Associations of Serum Vitamin D With Dental Caries and Periodontitis: The HUNT Study.

OBJECTIVE: To study the relationships of serum 25-hydroxyvitamin D [25(OH)D] with dental caries and periodontitis in a general Norwegian adult population. METHODS: We analysed a subsample of 1605 participants from the Trøndelag Health Study (HUNT) in Norway that had serum 25(OH)D) levels measured in HUNT3 (2006-08) and oral health assessed in the HUNT4 Oral Health Study (2017-19). Negative binomial and Poisson regression models were used to estimate the ratios of means (RMs; for count oral outcomes) and prevalence ratios (PRs; for dichotomous oral outcomes). RESULTS: Serum 25(OH)D was inversely associated with the number of decayed teeth in a dose-response gradient (<30.0 nmol/L: RM 1.41, 95% CI 1.07-1.85; 30.0-49.9 nmol/L: 1.14, 0.98-1.32 and ≥75.0 nmol/L: 0.84, 0.67-1.04, as compared to the 50.0-74.9 nmol/L group, P for trend <.001). Each 25 nmol/L decrease in 25(OH)D level was associated with a 15% (RM 1.15, 95% CI 1.05-1.26) increase in the mean number of decayed teeth. Serum 25(OH)D <30.0 nmol/L was associated with a 35% higher prevalence of severe periodontitis (PR 1.35, 95% CI 1.00-1.83). No association was observed between 25(OH)D and the number of natural teeth. CONCLUSION: The present study suggested that serum 25(OH)D level had an inverse and dose-response association with the number of decayed teeth, and serum 25(OH)D <30 nmol/L was associated with a higher prevalence of severe periodontitis in this Norwegian adult population.

A Machine Learning Approach to Predict Post-stroke Fatigue. The Nor-COAST study.

OBJECTIVE: This study aimed to predict fatigue 18 months post-stroke by utilizing comprehensive data from the acute and sub-acute phases after stroke in a machine-learning set-up. DESIGN: A prospective multicenter cohort-study with 18-month follow-up. SETTING: Outpatient clinics at 3 university hospitals and 2 local hospitals. PARTICIPANTS: 474 participants with the diagnosis of acute stroke (mean ± SD age; 70.5 (11.3), 59% male; N=474). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome, fatigue at 18 months, was assessed using the Fatigue Severity Scale (FSS-7). FSS-7≥5 was defined as fatigue. In total, 45 prediction variables were collected, at initial hospital-stay and 3-month post-stroke. RESULTS: The best performing model, random forest, predicted 69% of all subjects with fatigue correctly with a sensitivity of 0.69 (95% CI: 0.50, 0.86), a specificity of 0.74 (95% CI: 0.66, 0.83), and an Area under the Receiver Operator Characteristic curve of 0.79 (95% CI: 0.69, 0.87) in new unseen data. The proportion of subjects predicted to suffer from fatigue, who truly suffered from fatigue at 18-months was estimated to 0.41 (95% CI: 0.26, 0.57). The proportion of subjects predicted to be free from fatigue who truly did not have fatigue at 18-months was estimated to 0.90 (95% CI: 0.83, 0.96). CONCLUSIONS: Our findings indicate that the model has satisfactory ability to predict fatigue in the chronic phase post-stroke and may be applicable in clinical settings.

Change in physical activity and systolic blood pressure trajectories throughout mid-life and the development of dementia in older age: the HUNT study.

BACKGROUND: There is lack of research on combinations of possible modifiable risk factors for dementia in a life-time perspective. Dementia has currently no cure, and therefore new knowledge of preventive factors is important. The purpose of this study is to investigate if changes in physical activity (PA) in combinations with systolic blood pressure (SBP) trajectories in mid to late life are related to development of dementia in older age. METHODS: This prospective cohort study uses data from four consecutive surveys of the HUNT Study, Norway. Dementia was assessed in the HUNT4 70 + sub-study (2017-19). Group-based trajectory modelling identified three SBP trajectories from HUNT1 (1984-86) to HUNT3 (2006-2008): low, middle, and high. Change in PA was categorized into four groups based on high or low PA level at HUNT1 and HUNT3 and were combined with the SBP trajectories resulting in 12 distinct categories. Logistic regression was used to estimate odds ratios (ORs) of dementia. RESULTS: A total of 8487 participants (55% women, mean age (SD) 44.8 (6.5) years at HUNT1) were included. At HUNT4 70 + , 15.2% had dementia. We observed an overall decrease in OR of dementia across the PA/SBP categories when ranked from low to high PA (OR, 0.96; 95% CI, 0.93 to 1.00, P = 0.04). Within PA groups, a low SBP trajectory was associated with lower OR for dementia, apart from those with decreasing PA. The strongest association was observed for people with stable high PA and low SBP trajectory (OR, 0.38; 95% confidence interval (CI), 0.13 to 1.10 and adjusted risk difference, -8.34 percentage points; 95% CI, -15.32 to -1.36). CONCLUSION: Our findings illustrate the clinical importance of PA and SBP for dementia prevention and that favorable levels of both are associated with reduced occurrence of dementia.

Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease.

INTRODUCTION: The kynurenine pathway's (KP) malfunction is closely related to Alzheimer's disease (AD), for antagonistic kynurenic acid (KA) and agonistic quinolinic acid act on the N-methyl-D-aspartate receptor, a possible therapeutic target in treating AD. METHODS: In our longitudinal case-control study, KP metabolites in the cerebrospinal fluid were analyzed in 311 patients with AD and 105 cognitively unimpaired controls. RESULTS: Patients with AD exhibited higher concentrations of KA (ß = 0.18, P < 0.01) and picolinic acid (ß = 0.20, P < 0.01) than the controls. KA was positively associated with tau pathology (ß = 0.29, P < 0.01), and a higher concentration of KA was associated with the slower progression of dementia. DISCUSSION: The higher concentrations of neuroprotective metabolites KA and picolinic acid suggest that the activation of the KP's neuroprotective branch is an adaptive response in AD and may be a promising target for intervention and treatment. Highlights Patients with Alzheimer's disease (AD) exhibited higher concentrations of kynurenic acid and picolinic acid than controls. Higher concentrations of kynurenic acid were associated with slower progression of AD. Potential neurotoxic kynurenines were not increased among patients with AD. Activation of the kynurenine pathway's neuroprotective branch may be an adaptive response in AD.

Sex-specific associations of matrix metalloproteinases in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-ß (Aß) and tau pathology. However, there is a need for biomarkers reflecting additional pathological pathways. Matrix metalloproteinases (MMPs) have recently been highlighted as candidate biomarkers for sex-specific mechanisms and progression in AD. METHODS: In this cross-sectional study, we investigated nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in the cerebrospinal fluid of 256 memory clinic patients with mild cognitive impairment or dementia due to AD and 100 cognitively unimpaired age-matched controls. We studied group differences in MMP/TIMP levels and examined the associations with established markers of Aß and tau pathology as well as disease progression. Further, we studied sex-specific interactions. RESULTS: MMP-10 and TIMP-2 levels differed significantly between the memory clinic patients and the cognitively unimpaired controls. Furthermore, MMP- and TIMP-levels were generally strongly associated with tau biomarkers, whereas only MMP-3 and TIMP-4 were associated with Aß biomarkers; these associations were sex-specific. In terms of progression, we found a trend towards higher MMP-10 at baseline predicting more cognitive and functional decline over time exclusively in women. CONCLUSION: Our results support the use of MMPs/TIMPs as markers of sex differences and progression in AD. Our findings show sex-specific effects of MMP-3 and TIMP-4 on amyloid pathology. Further, this study highlights that the sex-specific effects of MMP-10 on cognitive and functional decline should be studied further if MMP-10 is to be used as a prognostic biomarker for AD.

Brain Morphometric Correlates of Depressive Symptoms among Patients with and without Dementia.

Introduction: Findings regarding brain morphometry among patients with dementia and concomitant depressive symptoms have been inconsistent. Thus, the aim of the present study was to test the hypothesis that dementia and concomitant depressive symptoms are associated with structural brain changes in the temporal lobe measured with structural magnetic resonance imaging (MRI). Methods: A sample of 492 patients from Norwegian memory clinics (n = 363) and Old Age Psychiatry services (n = 129) was studied. The assessment included the Cornell Scale for Depression in Dementia (CSDD), Instrumental Activities of Daily Living Scale, Mini Mental State Examination, and MRI of the brain, processed with FreeSurfer to derive ROI measures of cortical thickness, volume, and area using the Desikan-Killiany parcellation, as well as subcortical volumes. Dementia was diagnosed according to ICD-10 research criteria. Correlates of brain morphometry using multiple linear regression were examined. Results: Higher scores on the CSDD were associated with larger cortical volume (ß = 0.125; p value = 0.003) and area of the left isthmus of the cingulate gyrus (ß = 0.151; p value = <0.001) across all patients. Inclusion of an interaction term (dementia × CSDD) revealed a smaller area in the left temporal pole (ß = -0.345; p value = 0.001) and right-transverse temporal cortex (ß = -0.321; p value = 0.001) in patients with dementia and depressive symptoms. Discussion/Conclusion: We confirm the previous findings of structural brain changes in temporal regions among patients with dementia and concomitant depressive symptoms. This may contribute to a better understanding of the mechanisms underlying depression in dementia. To the best of our knowledge, this is the largest study conducted on this topic to date.

Cerebrospinal fluid catecholamines in Alzheimer's disease patients with and without biological disease.

Noradrenergic and dopaminergic neurons are involved in cognitive functions, relate to behavioral and psychological symptoms in dementia and are affected in Alzheimer's disease (AD). Amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N) hallmarks the AD neuropathology. Today, the AT(N) pathophysiology can be assessed through biomarkers. Previous studies report cerebrospinal fluid (CSF) catecholamine concentrations in AD patients without biomarker refinement. We explored if CSF catecholamines relate to AD clinical presentation or neuropathology as reflected by CSF biomarkers. CSF catecholamines were analyzed in AD patients at the mild cognitive impairment (MCI; n = 54) or dementia stage (n = 240) and in cognitively unimpaired (n = 113). CSF biomarkers determined AT status and indicated synaptic damage (neurogranin). The AD patients (n = 294) had higher CSF noradrenaline and adrenaline concentrations, but lower dopamine concentrations compared to the cognitively unimpaired (n = 113). AD patients in the MCI and dementia stage of the disease had similar CSF catecholamine concentrations. In the CSF neurogranin positively associated with noradrenaline and adrenaline but not with dopamine. Adjusted regression analyses including AT status, CSF neurogranin, age, gender, and APOEε4 status verified the findings. In restricted analyses comparing A+T+ patients to A-T- cognitively unimpaired, the findings for CSF adrenaline remained significant (p < 0.001) but not for CSF noradrenaline (p = 0.07) and CSF dopamine (p = 0.33). There were no differences between A+T+ and A-T- cognitively unimpaired. Thus, we find alterations in CSF catecholamines in symptomatic AD and the CSF adrenergic transmitters to increase simultaneously with synaptic damage as indexed by CSF neurogranin.

The Impact of Vascular Risk Factors on Post-stroke Cognitive Impairment: The Nor-COAST Study.

Introduction: Post-stroke cognitive impairment (PSCI) is common, but evidence on the impact of vascular risk factors is lacking. We explored the association between pre-stroke vascular risk factors and PSCI and studied the course of PSCI. Materials and Methods: Vascular risk factors were collected at baseline in stroke survivors (n = 635). Cognitive assessments of attention, executive function, memory, language, and the Montreal Cognitive Assessment (MoCA) were performed at 3 and/or 18 months post-stroke. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). PSCI was measured with global z; MoCA z-score; and z-score of the four assessed cognitive domains. Mixed-effect linear regression was applied with global z, MoCA z-score, and z-scores of the cognitive domains as dependent variables. Independent variables were the vascular risk factors (hypertension, hypercholesterolemia, smoking, diabetes mellitus, atrial fibrillation, coronary heart disease, previous stroke), time, and the interaction between these. The analyses were adjusted for age, education, and sex. There were between 5 and 25% missing data for the variables for PSCI. Results: Mean age was 71.6 years (SD 11.7); 42% were females; and the mean NIHSS score at admittance was 3.8 (SD 4.8). Regardless of vascular risk factors, global z, MoCA, and all the assessed cognitive domains were impaired at 3 and 18 months, with MoCA being the most severely impaired. Atrial fibrillation (AF) was associated with poorer language at 18 months and coronary heart disease (CHD) with poorer MoCA at 18 months (LR = 12.80, p = 0.002, and LR = 8.32, p = 0.004, respectively). Previous stroke was associated with poorer global z and attention at 3 and 18 months (LR = 15.46, p < 0.001, and LR = 16.20, p < 0.001). In patients without AF, attention improved from 3 to 18 months, and in patients without CHD, executive function improved from 3 to 18 months (LR = 10.42, p < 0.001, and LR = 9.33, p = 0.009, respectively). Discussion: Our findings indicate that a focal stroke lesion might be related to pathophysiological processes leading to global cognitive impairment. The poorer prognosis of PSCI in patients with vascular risk factors emphasizes the need for further research on complex vascular risk factor interventions to prevent PSCI.

A high cerebrospinal fluid soluble TREM2 level is associated with slow clinical progression of Alzheimer's disease.

INTRODUCTION: The progression rate of Alzheimer's disease (AD) varies and might be affected by the triggering receptor expressed on myeloid cells (TREM2) activity. We explored if cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), a proxy of microglial activity, is associated with clinical progression rate. METHODS: Patients with clinical AD (N = 231) were followed for up to 3 years after diagnosis. Cognitively healthy controls (N = 42) were followed for 5 years. CSF sTREM2 was analyzed by enzyme-linked immunosorbent assay. Group-based trajectory modeling revealed distinct clinical progression groups. RESULTS: Higher CSF sTREM2 was associated with slow clinical progression. The slow- and medium-progressing groups had higher CSF sTREM2 than the cognitively healthy, who had a similar level to patients with rapid clinical progression. DISCUSSION: CSF sTREM2 levels were associated with clinical progression in AD, regardless of core biomarkers. This could be useful in assessing disease development in relation to patient care and clinical trial recruitment.

Cerebrospinal fluid sTREM2 in Alzheimer's disease: comparisons between clinical presentation and AT classification.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid ß, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.

The Association Between Circulating Inflammatory Markers and the Progression of Alzheimer Disease in Norwegian Memory Clinic Patients With Mild Cognitive Impairment or Dementia.

OBJECTIVE: Neuroinflammation may play an important role in the pathogenesis and progression of Alzheimer disease (AD). The aim of the present study was to detect whether increased inflammatory activity at baseline could predict cognitive and functional decline in patients with amnestic mild cognitive impairment (aMCI) or AD dementia after 2 years. METHODS: Serum samples from 242 memory clinic patients with an aMCI (n=88) or AD dementia (n=154) were analyzed for C-reactive protein and for 14 other inflammatory markers [interleukin (IL)-1ß, interleukin-1 receptor antagonist, IL-6, IL-10, IL-12p40, IL-17a, IL-18, IL-22, IL-33, tumor necrosis factor, cluster of differentiation 40 ligand, interferon-γ, chemokine ligand (CCL) 2, and CCL4] by bead-based multiplex immunoassay. Disease progression was measured by the annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and annual decrease in the score on the Mini-Mental State Examination (MMSE). RESULTS: No association between increased levels of the inflammatory markers and change on the CDR-SB or MMSE score was found, but there was a significant difference in baseline IL-6 and interleukin-1 receptor antagonist levels between aMCI and AD dementia groups. CONCLUSION: Increased levels of inflammatory markers were not associated with faster progression as measured by the annual change on the CDR-SB or MMSE score.

Applicability of the locus of control of behaviour scale for people with dementia.

OBJECTIVE: To investigate the applicability of the Locus of Control of Behaviour scale (LoCB) for people with dementia. METHOD: A sample of 534 participants with dementia (78.4 mean age, 58% female) were included. Assessment included the LoCB, the Montgomery-Aasberg Depression Rating Scale (MADRS), the Mini-Mental Status Examination Norwegian revised (MMSE-NR) and the Instrumental Activities of Daily Living (I-ADL). Completion percentages and internal reliability of LoCB were examined for predefined MMSE-NR groups (0-4, 5-9, 10-14, 15-19, 20-24, 25-27, and 28-30). Factors associated with completion were analysed, and a principal component analysis (PCA) of the LoCB was performed. Sum score and component subscale scores were compared to MADRS and MMSE-NR scores. RESULTS: In total, 234 participants completed the LoCB. Completion percentages ranged from 74% (MMSE-NR 28-30) to 0% (MMSE-NR 0-9). Internal reliability was between 0.80 and 0.72 in groups with MMSE-NR > 9, except in MMSE-NR 20-24 (0.52). Age, MMSE-NR and education were associated with completion. The PCA yielded three components - powerful others, internal, and luck/fate - with explained variance of 41.3%. Participants with MADRS > 7 scored higher on the LoCB sum score, powerful others and internal subscale scores. No difference was found regarding the luck/fate subscale score. MMSE-NR did not affect LoCB scores. CONCLUSION: Older age, less education, and more cognitive impairment decreased the likelihood of completion. However, psychometric test results indicate that those who completed the LoCB understood the questions, even with severe cognitive impairment. We conclude, therefore, that the LoCB is applicable for investigating control orientation among people with dementia.

Cortisol levels among older people with and without depression and dementia.

Cortisol dysregulation has been reported in dementia and depression. Cortisol levels and its associates were investigated among older people living at home and in nursing homes, in a cross-sectional study. A sample of 650 older people, from the community (home and nursing homes) and specialized care (memory clinics and old age psychiatry wards), mean age 76.8 (SD = 10.3) (dementia n = 319, depression, n = 154, dementia plus depression n = 53, and reference group n = 124), was included. Assessment included the Mini Mental State Examination (MMSE), Cornell scale for depression in dementia, activities of daily living scales, and salivary cortisol. Number of drugs was registered. The results showed that the cortisol ratio was highest among patients with dementia and co-morbid depression in comparison to those with either depression or dementia and the reference group. Characteristics significantly associated with cortisol levels were higher MMSE score (in patients with dementia and co-morbid depression), male gender (in people with dementia), and number of medications (in the reference group). We conclude that the cortisol ratio was highest among patients with dementia and co-morbid depression in comparison to those with either depression or dementia and the reference group. The association of cortisol level with MMSE score among patients with dementia and depression could further indicate that increased stress is related to cognitive function.

Setting competencies and standards for a European Leadership Program in Geriatric Medicine: "The European Academy for Medicine of Ageing (EAMA) reloaded".

BACKGROUND: The European Academy for Medicine of Ageing (EAMA) was founded in 1995 as an "Advanced Postgraduate Course in Geriatric Medicine", in order to train future key opinion leaders in geriatric medicine. Recent changes across European Healthcare systems have changed the needs for leadership competences for geriatricians. Therefore, it became mandatory to further develop EAMA's learning objectives catalogue. MATERIALS AND METHODS: Following a comprehensive needs assessment among students and visiting professors of the EAMA, a template containing seven key domains derived from the needs assessment was developed. EAMA professors had the chance to feedback learning objectives aligned with the seven domains. Feedbacks were transcribed into a first draft of a learning objectives catalogue during this meeting. This first draft was reflected with EAMA network members (former EAMA students) and finalized following a second focus group among board members. RESULTS: 24 learning objectives which cover the spectrum of knowledge, skills and attitudes necessary to develop leadership roles in geriatric medicine are included in the new EAMA learning objectives catalogue. Rate of agreement achieved in open ratings was > 90% for all selected items among the board members. CONCLUSIONS: The recently developed learning objectives catalogue of EAMA presented within this publication reflects a clear shift from knowledge-based education and training towards a comprehensive programme design for leadership development.

Association between vascular comorbidity and progression of Alzheimer's disease: a two-year observational study in Norwegian memory clinics.

BACKGROUND: Vascular risk factors increase the risk of Alzheimer's disease (AD), but there is limited evidence on whether comorbid vascular conditions and risk factors have an impact on disease progression. The aim of this study was to examine the association between vascular disease and vascular risk factors and progression of AD. METHODS: In a longitudinal observational study in three Norwegian memory clinics, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. Vascular risk factors and vascular diseases were registered at baseline, and the vascular burden was estimated by the Framingham Stroke Risk Profile (FSRP). Cerebral medical resonance images (MRIs) were assessed for white matter hyperintensities (WMH), lacunar and cortical infarcts. The associations between vascular comorbidity and progression of dementia as measured by annual change in Clinical Dementia Rating Sum of Boxes (CDR-SB) scores were analysed by multiple regression analyses, adjusted for age and sex. RESULTS: Hypertension occurred in 83%, hypercholesterolemia in 53%, diabetes in 9%, 41% were overweight, and 10% were smokers. One third had a history of vascular disease; 16% had heart disease and 15% had experienced a cerebrovascular event. MRI showed lacunar infarcts in 16%, WMH with Fazekas score 2 in 26%, and Fazekas score 3 in 33%. Neither the vascular risk factors and diseases, the FSRP score, nor cerebrovascular disease was associated with disease progression in AD. CONCLUSIONS: Although vascular risk factors and vascular diseases were prevalent, no impact on the progression of AD after 2 years was shown.

Progression of Alzheimer's Disease: A Longitudinal Study in Norwegian Memory Clinics.

BACKGROUND: The course of Alzheimer's disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression. OBJECTIVE: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0-18), the cognitive test Mini-Mental State Examination (MMSE, 0-30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1). METHODS: The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics. RESULTS: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores. CONCLUSION: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate.

MRI-assessed atrophy subtypes in Alzheimer's disease and the cognitive reserve hypothesis.

BACKGROUND/AIMS: MRI assessment of the brain has demonstrated four different patterns of atrophy in patients with Alzheimer's disease dementia (AD): typical AD, limbic-predominant AD, hippocampal-sparing AD, and a subtype with minimal atrophy, previously referred to as no-atrophy AD. The aim of the present study was to identify and describe the differences between these four AD subtypes in a longitudinal memory-clinic study. METHODS: The medial temporal lobes, the frontal regions, and the posterior regions were assessed with MRI visual rating scales to categorize 123 patients with mild AD according to ICD-10 and NINCDS-ADRDA criteria and the clinical dementia rating scale (CDR) into atrophy subtypes. Demographic data, neuropsychological measures, cerebrospinal-fluid biomarkers, and progression rate of dementia at two-year follow-up were compared between the groups. RESULTS: Typical AD was found in 59 patients (48%); 29 (24%) patients had limbic-predominant AD; 19 (15%) had hippocampal-sparing AD; and 16 (13%) belonged to the group with minimal atrophy. No differences were found regarding cognitive test results or progression rates between the different subtypes. Using adjusted logistic regression analysis, we found that the patients in the minimal-atrophy group were less educated, had a lower baseline CDR sum of boxes score, and had higher levels of amyloid ß in the cerebrospinal fluid. CONCLUSION: Previous results concerning the prevalence and the similar phenotypic expressions of the four AD subtypes were confirmed. The main finding was that patients with minimal atrophy as assessed by MRI had less education than the other AD subtypes and that this could support the cognitive reserve hypothesis and, at least in part, explain the lower degree of atrophy in this group. Patients with less formal education might present with clinically typical AD symptoms before they have positive biomarkers of AD and this finding might challenge suggested biomarker-based criteria for AD.

Factors that influence the levels of cerebrospinal fluid biomarkers in memory clinic patients.

BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid ß (Aß), phospho tau (P-tau) and total tau (T-tau) are used increasingly to support a clinical diagnosis of Alzheimer's disease. The diagnostic power of these biomarkers has been reported to vary among different studies' results. The results are poorer when heterogeneous groups of patients have been included compared to studies where patients with Alzheimer's dementia (AD) and healthy controls have been studied. The aim of this study was to examine if age, APOE genotype and sex were associated with the levels of CSF biomarkers among patients referred to a memory clinic. METHODS: We included 257 patients from two memory clinics who had been assessed for dementia, including lumbar puncture. RESULTS: The mean age of the patients was 68.1 (SD: 8.0) years; 50.2% were women and 66.5% were APOE ε4 positive. Of these patients, 80.5% were diagnosed with AD or amnestic MCI. Both APOE ε4 and increasing age were associated with decreasing levels of Aß, but not the levels of the tau proteins. In multiple regression analyses, disease stage, defined as a MMSE ≥25 or <25, influenced factors associated with the CSF biomarkers. Among those with MMSE score ≥ 25, age, APOE ε4 genotype, and MMSE score, in addition to a diagnosis of AD, were associated with Aß level, with an explained variance of 0.43. When using P-tau or T-tau as a dependent variable, the presence of one or two APOE ε4 alleles, and MMSE score influenced the results, in addition to the diagnosis of AD. The explained variance was lower for P-tau (0.26) and for T-tau (0.32). Among those with MMSE <25, these variables explained very little of the variance. There were no gender differences. CONCLUSIONS: We found that factors in addition to a diagnosis of AD, were associated with the levels of CSF biomarkers. Among those with MMSE ≥25, lower levels of Aß were associated with several factors including increasing age. This is not reflected in clinical practice, where age-specific cutoffs exist only for T-tau. In this study, age was not associated with the levels of tau proteins.

Trajectories of depressive symptoms and their relationship to the progression of dementia.

BACKGROUND: The relationship between progression of Alzheimer's disease and depression and its underlying mechanisms has scarcely been studied. METHODS: A sample of 282 outpatients with Alzheimer's disease (AD; 105 with amnestic AD and 177 with Alzheimer's dementia) from Norway were followed up for an average of two years. Assessment included Cornell Scale for Depression in Dementia and Clinical Dementia Rating Scale (CDR) at baseline and follow-up to examine the relationship between AD and depression. Additionally, MRI of the brain, CSF dementia biomarkers and APOE status were assessed at baseline. Progression of dementia was defined as the difference between CDR sum of boxes at follow-up and baseline (CDR-SB change). Trajectories of depressive symptoms on the Cornell Scale were identified using growth mixture modeling. Differences between the trajectories in regard to patients' characteristics were investigated. RESULTS: Three distinct trajectories of depressive symptoms were identified: 231 (82.8%) of the patients had stable low-average scores on the Cornell Scale (Class 1); 11 (3.9%) had high and decreasing scores (Class 2); and 37 (13.3%) had moderate and increasing scores (Class 3). All classes had average probabilities over 80%, and confidence intervals were non-overlapping. The only significant characteristic associated with membership in class 3 was CDR-SB change. LIMITATIONS: Not all patients screened for participation were included in the study, but the included and non-included patients did not differ significantly. Some patients with amnestic MCI might have been misdiagnosed. CONCLUSION: A more rapid progression of dementia was found in a group of patients with increasing depressive symptoms.

Visual Evaluation of Medial Temporal Lobe Atrophy as a Clinical Marker of Conversion from Mild Cognitive Impairment to Dementia and for Predicting Progression in Patients with Mild Cognitive Impairment and Mild Alzheimer's Disease.

BACKGROUND/AIMS: To evaluate whether visual assessment of medial temporal lobe atrophy (vaMTA) can predict 2-year conversion from mild cognitive impairment (MCI) to dementia and progression of MCI and Alzheimer's disease dementia as measured by the Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB). METHODS: vaMTA was performed in 94 patients with MCI according to the Winblad criteria and in 124 patients with AD according to ICD-10 and NINCDS-ADRDA criteria. Demographic data, the Consortium to Establish a Registry for Alzheimer's Disease 10-word delayed recall, APOE ɛ4 status, Cornell Scale for Depression in Dementia, and comorbid hypertension were used as covariates. RESULTS: vaMTA was associated with MCI conversion in an unadjusted model but not in an adjusted model (p = 0.075), where delayed recall and APOE ɛ4 status were significant predictors. With CDR-SB change as the outcome, an interaction between vaMTA and diagnosis was found, but in the adjusted model only delayed recall and age were significant predictors. For vaMTA below 2, the association between vaMTA and CDR-SB change differed between diagnostic groups. Similar results were found based on a trajectory analysis. CONCLUSION: In adjusted models, memory function, APOE ɛ4 status and age were significant predictors of disease progression, not vaMTA. The association between vaMTA and CDR-SB change was different in patients with MCI and Alzheimer's disease dementia.