verbal recall, and category fluency. Following adjustment for age, the dementia incidence rate ratio [95% confidence interval] was 3.7 [1.5 to 9.3], indicating a significantly greater rate of progression to dementia in SCDJak/Bondi. CONCLUSIONS: This study highlights that the approach used to ascertain SCD has important implications for both SCD phenotypes and prognosis. This underscores the importance of how MCI is operationalized within SCD studies. More broadly, the findings add to a growing body of work indicating that objective cognition should not be overlooked in SCD, and offer a potential explanation for the heterogeneity across the SCD prognostic literature.

Elucidating distinct molecular signatures of Lewy body dementias.

Dementia with Lewy bodies and Parkinson's disease dementia are common neurodegenerative diseases that share similar neuropathological profiles and spectra of clinical symptoms but are primarily differentiated by the order in which symptoms manifest. The question of whether a distinct molecular pathological profile could distinguish these disorders is yet to be answered. However, in recent years, studies have begun to investigate genomic, epigenomic, transcriptomic and proteomic differences that may differentiate these disorders, providing novel insights in to disease etiology. In this review, we present an overview of the clinical and pathological hallmarks of Lewy body dementias before summarizing relevant research into genetic, epigenetic, transcriptional and protein signatures in these diseases, with a particular interest in those resolving "omic" level changes. We conclude by suggesting future research directions to address current gaps and questions present within the field.

The use of neuroimaging techniques in the early and differential diagnosis of dementia.

Dementia is a leading cause of disability and death worldwide. At present there is no disease modifying treatment for any of the most common types of dementia such as Alzheimer's disease (AD), Vascular dementia, Lewy Body Dementia (LBD) and Frontotemporal dementia (FTD). Early and accurate diagnosis of dementia subtype is critical to improving clinical care and developing better treatments. Structural and molecular imaging has contributed to a better understanding of the pathophysiology of neurodegenerative dementias and is increasingly being adopted into clinical practice for early and accurate diagnosis. In this review we summarise the contribution imaging has made with particular focus on multimodal magnetic resonance imaging (MRI) and positron emission tomography imaging (PET). Structural MRI is widely used in clinical practice and can help exclude reversible causes of memory problems but has relatively low sensitivity for the early and differential diagnosis of dementia subtypes. 18F-fluorodeoxyglucose PET has high sensitivity and specificity for AD and FTD, while PET with ligands for amyloid and tau can improve the differential diagnosis of AD and non-AD dementias, including recognition at prodromal stages. Dopaminergic imaging can assist with the diagnosis of LBD. The lack of a validated tracer for α-synuclein or TAR DNA-binding protein 43 (TDP-43) imaging remain notable gaps, though work is ongoing. Emerging PET tracers such as 11C-UCB-J for synaptic imaging may be sensitive early markers but overall larger longitudinal multi-centre cross diagnostic imaging studies are needed.

From protein biomarkers to proteomics in dementia with Lewy Bodies.

Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia. Despite considerable research progress, there remain gaps in our understanding of the pathophysiology and there is no disease-modifying treatment. Proteomics is a powerful tool to elucidate complex biological pathways across heterogenous conditions. This review summarizes the widely used proteomic methods and presents evidence for protein dysregulation in the brain and peripheral tissues in DLB. Proteomics of post-mortem brain tissue shows that DLB shares common features with other dementias, such as synaptic dysfunction, but retains a unique protein signature. Promising diagnostic biomarkers are being identified in cerebrospinal fluid (CSF), blood, and peripheral tissues, such as serum Heart-type fatty acid binding protein. Research is needed to track these changes from the prodromal stage to established dementia, with standardized workflows to ensure replicability. Identifying novel protein targets in causative biological pathways could lead to the development of new targeted therapeutics or the stratification of participants for clinical trials.

Plasma metabolites distinguish dementia with Lewy bodies from Alzheimer's disease: a cross-sectional metabolomic analysis.

Background: In multifactorial diseases, alterations in the concentration of metabolites can identify novel pathological mechanisms at the intersection between genetic and environmental influences. This study aimed to profile the plasma metabolome of patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), two neurodegenerative disorders for which our understanding of the pathophysiology is incomplete. In the clinical setting, DLB is often mistaken for AD, highlighting a need for accurate diagnostic biomarkers. We therefore also aimed to determine the overlapping and differentiating metabolite patterns associated with each and establish whether identification of these patterns could be leveraged as biomarkers to support clinical diagnosis. Methods: A panel of 630 metabolites (Biocrates MxP Quant 500) and a further 232 metabolism indicators (biologically informative sums and ratios calculated from measured metabolites, each indicative for a specific pathway or synthesis; MetaboINDICATOR) were analyzed in plasma from patients with probable DLB (n = 15; age 77.6 ± 8.2 years), probable AD (n = 15; 76.1 ± 6.4 years), and age-matched cognitively healthy controls (HC; n = 15; 75.2 ± 6.9 years). Metabolites were quantified using a reversed-phase ultra-performance liquid chromatography column and triple-quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, or by using flow injection analysis in MRM mode. Data underwent multivariate (PCA analysis), univariate and receiving operator characteristic (ROC) analysis. Metabolite data were also correlated (Spearman r) with the collected clinical neuroimaging and protein biomarker data. Results: The PCA plot separated DLB, AD and HC groups (R2 = 0.518, Q2 = 0.348). Significant alterations in 17 detected metabolite parameters were identified (q ≤ 0.05), including neurotransmitters, amino acids and glycerophospholipids. Glutamine (Glu; q = 0.045) concentrations and indicators of sphingomyelin hydroxylation (q = 0.039) distinguished AD and DLB, and these significantly correlated with semi-quantitative measurement of cardiac sympathetic denervation. The most promising biomarker differentiating AD from DLB was Glu:lysophosphatidylcholine (lysoPC a 24:0) ratio (AUC = 0.92; 95%CI 0.809-0.996; sensitivity = 0.90; specificity = 0.90). Discussion: Several plasma metabolomic aberrations are shared by both DLB and AD, but a rise in plasma glutamine was specific to DLB. When measured against plasma lysoPC a C24:0, glutamine could differentiate DLB from AD, and the reproducibility of this biomarker should be investigated in larger cohorts.

RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia-an international Delphi consensus.

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson's disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia.

The promise of amplification assays for accurate early detection of α-synucleinopathies: A review.

Lewy body dementia encompasses the common neurodegenerative disorders Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Lewy Body disease (LBD) is characterized by abnormal aggregates of α-synuclein (α-syn) in the brain which form Lewy bodies. LBD is commonly misdiagnosed/underdiagnosed, especially in early stages. There remains a great need for reliable biomarkers to assist with LBD diagnosis. Amplification techniques such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) represent an important advance for biomarker detection. Amplification assays detect the ability of pathogenic protein to induce conformational change in normal protein; α-syn has been shown to propagate in a prion-like manner, making it a candidate for such analysis. In this review, we describe the diagnostic potential of amplification techniques for differentiating α-synucleinopathies from other neurodegenerative disorders such as Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism, as well as α-synucleinopathies from each other. Recent studies report accurate detection of α-syn seeding activity in human tissues such as cerebrospinal fluid (CSF), submandibular gland (SMG), and posterior cervical skin. Adaptation to clinical settings may present challenges. However, the high accuracy of recent results, combined with the success of amplification assay diagnostics in clinical practice for Creutzfeldt-Jakob disease, suggest high promise for eventual clinical application.

Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy.

OBJECTIVES: This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). METHODS: Plasma phosphorylated tau at threonine-181 (p-tau181), amyloid beta (Αß)42, Aß40, neurofilament light (NfL) and glial fibrillar acidic protein (GFAP) were measured using highly sensitive single molecule immunoassays (Simoa) in a multicentre cohort of 300 participants (controls=73, amyloid positive mild cognitive impairment (MCI+) and AD dementia=63, LBD=117, FTD=28, PSP=19). LBD participants had known positron emission tomography (PET)-Aß status. RESULTS: P-tau181 was elevated in MCI+AD compared with all other groups. Aß42/40 was lower in MCI+AD compared with controls and FTD. NfL was elevated in all dementias compared with controls while GFAP was elevated in MCI+AD and LBD. Plasma biomarkers could classify between MCI+AD and controls, FTD and PSP with high accuracy but showed limited ability in differentiating MCI+AD from LBD. No differences were detected in the levels of plasma biomarkers when comparing PET-Aß positive and negative LBD. P-tau181, NfL and GFAP were associated with baseline and longitudinal cognitive decline in a disease specific pattern. CONCLUSION: This large study shows the role of plasma biomarkers in differentiating patients with different dementias, and at monitoring longitudinal change. We confirm that p-tau181 is elevated in MCI+AD, versus controls, FTD and PSP, but is less accurate in the classification between MCI+AD and LBD or detecting amyloid brain pathology in LBD. NfL was elevated in all dementia groups, while GFAP was elevated in MCI+AD and LBD.

In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer's disease.

INTRODUCTION: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging. METHODS: Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer's disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195. RESULTS: Global [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (ß=0.63, F(1,35)=35.24, p<0.001), deep WMH (ß=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (ß=0.66-0.76, t=3.90-5.58, FDR-corrected p (pFDR)=<0.001-0.002) and orbitofrontal cortex (ß=0.51-0.57, t=3.53-4.30, pFDR=0.001-0.004). CONCLUSION: Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.

Epigenetic regulation in the pathophysiology of Lewy body dementia.

Lewy body dementia encompasses both dementia with Lewy bodies and Parkinson's disease dementia. Although both are common causes of dementia, they remain relatively understudied. The review summarises the clinico-pathologic characteristics of Lewy Body dementia and discusses the genetic and environmental evidence contributing to the risk of developing the condition. Considering that the pathophysiology of Lewy body dementia is not yet fully understood, here we focus on the role of epigenetic mechanisms as potential key mediators of gene-environment interactions in the development of the disease. We examine available important data on genomics, epigenomics, gene expression and proteomic studies in Lewy body dementia on human post-mortem brain and peripheral tissues. Genetic variation and epigenetic modifications in key genes involved in the disorder, such as apolipoprotein E (APOE), α-synuclein (SNCA) and glucocerobrosidase (GBA), suggest a central involvement of epigenetics in DLB but conclusive evidence is scarce. This is due to limitations of existing literature, such as small sample sizes, lack of replication and lack of studies interrogating cell-type specific epigenetic modifications in the brain. Future research in the field can improve the understanding of this common but complex and rapidly progressing type of dementia and potentially open early diagnostic and effective therapeutic targets.

Peak Width of Skeletonized Mean Diffusivity as a Marker of Diffuse Cerebrovascular Damage.

BACKGROUND: The peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). We assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition. METHODS: 145 participants underwent 3T brain MRI and cognitive assessment. 112 were patients with mild cognitive impairment, Alzheimer's disease, progressive supranuclear palsy, dementia with Lewy bodies, or frontotemporal dementia. PSMD, SVD burden [white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds, lacunes], average mean diffusivity (MD), gray matter (GM), white matter (WM), and total intracranial volume were quantified. Robust linear regression was conducted to examine associations between variables. Dominance analysis assessed the relative importance of markers in predicting various outcomes. Regional analyses examined spatial overlap between PSMD and WMH. RESULTS: PSMD was associated with global and regional SVD measures, especially WMH and microbleeds. Dominance analysis demonstrated that among SVD markers, WMH was the strongest predictor of PSMD. Furthermore, PSMD was more closely associated to WMH than with GM and WM volumes. PSMD was associated with WMH across all regions, and correlations were not significantly stronger in corresponding regions (e.g., frontal PSMD and frontal WMH) compared to non-corresponding regions. PSMD outperformed all four conventional SVD markers and MD in predicting cognition, but was comparable to GM and WM volumes. DISCUSSION: PSMD was robustly associated with established SVD markers. This new measure appears to be a marker of diffuse brain injury, largely due to vascular pathology, and may be a useful and convenient metric of overall cerebrovascular burden.

Efficacy of a dementia intensive support (DIS) service at preventing admissions to medical and psychiatric wards: qualitative and quantitative evaluation.

AIMS AND METHOD: To establish whether a dementia intensive support (DIS) service that is part of a crisis resolution and home treatment team for older people is preventing admissions to acute hospital and psychiatric wards. The number of referrals in 2017 to the DIS service was established and those admitted to hospital ascertained. Senior doctors examined 30 sets of notes in detail and reached a conclusion on whether DIS had contributed to admission prevention. This information was then re-examined in two meetings with at least eight senior psychiatrists present. A consensus opinion was then reached as to whether DIS had contributed to admission prevention in each case. RESULTS: Over 12 months, 30/171 patients (18%) referred were admitted to hospital. For the subset of 30 referrals examined in detail, DIS contributed to admission avoidance in 21 cases (70%). CLINICAL IMPLICATIONS: Our evaluation demonstrates that the DIS service is an effective way of preventing admission.

Asymmetrical atrophy of thalamic subnuclei in Alzheimer's disease and amyloid-positive mild cognitive impairment is associated with key clinical features.

INTRODUCTION: Although widespread cortical asymmetries have been identified in Alzheimer's disease (AD), thalamic asymmetries and their relevance to clinical severity in AD remain unclear. METHODS: Lateralization indices were computed for individual thalamic subnuclei of 65 participants (33 healthy controls, 14 amyloid-positive patients with mild cognitive impairment, and 18 patients with AD dementia). We compared lateralization indices across diagnostic groups and correlated them with clinical measures. RESULTS: Although overall asymmetry of the thalamus did not differ between groups, greater leftward lateralization of atrophy in the ventral nuclei was demonstrated in AD, compared with controls and amyloid-positive mild cognitive impairment. Increased posterior ventrolateral and ventromedial nuclei asymmetry were associated with worse cognitive dysfunction, informant-reported neuropsychiatric symptoms, and functional ability. DISCUSSION: Leftward ventral thalamic atrophy was associated with disease severity in AD. Our findings suggest the clinically relevant involvement of thalamic nuclei in the pathophysiology of AD.

Peripheral DNA methylation, cognitive decline and brain aging: pilot findings from the Whitehall II imaging study.

AIM: The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. METHODS: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. RESULTS: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to ß-amyloid processing and glutamatergic signaling. CONCLUSION: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging.

Age-related Disturbances in DNA (hydroxy)methylation in APP/PS1 Mice.

Brain aging has been associated with aberrant DNA methylation patterns, and changes in the levels of DNA methylation and associated markers have been observed in the brains of Alzheimer's disease (AD) patients. DNA hydroxymethylation, however, has been sparsely investigated in aging and AD. We have previously reported robust decreases in 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the hippocampus of AD patients compared to non-demented controls. In the present study, we investigated 3- and 9-month-old APPswe/PS1ΔE9 transgenic and wild-type mice for possible age-related alterations in 5-mC and 5-hmC levels in three hippocampal sub-regions using quantitative immunohistochemistry. While age-related increases in levels of both 5-mC and 5-hmC were found in wild-type mice, APPswe/PS1ΔE9 mice showed decreased levels of 5-mC at 9 months of age and no age-related changes in 5-hmC throughout the hippocampus. Altogether, these findings suggest that aberrant amyloid processing impact on the balance between DNA methylation and hydroxymethylation in the hippocampus during aging in mice.

High dose rivastigmine in the symptom management of Lewy body dementia.

A man presented in late 2004 at the age of 65 with a decline in memory. He was diagnosed with Lewy body dementia and started on 3 mg rivastigmine a day, which made a marked clinical improvement. He lived with the illness for 10 years, over which time the dose of acetylcholinesterase inhibitors (ChEI) he took rose to two 9.5 mg rivastigmine patches and 7.5 mg donepezil, significantly above British National Formulary (BNF) limits. He demonstrated clear clinical response to ChEI and showed improvements in alertness and functioning. He did not exhibit life-threatening cardiac side effects and his death in 2014 was not related to the ChEI.

DNMT3A moderates cognitive decline in subjects with mild cognitive impairment: replicated evidence from two mild cognitive impairment cohorts.

Epigenetic dysregulation has been associated with cognitive decline and Alzheimer's disease. The present study investigated associations between common SNPs in genes regulating DNA methylation and age-related changes in cognitive decline in two independent prospective cohorts of patients suffering from mild cognitive impairment. An association between the rs1187120 SNP in DNMT3A and annual decline in cognitive functioning was discovered and replicated, suggesting that DNMT3A moderates cognitive decline in subjects with mild cognitive impairment.

Be vigilant for perinatal mental health problems.

The postnatal period appears to be associated with higher rates of adjustment disorder, generalised anxiety disorder, and depression. Women who have a history of serious mental illness are at higher risk of developing a postpartum relapse, even if they have been well during pregnancy. Psychiatric causes of maternal death are more common than some direct causes of death. UK rates increased from 13/100,000 in 2006-2008 to 16/100,000 in 2010-2012, higher than, for example, mortality caused by haemorrhage or anaesthetic complications of childbirth. Postnatal depression is more severe than baby blues, follows a chronic course and may relapse outside the perinatal period. Although 13% of patients already have depression in pregnancy, the majority tend to be diagnosed after delivery; up to 19% from childbirth to three months postpartum. NICE recommends using the Two Question Depression Screen and the Generalized Anxiety Disorder scale from the booking visit through to one year postpartum. A positive response to depression or anxiety questions warrants a full assessment using either PHQ-9 or the Edinburgh Postnatal Depression Scale. Bipolar disorder may present as a first depressive episode in pregnancy or the postnatal period. In the postpartum period women have a high risk of severe relapse. Postpartum psychosis has a sudden and dramatic presentation with delusions, mania, severe depression, or mixed episodes with wide fluctuations of symptoms and severe mood swings.

Establishing the cause of memory loss in older people.

Common causes of memory loss in older people are mild cognitive impairment, the various types of dementia, and psychiatric illness, mainly depression. Around 10% of patients with mild cognitive impairment progress to dementia each year. Alzheimer's disease accounts for 60-80% of cases. Other common types of dementia are vascular, fronto-temporal, Lewy body, Parkinson's, and mixed type dementia. There is evidence to suggest that dementia pathology is established before the onset of symptoms, and thus mild cognitive impairment can be considered as a predementia stage. NICE guidance suggests examination of: attention, concentration, short- and long-term memory, praxis, language and executive function. Particular attention should be paid to any signs of neglect, state of dress, agitation or poor attention. Dysphasia and difficulty in naming objects is often present. Mood symptoms (including suicidal ideation) may be primary or comorbid. Abnormal thoughts and perceptions should be probed for, as psychotic symptoms are common. Primary care options for cognitive testing include the General Practitioner Assessment of Cognition or the Abbreviated Mental Test Score. Physical examination should include observation of gait, inspection for tremor; examination for rigidity, bradykinesia, frontal release signs, upper motor neurone lesions, pulse and BP. Structural brain imaging can improve diagnostic accuracy, exclude other pathologies and act as a prognostic marker of dementia progression but the overlap in structural changes between the dementias makes imaging alone insufficient for diagnostic purposes. NICE guidelines recommend referral to a memory clinic for patients with mild cognitive impairment, those at high risk of dementia, such as patients with learning disabilities, Parkinson's disease, or patients who have had several strokes.

Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain.

Epigenetic processes play a key role in the central nervous system and altered levels of 5-methylcytosine have been associated with a number of neurologic phenotypes, including Alzheimer's disease (AD). Recently, 3 additional cytosine modifications have been identified (5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine), which are thought to be intermediate steps in the demethylation of 5-methylcytosine to unmodified cytosine. Little is known about the frequency of these modifications in the human brain during health or disease. In this study, we used immunofluorescence to confirm the presence of each modification in human brain and investigate their cross-tissue abundance in AD patients and elderly control samples. We identify a significant AD-associated decrease in global 5-hydroxymethylcytosine in entorhinal cortex and cerebellum, and differences in 5-formylcytosine levels between brain regions. Our study further implicates a role for epigenetic alterations in AD.