Optimized RT-qPCR and a novel normalization method for validating circulating miRNA biomarkers in ageing-related diseases.

Circulating miRNAs have potential as minimally invasive biomarkers for diagnosing various diseases, including ageing-related disorders such as Alzheimer's disease (AD). However, the lack of standardization in the common analysis method, RT-qPCR, and specifically in the normalization step, has resulted in inconsistent data across studies, hindering miRNA clinical implementation as well as basic research. To address this issue, this study proposes an optimized protocol for key steps in miRNA profiling, which incorporates absorbance-based haemolysis detection for assessing sample quality, double spike-in controls for miRNA isolation and reverse transcription, and the use of 7 stable normalizers verified in an aging population, including healthy subjects and individuals at different stages of Alzheimer's disease (140 subjects). The stability of these 7 normalizers was demonstrated using our novel method called BestmiRNorm for identifying optimal normalizers. BestmiRNorm, developed utilizing the Python programming language, enables the assessment of up to 11 potential normalizers. The standardized application of this optimized RT-qPCR protocol and the recommended normalizers are crucial for the development of miRNAs as biomarkers for AD and other ageing-related diseases in clinical diagnostics and basic research.

Characteristics of subjective cognitive decline associated with amyloid positivity.

INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.

Abnormalities of DYRK1A-Cytoskeleton Complexes in the Blood Cells as Potential Biomarkers of Alzheimer's Disease.

BACKGROUND: DYRK1A is implicated in mental retardation and Alzheimer's disease (AD) dementia of Down syndrome (DS) individuals. The protein is associated with cytoskeleton and altered expression has been shown to impair the cytoskeletal network via dosage effect. OBJECTIVE: Our original observations of marked reduction of cytoskeletal proteins associated with DYRK1A in brains and lymphoblastoid cell lines from DS and AD prompted an investigation whether cytoskeleton abnormalities could potentially be used as biomarkers of AD. METHODS: Our assay relied on quantification of co-immunoprecipitated cytoskeletal proteins with DYRK1A (co-IP assay) and analysis of the profile of G- and F-actin fractions obtained by high-speed centrifugations (spin-down assay). RESULTS: In co-IP assay, both DS and AD samples displayed reduced abundance of associated cytoskeletal proteins. In spin-down assay, G-actin fractions of controls displayed two closely spaced bands of actin in SDS-PAGE; while in AD and DS, only the upper band of the doublet was present. In both assays, alterations of actin cytoskeleton were present in DS, sporadic and familial AD cases, and in asymptomatic persons who later progressed to confirmed AD, but not in non-AD donors. In blind testing involving six AD and six controls, the above tests positively identified ten cases. Analysis of blood samples revealed the diversity of mild cognitive impairment (MCI) cases regarding the presence of the AD biomarker allowing distinction between likely prodromal AD and non-AD MCI cases. CONCLUSIONS: Both brain tissue and lymphocytes from DS and AD displayed similar semi-quantitative and qualitative alterations of actin cytoskeleton. Their specificity for AD-type dementia and the presence before clinical onset of the disease make them suitable biomarker candidates for early and definite diagnosis of AD. The presence of alterations in peripheral tissue points to systemic underlying mechanisms and suggests that early dysfunction of cytoskeleton may be a predisposing factor in the development of AD.

The Erlangen Score Algorithm in the diagnosis and prediction of the progression from subjective cognitive decline and mild cognitive impairment to Alzheimer-type dementia.

The evaluation of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) (ß-amyloid, t-tau, p-tau) can be used to estimate the risk of developing dementia in patients at the pre-clinical stages of AD, i.e. subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Erlangen Score Algorithm allows interpretation of CSF biomarker concentrations and is cut-off value independent. The aim of this study was to establish if this algorithm can be applied for routine diagnostic testing in clinical and preclinical subjects and has prognostic value. We analysed 217 patients from the memory clinic with the diagnosis of SCD (n = 31), MCI (n = 104), and AD (n = 82) with clinical follow-up amounting to 14.33 months (SD = 6.82). It was found that the highest Erlangen Score dominated in the AD group and was the rarest in the SCD group. In the group of patients with progression of symptoms during our period of observation, the AD pathology was confirmed in 93.75% of cases. Among the non-progressing subjects (n = 119) the algorithm indicated the risk of developing AD as possible in 40.34% and probable in 15.97% of cases. To conclude, the Erlangen Score Algorithm is a useful tool to determinate the risk of developing AD before the onset of dementia or to confirm the AD diagnosis. It is extremely valuable in preclinical stages of AD for planning purposes and early intervention as well as for future clinical trials.

Association of Cerebral Amyloid-ß Aggregation With Cognitive Functioning in Persons Without Dementia.

Importance: Cerebral amyloid-ß aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-ß aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. Conclusions and Relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.

Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia.

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-ß1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.

Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment.

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-ß1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.

Profile of 6 microRNA in blood plasma distinguish early stage Alzheimer's disease patients from non-demented subjects.

Alzheimer's disease (AD) is the most common age-related dementia. Among its major challenges is identifying molecular signatures characteristic for the early AD stage in patients with Mild Cognitive Impairment (MCI-AD), which could serve for deciphering the AD pathomechanism and also as non-invasive, easy-to-access biomarkers. Using qRT-PCR we compared the microRNA (miRNA) profiles in blood plasma of 15 MCI-AD patients, whose diagnoses were confirmed by cerebrospinal fluid (CSF) biomarkers, with 20 AD patients and 15 non-demented, age-matched individuals (CTR).To minimize methodological variability, we adhered to standardization of blood and CSF assays recommended by the international Joint Programming for Neurodegenerative Diseases (JPND) BIOMARKAPD consortium, and we employed commercially available Exiqon qRT-PCR-assays. In the first screening, we assessed 179 miRNAs of plasma. We confirmed 23 miRNAs reported earlier as AD biomarker candidates in blood and found 26 novel differential miRNAs between AD and control subjects. For representative 15 differential miRNAs, the TargetScan, MirTarBase and KEGG database analysis indicated putative protein targets among such AD hallmarks as MAPT (Tau), proteins involved in amyloidogenic proteolysis, and in apoptosis. These 15 miRNAs were verified in separate, subsequent subject groups. Finally, 6 miRNAs (3 not yet reported in AD context and 3 reported in AD blood) were selected as the most promising biomarker candidates differentiating early AD from controls with the highest fold changes (from 1.32 to 14.72), consistent significance, specificities from 0.78 to 1 and sensitivities from 0.75 to 1. (patent pending, PCT/IB2016/052440).

Association between Cerebrospinal Fluid Biomarkers for Alzheimer's Disease, APOE Genotypes and Auditory Verbal Learning Task in Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease.

In the course of Alzheimer's disease (AD), early pathological changes in the brain start decades before any clinical manifestation. The concentration levels of AD cerebrospinal fluid (CSF) biomarkers, such as amyloid-ß1-42 (Aß1-42), total tau (T-tau), and phosphorylated tau (P-tau), may reflect a cerebral pathology facilitating an early diagnosis of the disease and predicting a cognitive deterioration. The aim of this study was to estimate the prevalence of AD CSF biomarkers in those individuals with a subjective cognitive decline (SCD), a mild cognitive impairment (MCI), and Alzheimer's dementia (AD-D), together with the relationships between the biomarkers, an APOE ɛ4 presence, and a verbal episodic memory performance. We included 252 patients from the memory clinic with a diagnosis of SCD (n = 85), MCI (n = 87), and AD-D (n = 80). A verbal episodic memory performance level was assessed and was based on a delayed recall trial from the 10-word list of an auditory verbal learning task (AVLT). We found that the patients with more severe cognitive impairments had significantly lower levels of Aß1-42 and higher levels of T-tau and P-tau. This pattern was also typical for the APOE ɛ4 carriers, who had lower levels of Aß1-42 than the noncarriers in the AD-D and MCI groups. The levels of T-tau and P-tau were significantly higher in the APOE ɛ4 carriers than in the noncarriers, but only in the MCI patients. The AVLT performance in the whole study samples was predicted by age, Aß1-42, and the T-tau CSF biomarkers, but not by the APOE genotyping.

Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics.

BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples. OBJECTIVE: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers. METHODS: Three matrices were validated in this study: (A) human pooled CSF, (B) Aß peptides spiked into human prediluted plasma, and (C) Aß peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study. RESULTS: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects. CONCLUSION: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.

The Central Biobank and Virtual Biobank of BIOMARKAPD: A Resource for Studies on Neurodegenerative Diseases.

Biobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer's and Parkinson's disease (BIOMARKAPD) is a European multicenter study, funded by the EU Joint Programme-Neurodegenerative Disease Research, which aims to improve the clinical use of body fluid markers for the diagnosis and prognosis of Alzheimer's disease (AD) and Parkinson's disease (PD). The objective was to standardize the assessment of existing assays and to validate novel fluid biomarkers for AD and PD. To support the validation of novel biomarkers and assays, a central and a virtual biobank for body fluids and associated data from subjects with neurodegenerative diseases have been established. In the central biobank, cerebrospinal fluid (CSF) and blood samples were collected according to the BIOMARKAPD standardized pre-analytical procedures and stored at Integrated BioBank of Luxembourg. The virtual biobank provides an overview of available CSF, plasma, serum, and DNA samples at each site. Currently, at the central biobank of BIOMARKAPD samples are available from over 400 subjects with normal cognition, mild cognitive impairment (MCI), AD, frontotemporal dementia (FTD), vascular dementia, multiple system atrophy, progressive supranuclear palsy, PD, PD with dementia, and dementia with Lewy bodies. The virtual biobank contains information on over 8,600 subjects with varying diagnoses from 21 local biobanks. A website has been launched to enable sample requests from the central biobank and virtual biobank.

Evaluation of the safety profile of Zolafren®, a generic olanzapine formulation, in patients with bipolar disorder: a post-authorization safety study.

INTRODUCTION: Prior to registration, no clinical trial evaluating safety and tolerability of Zolafren® (Adamed Sp. z o.o., Czosnów, Poland), a generic olanzapine formulation, had been performed. Therefore, the aim of this post-authorization safety study (PASS) was to evaluate the safety and tolerability of Zolafren in patients with bipolar disorder (BD). METHODS: Adverse events (AEs) associated with the use of Zolafren were recorded in a PASS, in an open-label, non-randomized, multicenter observational study involving 20,698 outpatients with BD. RESULTS: Zolafren was used in both monotherapy (82.8%) and polytherapy (17.2%) at a mean dose of 12.1±4.2 mg. The most commonly used formulation was coated tablets (70.9%). Orally dissolving tablets (19.7%) and hard capsules (9.4%) were less commonly used. During a period of 171±47 days of exposure to Zolafren, 5883 AEs were reported in 2138 patients (10.3% of the study population). None of the reported AEs were severe. Zolafren-associated AEs were the reason for discontinuation in 43 patients and the reason for dose reduction in a further 762 patients. The most common AE was weight gain (by 1.6±3.3 kg) which was considered unrelated to the dose of Zolafren. During follow-up, the percentage of patients with very good tolerance with Zolafren increased from 44.4% to 59.8%. The percentage of patients who had confidence in Zolafren also increased. CONCLUSION: The results of this PASS support the safety of Zolafren use and indicate a high tolerance in patients treated for BD. FUNDING: Adamed Sp. z o.o., Czosnów, Poland.

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

IMPORTANCE: Cerebral amyloid-ß aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Depressive symptoms in patients diagnosed with benign prostatic hyperplasia.

BACKGROUND: Symptoms of depression are common in patients diagnosed with benign prostatic hyperplasia (BPH) and are usually a reaction to deterioration of health, severity of lower urinary tract symptoms, and erectile dysfunction. The aim of this observational study was to evaluate the prevalence of depressive symptoms in patients diagnosed with BPH and factors affecting their occurrence in a large Polish cohort. PATIENTS AND METHODS: Four thousand thirty-five men (4,035) diagnosed with BPH participated in the survey (age 65 ± 8 years). The occurrence of symptoms of depression was assessed using the Beck depression inventory, severity of lower urinary tract symptoms (LUTS) on the basis of the international prostate symptoms score, and erectile dysfunction using the international index of erectile function (IIEF-5). RESULTS: Depressive symptoms were found in 22.4% of patients (mild in 20.8% and moderate/severe in 1.6%). Erectile dysfunction was found in 71.9% of patients. Monotherapy for BPH was prescribed to 50.9% of patients (mostly ARA-selective α1-selective alpha-adrenolytic-47.5%), while polytherapy (ARA with a 5-alpha reductase inhibitor-5αRI) to 47.9%. Logistic regression analysis showed a bidirectional relation between the occurrence of depressive symptoms and erectile dysfunction. The occurrence of both depressive symptoms and erectile dysfunction was related to severity of LUTS, nocturia, the use of 5αRI, comorbidity, and sedentary life style. CONCLUSIONS: Prevalence of depressive symptoms in patients diagnosed with BPH is associated with severity of LUTS, erectile dysfunction, nocturia, BPH pharmacotherapy (5αRIs), sedentary life style, and comorbidities including obesity.

[Pharmacological treatment of behavioral symptoms in dementia patients]. / Farmakologiczne leczenie zaburzen zachowania u osób z otepieniem.

Cognitive manifestations usually are the primary abnormalities in dementia. In most cases cognitive deterioration arise in association with behavioral disturbances, and may accelerate institutionalization of patients. Noncognitive symptoms are distressing for both patients and their caregivers. These symptoms are described as "behavioral and psychological symptoms of dementia--BPSD" or neuropsychiatric symptoms. BPSD occurs in all types of dementia, and often are among the most prominent symptoms in the clinical course of the disease. Some disturbances like agitation and aggression may be disruptive and life-treating for patients and surrounding people. Non-pharmacological interventions should be recommended as a first line treatment unless BPSD symptoms are severe, persistent or recurrent. Drug treatment should have a specific target symptom. Atypical antipsychotics are widely used as the first line pharmacological approach to treat BPSD. Antidepressants, anxiolytics and antiepileptic's are also used. Treatment with cholinesterase inhibitors and/or memantine may delay the onset of BPSD and reduce the severity of some symptoms. Effective and safe treatment of BPSD should significantly improves the quality of life of patients and their caregivers.

N-acetylaspartate, choline, myoinositol, glutamine and glutamate (glx) concentration changes in proton MR spectroscopy (1H MRS) in patients with mild cognitive impairment (MCI).

BACKGROUND: Purpose of study was evaluation of regional metabolic disorders using 1H MRS in patients with MCI, as a predictor of clinical conversion to dementia based on clinical follow-up. MATERIAL/METHODS: The study group consisted of 31 subjects with diagnosis of MCI based on criteria the Mayo Clinic Group. ¹H MRS was performed with a single-voxel method using PRESS sequence. The volume of interest (VOI) was located in the hippocampal formation and posterior part of the cingulated gyrus. RESULTS: Patients had annual clinical control at least twice. At the beginning, 9 had amnestic MCI and the others had multidomain MCI. During follow-up (median 3 yrs) 8 subjects had stable disease (SD), 13 had disease progression (DP) and 10 develop Alzheimer disease (AD). Baseline metabolic ratios (1H MRS) between 3 groups indicated significant difference (P < 0.05) in left frontal lobe in mI/H20 ratio, between patients with SD (0.27) and DP. In comparing the groups with DP and AD, a significant difference in NAA/Cr (1.77 vs. 1.43) was found. A significant difference within left temporal external lobes was found between SD and DP in NAA/H2O ratio (0.55 vs. 0.51). An additional significant difference within medial temporal lobe was found between DP and AD in Glx/H2O ratio (0.44 vs. 0.34) on the right side. CONCLUSIONS: 1H MRS seems to be sensitive method allows prediction of which patients are liable to progress from MCI to AD. Combined with other biomarkers of disease staging, it is an important approach in the preclinical AD diagnosis, as well as the assessment of dementia progression.

The impact of mitochondrial and nuclear DNA variants on late-onset Alzheimer's disease risk.

We investigated the potential contribution of mitochondrial DNA (mtDNA) variants, haplogroups, and polymorphisms in nuclear genes essential for mitochondrial biogenesis and function (PGC-1α TFAM) to late-onset Alzheimer's disease (LOAD) risk. Epistatic interaction analysis was conducted between the studied variables. Our results demonstrate that mtDNA haplogroups and subhaplogroups with putative role in partial uncoupling of oxidative phosphorylation are significantly associated with a decreased LOAD risk (OR <1). Conversely, mtDNA haplogroup H (p = 0.049) and HV cluster (p = 0.018) are significant LOAD risk factors, which was additionally confirmed by meta-analysis (OR = 1.22, OR = 1.25, respectively). Haplogroup K was demonstrated to exert a neutralizing effect on the high risk associated with APOE4+ status (p = 0.014). Further, two synergistic interactions between subhaplogroup H5 and APOE4 status (p = 0.009) and between TFAM rs1937 and APOE4 status (p < 0.001) were detected, influencing LOAD risk. No interaction pointing to a dual mitochondrial-nuclear genome variation effect on LOAD occurrence was identified.

Intra-familial clinical heterogeneity due to FTLD-U with TDP-43 proteinopathy caused by a novel deletion in progranulin gene (PGRN).

Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1-13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g.2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation and is associated with substantial intra-familial clinical heterogeneity. Although presenting features were different, rapid and substantial deterioration in the disease course was observed in both family members.

Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease.

Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease.