Clinical applicability of quantitative atrophy measures on MRI in patients suspected of Alzheimer's disease.

OBJECTIVES: Neurodegeneration in suspected Alzheimer's disease can be determined using visual rating or quantitative volumetric assessments. We examined the feasibility of volumetric measurements of gray matter (GMV) and hippocampal volume (HCV) and compared their diagnostic performance with visual rating scales in academic and non-academic memory clinics. MATERIALS AND METHODS: We included 231 patients attending local memory clinics (LMC) in the Netherlands and 501 of the academic Amsterdam Dementia Cohort (ADC). MRI scans were acquired using local protocols, including a T1-weighted sequence. Quantification of GMV and HCV was performed using FSL and FreeSurfer. Medial temporal atrophy and global atrophy were assessed with visual rating scales. ROC curves were derived to determine which measure discriminated best between cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's dementia (AD). RESULTS: Patients attending LMC (age 70.9 ± 8.9 years; 47% females; 19% CN; 34% MCI; 47% AD) were older, had more cerebrovascular pathology, and had lower GMV and HCV compared to those of the ADC (age 64.9 ± 8.2 years; 42% females; 35% CN, 43% MCI, 22% AD). While visual ratings were feasible in > 95% of scans in both cohorts, quantification was achieved in 94-98% of ADC, but only 68-85% of LMC scans, depending on the software. Visual ratings and volumetric outcomes performed similarly in discriminating CN vs AD in both cohorts. CONCLUSION: In clinical settings, quantification of GM and hippocampal atrophy currently fails in up to one-third of scans, probably due to lack of standardized acquisition protocols. Diagnostic accuracy is similar for volumetric measures and visual rating scales, making the latter suited for clinical practice. In a real-life clinical setting, volumetric assessment of MRI scans in dementia patients may require acquisition protocol optimization and does not outperform visual rating scales. KEY POINTS: • In a real-life clinical setting, the diagnostic performance of visual rating scales is similar to that of automatic volumetric quantification and may be sufficient to distinguish Alzheimer's disease groups. • Volumetric assessment of gray matter and hippocampal volumes from MRI scans of patients attending non-academic memory clinics fails in up to 32% of cases. • Clinical MR acquisition protocols should be optimized to improve the output of quantitative software for segmentation of Alzheimer's disease-specific outcomes.

Acute response to cholinergic challenge predicts long-term response to galantamine treatment in patients with Alzheimer's disease.

AIMS: Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response. METHODS: This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non-responders. RESULTS: A single dose of galantamine significantly reduced saccadic reaction time (-0.0099; 95% CI = -0.0195, -0.0003; P = .0430), absolute frontal EEG parameters in alpha (-14.9; 95% CI = -21.0, -8.3; P = .0002), beta (-12.6; 95% CI = -19.4, -5.3; P = .0019) and theta (-17.9; 95% CI = -25.0, -10.0; P = .0001) frequencies. Relative frontal (-1.669; 95% CI = -2.999, -0.339; P = .0156) and occipital (-1.856; 95% CI = -3.339, -0.372; P = .0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P = .0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (-20.4; 95% CI = -31.6, -7.47; P = .0046), beta (-15.7; 95% CI = -28.3, -0.93; P = .0390) and theta (-25.9; 95% CI = -38.4, -10.9; P = .0024) EEG parameters and of relative frontal theta power (-3.27%; 95% CI = -5.96, -0.58; P = .0187) on EEG significantly distinguished responders (n = 11) from non-responders (n = 32) after 6 months. CONCLUSIONS: This study demonstrates that acute PD effects after single dose of galantamine are correlated with long-term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.

Use of a digital tool to support the diagnostic process in memory clinics-a usability study.

BACKGROUND: Both memory clinic professionals and patients see value in digital tools, yet these hardly find their way to clinical practice. We explored the usability of a digital tool to support the diagnostic work-up in daily memory clinic practice. We evaluated four modules that integrate multi-modal patient data (1.cognitive test; cCOG, and 2. MRI quantification; cMRI) into useful diagnostic information for clinicians (3. cDSI) and understandable and personalized information for patients (4. patient report). METHODS: We conducted a mixed-methods study in five Dutch memory clinics. Fourteen clinicians (11 geriatric specialists/residents, two neurologists, one nurse practitioner) were invited to integrate the tool into routine care with 43 new memory clinic patients. We evaluated usability and user experiences through quantitative data from questionnaires (patients, care partners, clinicians), enriched with thematically analyzed qualitative data from interviews (clinicians). RESULTS: We observed wide variation in tool use among clinicians. Our core findings were that clinicians: 1) were mainly positive about the patient report, since it contributes to patient-centered and personalized communication. This was endorsed by patients and care partners, who indicated that the patient report was useful and understandable and helped them to better understand their diagnosis, 2) considered the tool acceptable in addition to their own clinical competence, 3) indicated that the usefulness of the tool depended on the patient population and purpose of the diagnostic process, 4) addressed facilitators (ease of use, practice makes perfect) and barriers (high workload, lack of experience, data unavailability). CONCLUSION: This multicenter usability study revealed a willingness to adopt a digital tool to support the diagnostic process in memory clinics. Clinicians, patients, and care partners appreciated the personalized diagnostic report. More attention to education and training of clinicians is needed to utilize the full functionality of the tool and foster implementation in actual daily practice. These findings provide an important step towards a lasting adoption of digital tools in memory clinic practice.

Motivations of patients and their care partners for visiting a memory clinic. A qualitative study.

OBJECTIVE: We investigated motivations of patients and care partners for their memory clinic visit, and whether these are expressed in consultations. METHODS: We included data from 115 patients (age 71 ± 11, 49% Female) and their care partners (N = 93), who completed questionnaires after their first consultation with a clinician. Audio-recordings of these consultations were available from 105 patients. Motivations for visiting the clinic were content-coded as reported by patients in the questionnaire, and expressed by patients and care partners in consultations. RESULTS: Most patients reported seeking a cause for symptoms (61%) or to confirm/exclude a (dementia) diagnosis (16%), yet 19% reported another motivation: (more) information, care access, or treatment/advice. In the first consultation, about half of patients (52%) and care partners (62%) did not express their motivation(s). When both expressed a motivation, these differed in about half of dyads. A quarter of patients (23%) expressed a different/complementary motivation in the consultation, then reported in the questionnaire. CONCLUSION: Motivations for visiting a memory clinic can be specific and multifaceted, yet are often not addressed during consultations. PRACTICE IMPLICATIONS: We should encourage clinicians, patients, and care partners to talk about motivations for visiting the memory clinic, as a starting point to personalize (diagnostic) care.

Young-onset dementia in memory clinics in the Netherlands: Study design and description of PRECODE-GP.

The disease trajectory and healthcare requirements of patients with young-onset dementia (YOD) differ from those of older patients. Accurate data about YOD is crucial to improve diagnosis and optimize care. PRECODE-GP aims to set up a prospective national database of patients with YOD to gain insight into the occurrence and characteristics of patients with YOD in memory clinics in the Netherlands. The national database includes data from dementia patients aged <70 years at diagnosis, collected by local memory clinics (MCs). Data included demographic information, clinical variables, and (etiological) diagnoses. Between July 2019 and December 2022, 781 patients with a mean age of 62±6y at diagnosis (range 37 to 69y) were included from 39 MCs. Most (n = 547,70%) were diagnosed with dementia due to Alzheimer's disease (AD). Patients with Frontotemporal lobe dementia (FTD, n = 87, 11%) were youngest (61±6.0y). Over half (55%) of patients were experiencing symptoms for ≥2 years. We initiated a Dutch national YOD database to improve diagnosis and care for this underrepresented and vulnerable patient group. The database provides a basis for future in-depth studies on YOD.

What patients want to know, and what we actually tell them: The ABIDE project.

BACKGROUND: We studied to what degree and at whose initiative 25 informational topics, formerly identified as important, are discussed in diagnostic consultations. METHODS: Audio recordings of clinician-patient consultations of 71 patients and 32 clinicians, collected in eight Dutch memory clinics, were independently content-coded by two coders. The coding scheme encompassed 25 informational topics. RESULTS: Approximately half (Mdn = 12) of the 25 topics were discussed per patient during the diagnostic process, with a higher frequency among individuals receiving a dementia diagnosis (Mdn = 14) compared to others (Mdn = 11). Individual topics ranged from being discussed with 2/71 (3%) to 70/71 (99%) of patients. Patients and/or care partners rarely initiated topic discussion (10%). When they did, they often enquired about one of the least frequently addressed topics. CONCLUSION: Most patients received information on approximately half of the important informational topics. Providing the topic list to patients and care partners beforehand could allow consultation preparation and stimulate participation.

Decision tree supports the interpretation of CSF biomarkers in Alzheimer's disease.

INTRODUCTION: We developed and validated a clinically applicable decision tree for the use of cerebrospinal fluid biomarkers in the diagnosis of Alzheimer's disease (AD). METHODS: Subjects with probable AD (n = 1004) and controls (n = 442) were included. A decision tree was modeled using Classification And Regression Tree analysis in a training cohort (AD n = 221; controls n = 221) and validated in an independent cohort (AD n = 783; controls n = 221). Diagnostic performance was compared to previously defined cutoffs (amyloid ß 1-42 < 813 pg/ml; tau>375 pg/ml). RESULTS: Two cerebrospinal fluid AD biomarker profiles were revealed: the "classical" AD biomarker profile (amyloid ß 1-42: 647-803 pg/ml; tau >374 pg/ml) and an "atypical" AD biomarker profile with strongly decreased amyloid ß 1-42 (<647 pg/ml) and normal tau concentrations (<374 pg/ml). Compared to previous cutoffs, the decision tree performed better on diagnostic accuracy (86% [84-88] vs 80% [78-83]). DISCUSSION: Two cerebrospinal fluid AD biomarker profiles were identified and incorporated in a readily applicable decision tree, which improved diagnostic accuracy.

Development and Usability of ADappt: Web-Based Tool to Support Clinicians, Patients, and Caregivers in the Diagnosis of Mild Cognitive Impairment and Alzheimer Disease.

BACKGROUND: As a result of advances in diagnostic testing in the field of Alzheimer disease (AD), patients are diagnosed in earlier stages of the disease, for example, in the stage of mild cognitive impairment (MCI). This poses novel challenges for a clinician during the diagnostic workup with regard to diagnostic testing itself, namely, which tests are to be performed, but also on how to engage patients in this decision and how to communicate test results. As a result, tools to support decision making and improve risk communication could be valuable for clinicians and patients. OBJECTIVE: The aim of this study was to present the design, development, and testing of a Web-based tool for clinicians in a memory clinic setting and to ascertain whether this tool can (1) facilitate the interpretation of biomarker results in individual patients with MCI regarding their risk of progression to dementia, (2) support clinicians in communicating biomarker test results and risks to MCI patients and their caregivers, and (3) support clinicians in a process of shared decision making regarding the diagnostic workup of AD. METHODS: A multiphase mixed-methods approach was used. Phase 1 consisted of a qualitative needs assessment among professionals, patients, and caregivers; phase 2, consisted of an iterative process of development and the design of the tool (ADappt); and phase 3 consisted of a quantitative and qualitative assessment of usability and acceptability of ADappt. Across these phases, co-creation was realized via a user-centered qualitative approach with clinicians, patients, and caregivers. RESULTS: In phase 1, clinicians indicated the need for risk calculation tools and visual aids to communicate test results to patients. Patients and caregivers expressed their needs for more specific information on their risk for developing AD and related consequences. In phase 2, we developed the content and graphical design of ADappt encompassing 3 modules: a risk calculation tool, a risk communication tool including a summary sheet for patients and caregivers, and a conversation starter to support shared decision making regarding the diagnostic workup. In phase 3, ADappt was considered to be clear and user-friendly. CONCLUSIONS: Clinicians in a memory clinic setting can use ADappt, a Web-based tool, developed using multiphase design and co-creation, for support that includes an individually tailored interpretation of biomarker test results, communication of test results and risks to patients and their caregivers, and shared decision making on diagnostic testing.

A novel cognitive-functional composite measure to detect changes in early Alzheimer's disease: Test-retest reliability and feasibility.

INTRODUCTION: To improve the detection of changes in Alzheimer's disease (AD), we designed the cognitive-functional composite (CFC). As a first validation step, we investigated its test-retest reliability and feasibility of use. METHODS: We performed a test-retest study with 2-3 weeks between assessments, including patients with mild cognitive impairment (MCI) or mild AD dementia and cognitively healthy participants. We calculated intraclass correlation coefficients (ICCs) type absolute agreement for all CFC measures and compared baseline and retest scores using paired-samples t-tests. We evaluated feasibility by interviewing participants. RESULTS: Forty-three patients (40% female, mean age = 69.9) and 30 controls (50% female, mean age = 65) were included. Subtest intraclass correlation coefficients ranged from .70 to .96. We found negligible improvements after retesting on only two subtests. Overall, patients perceived the administration of the CFC as feasible. DISCUSSION: The CFC is a stable and feasible measure in MCI and mild AD dementia, and thereby meets important quality metrics for clinically meaningful outcome measures.

Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid Alzheimer's disease biomarkers in a nonacademic, multicenter memory clinic cohort: The ABIDE project.

INTRODUCTION: We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting. METHODS: We collected CSF samples from 137 participants in eight local memory clinics. Amyloid ß(1-42) (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed. RESULTS: Biomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aß42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aß42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aß42 and 96% for both t-tau and p-tau. DISCUSSION: The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods.

Clinicians' views on conversations and shared decision making in diagnostic testing for Alzheimer's disease: The ABIDE project.

INTRODUCTION: This study explores clinicians' views on and experiences with when, how, and by whom decisions about diagnostic testing for Alzheimer's disease are made and how test results are discussed with patients. METHODS: Following a preparatory focus group with 13 neurologists and geriatricians, we disseminated an online questionnaire among 200 memory clinic clinicians. RESULTS: Respondents were 95 neurologists and geriatricians (response rate 47.5%). Clinicians (74%) indicated that decisions about testing are made before the first encounter, yet they favored a shared decision-making approach. Patient involvement seems limited to receiving information. Clinicians with less tolerance for uncertainty preferred a bigger say in decisions (P < .05). Clinicians indicated to always communicate the diagnosis (94%), results of different tests (88%-96%), and risk of developing dementia (66%). DISCUSSION: Clinicians favor patient involvement in deciding about diagnostic testing, but conversations about decisions and test results can be improved and supported.

Patients' and caregivers' views on conversations and shared decision making in diagnostic testing for Alzheimer's disease: The ABIDE project.

INTRODUCTION: This study aims to assess patients' and caregivers' views on and experiences with (1) decisions about diagnostic testing for Alzheimer's disease (AD) and (2) receiving test results. METHODS: We conducted separate focus groups with patients from three hospitals who underwent diagnostic testing for AD (N = 11) and their caregivers (N = 11). Audio recordings were transcribed verbatim and analyzed using MaxQDA. RESULTS: Patients and caregivers preferred and perceived active involvement in decision making, but the decision to initiate diagnostic testing seems to be made before the clinician-patient encounter. Patients and caregivers indicate that decisions are driven by a strong need to explain the patient's symptoms. They missed information on why different diagnostic tests were used, what the results of these tests were, and to what extent these results were (ab)normal. DISCUSSION: The decision-making process around diagnostic testing for AD and the information provision before and after diagnostic testing could be improved.

Alzheimer's biomarkers in daily practice (ABIDE) project: Rationale and design.

INTRODUCTION: The Alzheimer's biomarkers in daily practice (ABIDE) project is designed to translate knowledge on diagnostic tests (magnetic resonance imaging [MRI], cerebrospinal fluid [CSF], and amyloid positron emission tomography [PET]) to daily clinical practice with a focus on mild cognitive impairment (MCI). METHODS: ABIDE is a 3-year project with a multifaceted design and is structured into interconnected substudies using both quantitative and qualitative research methods. RESULTS: Based on retrospective data, we develop personalized risk estimates for MCI patients. Prospectively, we collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in a tertiary setting, to optimize application of these tests in daily practice. Furthermore, ABIDE will develop strategies for optimal patient-clinician conversations. DISCUSSION: Ultimately, this will result in a set of practical tools for clinicians to support the choice of diagnostic tests and facilitate the interpretation and communication of their results.

Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease.

BACKGROUND: Immunoreactivity for several chemokines and for their related receptors has been demonstrated in resident cells of the central nervous system, and the up-regulation of some of them is associated with pathological changes found in Alzheimer disease (AD). OBJECTIVE: To determine interferon-gamma-inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), and interleukin 8 (IL-8) levels in cerebrospinal fluid (CSF) from subjects with amnestic mild cognitive impairment (MCI) and patients with AD as compared with age-matched controls. PATIENTS: Thirty-eight subjects with amnestic MCI, 36 patients with AD, and 41 age-matched subjects with noninflammatory affections of the nervous system. DESIGN: Evaluation of CSF chemokine production at time of diagnosis of MCI and AD; correlation with clinical and personal data. Longitudinal evaluation of subjects with MCI until conversion to AD. RESULTS: Cerebrospinal fluid IP-10 concentration was significantly increased in patients with MCI and mild AD but not in patients with severe AD (Mini-Mental State Examination score <15), whereas MCP-1 and IL-8 levels were increased in patients with MCI and all patients with AD. A significant positive correlation between Mini-Mental State Examination score and CSF IP-10 or MCP-1 concentration was observed in patients with AD. No correlation between IP-10 levels and age was found, whereas MCP-1 and IL-8 levels correlated positively with age. Out of 38 subjects with MCI, 19 developed AD within a 1- to 3-year follow-up. CONCLUSIONS: The presence of inflammatory molecules is likely to be a very early event in AD pathogenesis, even preceding the clinical onset of the disease, as demonstrated by subjects with MCI who developed AD over time. Interferon-gamma-inducible protein 10 is specifically increased in MCI and seems to decrease with the progression of AD, whereas MCP-1 and IL-8 are up-regulated also in late stages of the disease, suggesting a role in phases in which neurodegeneration is prevalent.

The transmethylation cycle in the brain of Alzheimer patients.

Homocysteine accumulation, frequently observed in plasma of AD patients, may be a sign of a reduced activity of the brain methionine-homocysteine transmethylation cycle. S-Adenosylmethionine (SAM) is the main methyl donor in several transmethylation reactions. The demethylated product of SAM, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine, which can be remethylated to methionine by transfer of a methyl group of 5-methyltetrahydrofolate (5-MTHF). A reduced activity of the transmethylation cycle in the brain may result in hypomethylation of the promoter of the presenilin 1 (PS1) gene, which will lead to overexpression of presenilin 1 and, consequently, to increased Abeta(1-42) (Abeta42) formation. Brain transmethylation was studied in 30 patients with 'probable' AD and 28 age-matched non-demented controls by measuring the cerebrospinal fluid (CSF) levels of SAM, SAH and 5-MTHF. 5-MTHF was determined by HPLC with electrochemical detection, while SAM and SAH were assayed by stable isotope dilution tandem mass spectrometry. We found no statistical differences between AD patients and controls for 5-MTHF, SAM and SAH levels, and the SAM/SAH-ratio in CSF. These findings argue against a possible change in methylation of the promoter and expression of PS1.

Total tau and phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations.

BACKGROUND: Frontotemporal dementia (FTD) is a pathologically heterogeneous group of presenile neurodegenerative disorders, with or without the deposition of hyperphosphorylated tau protein in affected brain regions. Mutations in the tau gene have been found in the familial form of FTD, linked to chromosome 17q21-22, showing a spectrum of tauopathy. OBJECTIVE: To evaluate levels of total tau, phosphorylated tau 181 (Ptau-181), and amyloid-beta1-42 in the cerebrospinal fluid (CSF) of patients with FTD, with special emphasis on FTD due to tau mutations. DESIGN: Case-control study. SETTING: Outpatient neurology clinics at 2 university medical centers, in Rotterdam and Amsterdam (the Netherlands). PATIENTS: Twenty-six patients with FTD (9 with tau mutations 7 P301L and 2 G272V), 18 patients with Alzheimer disease (AD), and 13 nondemented controls. METHODS: Total tau, Ptau-181, and amyloid-beta1-42 levels in CSF, obtained by lumbar puncture, were determined by sandwich enzyme-linked immunosorbent assay. Patients were diagnosed after clinical examination, neuropsychologic evaluation, and neuroimaging. Differences between patient groups were statistically evaluated using nonparametric tests. RESULTS: Although CSF levels of total tau were mildly increased in FTD patients compared with nondemented controls (P =.05), median CSF total tau levels were low in the subgroup with tau mutations compared with AD patients. Furthermore, CSF levels of Ptau-181 and amyloid-beta1-42 were not different in FTD patients, including the patients with tau mutations, compared with nondemented controls. CONCLUSIONS: The tauopathy in P301L and G272V does not appear to be associated with an evident increase in CSF levels of Ptau-181 in FTD patients with these tau mutations, in contrast with findings in patients with AD.

Functional brain connectivity and neurocognitive functioning in patients with long-standing type 1 diabetes with and without microvascular complications: a magnetoencephalography study.

OBJECTIVE: Hyperglycemia-associated microvascular disease may underlie changes in cerebral functioning and cognitive performance in patients with type 1 diabetes. Functional connectivity, an indicator of functional interactions and information exchange between brain regions, provides a measure of cerebral functioning. This study addresses functional connectivity and cognition in type 1 diabetic patients with and without proliferative retinopathy, relative to healthy control subjects, using magnetoencephalography. RESEARCH DESIGN AND METHODS: Fluctuations in magnetic field at scalp for Delta, theta, lower and upper alpha, beta, and lower and upper gamma frequency bands were measured using magnetoencephalography. Synchronization likelihood, a measure of functional connectivity, was computed. Using neuropsychological tests, cognitive functioning was assessed and its associations with functional connectivity were determined. RESULTS: Compared with control subjects, type 1 diabetic patients performed poorer on general cognitive ability, information processing speed, and motor speed, irrespective of their microvascular complication status. Functional connectivity, however, was lowest for type 1 diabetic patients with retinopathy, compared with type 1 diabetic patients without microvascular complications and control subjects, whereas type 1 diabetic patients without microvascular complications showed an increase relative to control subjects. Positive associations were found between functional connectivity and executive functioning, memory, information processing speed, motor speed, and attention. CONCLUSIONS: Compared with healthy control subjects, functional connectivity and cognition differed in type 1 diabetic patients irrespective of microvascular complication status, indicating that chronic hyperglycemia, among other factors, may negatively affect brain functioning even before microvascular damage becomes manifest. The association found between synchronization likelihood and cognition suggests functional connectivity plays a significant role in cognitive functioning.

Inflammatory markers in AD and MCI patients with different biomarker profiles.

OBJECTIVE: The aim of this study was to demonstrate the involvement of the inflammatory proteins IL-6, ACT and CRP early in the pathology process of AD in patients with mild cognitive impairment (MCI) and AD. METHODS: IL-6, ACT, CRP, Abeta42, phospho-tau (p-tau) and total tau concentrations in serum and CSF of 145 patients with probable AD and 67 patients with MCI were measured by sandwich ELISA. MCI patients were characterized as high- respectively low-risk MCI according to their Abeta42/tau risk profile. RESULTS: CSF and serum CRP levels were significantly higher in MCI compared to AD patients after adjustment for age, ApoE epsilon4 genotype and cardiovascular diseases (p<0.01). This difference remained present in patients with a low-risk biomarker profile for AD after adjustment for abovementioned covariates. CSF IL-6 levels were also significantly higher in MCI patients with a low-risk CSF profile. CONCLUSIONS: These findings suggest that inflammatory processes might be involved in early stages of AD, even before Abeta and tau changes are present in CSF of MCI patients.

CSF biomarker levels in early and late onset Alzheimer's disease.

OBJECTIVE: To compare CSF levels of beta-amyloid 1-42 (Abeta(1-42)), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) between AD patients and controls according to age. METHODS: 248 AD patients (48% men) and 127 controls (51% men, 22 volunteers and 105 subjective complainers) underwent lumbar puncture. Both patients and controls were divided into a young (<65 years) and old (>or=65 years) group. RESULTS: All three biomarkers showed main effects of diagnosis (p<0.001). There was an interaction between diagnosis and age for all three biomarkers (p<0.05), as old controls had lower Abeta(1-42) and higher (p)tau than young controls (Abeta(1-42) 699+/-250 versus 866+/-191pg/ml, tau 408+/-245 versus 243+/-102pg/ml, ptau-181 60+/-28 versus 42+/-15pg/ml), but there was no difference according to age among AD patients (Abeta(1-42) 451+/-178 versus 425+/-146pg/ml, tau 741+/-460 versus 798+/-467pg/ml, ptau-181 91+/-42 versus 91+/-41pg/ml). CONCLUSION: We found that the older control group had lower Abeta(1-42) and higher (p)tau compared to the younger control group. This suggests that older individuals may have AD pathology, even in the absence of objective cognitive impairment.

CSF and MRI markers independently contribute to the diagnosis of Alzheimer's disease.

BACKGROUND: Decreased amyloid beta (1-42) (Abeta42) and increased (phosphorylated) tau in cerebrospinal fluid (CSF) are considered to be a reflection of plaques, tangles, and neuronal degeneration in Alzheimer's disease (AD). Atrophy of the medial temporal lobe (MTA) on magnetic resonance imaging (MRI) reflects neuronal loss in this area. OBJECTIVE: To compare diagnostic accuracy of CSF biomarkers and MTA in AD versus controls. METHODS: Abeta42, tau and tau phosphorylated at threonine 181 (Ptau-181) were measured in CSF from 61 AD patients and 32 controls by sandwich enzyme-linked immunosorbent assay. A CSF biomarker profile for AD was constructed. MTA was rated visually on MRI. RESULTS: When AD patients and controls were evaluated separately, no correlations were present between the CSF markers and MTA score. Both MTA and CSF biomarker profile were independently associated with the diagnosis AD (MTA: OR (95% CI)=28 (3-239); CSF biomarker profile: OR (95% CI)=57 (13-262)). Among individuals younger than 65 years old and without MTA 60% suffered AD, and the finding of an abnormal CSF biomarker profile was limited to AD patients only. CONCLUSIONS: MTA and CSF biomarkers seem to be of incremental value for the diagnosis AD. CSF analysis is most sensitive in the absence of MTA, and especially among early-onset AD patients.