The Associations Between Serum Insulin-like Growth Factor-I, Brain White Matter Volumes, and Cognition in Mild Cognitive Impairment and Alzheimer's Disease.

Background: Insulin-like growth factor-I (IGF-I) regulates myelin, but little is known whether IGF-I associates with white matter functions in subjective and objective mild cognitive impairment (SCI/MCI) or Alzheimer's disease (AD). Objective: To explore whether serum IGF-I is associated with magnetic resonance imaging - estimated brain white matter volumes or cognitive functions. Methods: In a prospective study of SCI/MCI (n = 106) and AD (n = 59), we evaluated the volumes of the total white matter, corpus callosum (CC), and white matter hyperintensities (WMHs) as well as Mini-Mental State Examination (MMSE), Trail Making Test A and B (TMT-A/B), and Stroop tests I-III at baseline, and after 2 years. Results: IGF-I was comparable in SCI/MCI and AD (113 versus 118 ng/mL, p = 0.44). In SCI/MCI patients, the correlations between higher baseline IGF-I and greater baseline and 2-year volumes of the total white matter and total CC lost statistical significance after adjustment for intracranial volume and other covariates. However, after adjustment for covariates, higher baseline IGF-I correlated with better baseline scores of MMSE and Stroop test II in SCI/MCI and with better baseline results of TMT-B and Stroop test I in AD. IGF-I did not correlate with WMH volumes or changes in any of the variables. Conclusions: Both in SCI/MCI and AD, higher IGF-I was associated with better attention/executive functions at baseline after adjustment for covariates. Furthermore, the baseline associations between IGF-I and neuropsychological test results in AD may argue against significant IGF-I resistance in the AD brain.

Low Serum Insulin-like Growth Factor-I Is Associated with Decline in Hippocampal Volume in Stable Mild Cognitive Impairment but not in Alzheimer's Disease.

BACKGROUND: Serum insulin-like growth factor-I (IGF-I) has shown some association with hippocampal volume in healthy subjects, but this relation has not been investigated in stable mild cognitive impairment (sMCI) or Alzheimer's disease (AD). OBJECTIVE: At a single memory clinic, we investigated whether serum IGF-I was associated with baseline magnetic resonance imaging (MRI)-estimated brain volumes and longitudinal alterations, defined as annualized changes, up to 6 years of follow-up. METHODS: A prospective study of patients with sMCI (n = 110) and AD (n = 60). Brain regions included the hippocampus and amygdala as well as the temporal, parietal, frontal, and occipital lobes, respectively. RESULTS: Serum IGF-I was statistically similar in sMCI and AD patients (112 versus 123 ng/mL, p = 0.31). In sMCI, serum IGF-I correlated positively with all baseline MRI variables except for the occipital lobe, and there was also a positive correlation between serum IGF-I and the annualized change in hippocampal volume (rs = 0.32, p = 0.02). Furthermore, sMCI patients having serum IGF-I above the median had lower annual loss of hippocampal volume than those with IGF-I below the median (p = 0.02). In contrast, in AD patients, IGF-I did not associate with baseline levels or annualized changes in brain volumes. CONCLUSION: In sMCI patients, our results suggest that IGF-I exerted neuroprotective effects on the brain, thereby maintaining hippocampal volume. In AD, serum IGF-I did not associate with brain volumes, indicating that IGF-I could not induce neuroprotection in this disease. This supports the notion of IGF-I resistance in AD.

Higher thyroid function is associated with accelerated hippocampal volume loss in Alzheimer's disease.

BACKGROUND: In epidemiological studies, higher thyroid hormone (TH) levels have been associated with lower brain volume and increased risk of Alzheimer's disease (AD) in elderly individuals. However, the relationships between serum THs and hippocampal atrophy rates have previously not been investigated. METHODS: A prospective study of patients with AD (n = 55), stable mild cognitive impairment (sMCI; n = 84) and healthy controls (n = 29) recruited at a single memory clinic. We investigated whether serum THs were associated with magnetic resonance imaging (MRI)-estimated hippocampal volumes at baseline and with longitudinal alterations, defined as annualized percent changes. RESULTS: Serum levels of free triiodothyronine (FT3) and FT3/free thyroxine (FT4) ratio were reduced in AD and sMCI patients compared with the controls (p < 0.05). Hierarchical linear regression analyses showed that higher serum FT3/FT4 ratio was associated with greater baseline hippocampal volume in all study groups. Only in AD patients, higher serum FT4 was associated with lower baseline volume of the left hippocampus. Finally, exclusively in the AD group, higher serum levels of FT3 and FT3/FT4 ratio, and lower serum TSH levels, were associated with greater annual hippocampal volume loss. CONCLUSIONS: In all study groups, FT3/FT4 ratio was related to baseline hippocampal volume. However, only in AD patients, higher levels of THs were associated with greater annual loss of hippocampal volume, suggesting that excessive TH levels exert a deleterious effect on the hippocampus in the presence of existing AD neuropathology.

Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-ß in patients with subcortical small-vessel disease.

Introduction: Subcortical small-vessel disease (SSVD) is the most common vascular cognitive disorder. However, because no disease-specific cerebrospinal fluid (CSF) biomarkers are available for SSVD, our aim was to identify such markers. Methods: We included 170 healthy controls and patients from the Gothenburg Mild Cognitive Impairment (MCI) study clinically diagnosed with SSVD dementia, Alzheimer's disease (AD), or mixed AD/SSVD. We quantified CSF levels of amyloid-ß (Aß)x-38, Aßx-40, Aßx-42, as well as soluble amyloid precursor protein (sAPP)-α and sAPP-ß. Results: sAPP-ß was lower in SSVD patients than in AD patients and controls. Receiver-operating characteristic (ROC) analyses showed that sAPP-ß moderately separated SSVD from AD and controls. Moreover, the CSF/serum albumin ratio was elevated exclusively in SSVD and could moderately separate SSVD from the other groups in ROC analyses. Discussion: SSVD has a biomarker profile that differs from that of AD and controls, and to some extent also from mixed AD/SSVD, suggesting that signs of blood-brain barrier (BBB) dysfunction and sAPP-ß could be additional tools to diagnose SSVD. Highlights: Patients with subcortical small-vessel disease (SSVD) exhibited reduced levels of sAPP-ß and disturbances of the blood-brain barrier (BBB).This biochemical pattern is different from that of Alzheimer's disease (AD) and to some degree from that of mixed AD/SSVD.Our findings are speaking in favor of the concept that SSVD is a distinct vascular cognitive disorder (VCD) form.

Neuropsychological Test Performance Among Native and Non-Native Swedes: Second Language Effects.

OBJECTIVE: We aimed to study second language effects on neuropsychological (NP) test performance. METHOD: We administered an NP test battery in Swedish to 322 healthy community dwelling participants, recruited through the Gothenburg Pilot phase of the Swedish CArdioPulmonary BioImage Study (SCAPIS Pilot). All participants were conversationally fluent Swedish speakers (237 native, 85 non-native, mean age 61.1 years). We compared the NP scores of native and non-native participants. We also investigated the influence of (a) age of arrival to Sweden, (b) majority language family of the birth country, and (c) proficiency in Swedish as assessed with a 30 item Boston naming test (BNT). RESULTS: Native speakers obtained better results on all NP tasks with a verbal component, whereas no significant differences were seen on completely nonverbal tasks (Rey complex figure). For non-native speakers, lower age at arrival to Sweden, arrival from a country where Swedish was also spoken, or arrival from a country with a majority language closer to Swedish, were all linked to better NP scores. Dichotomizing by BNT showed that normally-to-highly proficient non-native speakers obtained better scores. CONCLUSIONS: Second language effects may contribute to misclassification of non-native speakers. Assumptions of fluency based on short conversations may be misleading. A proficiency assessment with BNT may improve NP score interpretation among non-native speakers.

Validity and reliability of the medial temporal lobe atrophy scale in a memory clinic population.

BACKGROUND: Visual rating of medial temporal lobe atrophy (MTA) is often performed in conjunction with dementia workup. Most prior studies involved patients with known or probable Alzheimer's disease (AD). This study investigated the validity and reliability of MTA in a memory clinic population. METHODS: MTA was rated in 752 MRI examinations, of which 105 were performed in cognitively healthy participants (CH), 184 in participants with subjective cognitive impairment, 249 in subjects with mild cognitive impairment, and 214 in patients with dementia, including AD, subcortical vascular dementia and mixed dementia. Hippocampal volumes, measured manually or using FreeSurfer, were available in the majority of cases. Intra- and interrater reliability was tested using Cohen's weighted kappa. Correlation between MTA and quantitative hippocampal measurements was ascertained with Spearman's rank correlation coefficient. Moreover, diagnostic ability of MTA was assessed with receiver operating characteristic (ROC) analysis and suitable, age-dependent MTA thresholds were determined. RESULTS: Rater agreement was moderate to substantial. MTA correlation with quantitative volumetric methods ranged from -0.20 (p< 0.05) to -0.68 (p < 0.001) depending on the quantitative method used. Both MTA and FreeSurfer are able to distinguish dementia subgroups from CH. Suggested age-dependent MTA thresholds are 1 for the age group below 75 years and 1.5 for the age group 75 years and older. CONCLUSIONS: MTA can be considered a valid marker of medial temporal lobe atrophy and may thus be valuable in the assessment of patients with cognitive impairment, even in a heterogeneous patient population.

Cerebrospinal Fluid Sulfatide Levels Lack Diagnostic Utility in the Subcortical Small Vessel Type of Dementia.

BACKGROUND: Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs. OBJECTIVE: To study the diagnostic utility of CSF ST levels in SSVD. METHODS: This was a mono-center, cross-sectional study of SSVD (n = 16), Alzheimer's disease (n = 40), mixed dementia (n = 27), and healthy controls (n = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS: CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r = 0.64, p < 0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r = 0.30, p < 0.05), but it did not correlate with CSF NFL level. CONCLUSION: Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.

Self-reported cognitive impairment and daily life functioning 7-12 years after seeking care for stress-related exhaustion.

The overall aim of this study was to investigate self-reported cognitive difficulties, daily life activities, and health/sleep factors in former patients with exhaustion disorder (ED) who still fulfill the clinical criteria for exhaustion 7-12 years after seeking care. The Sahlgrenska Self-reported Cognitive Impairment Questionnaire (SASCI-Q) was used to measure cognitive difficulties, daily life activities, and health/sleep factors. Three groups were compared: previous patients still judged to be clinically exhausted seven years or more after seeking care (n = 51); previous patients considered clinically recovered (n = 98); and healthy controls (n = 50). Patients who still fulfilled the diagnostic criteria for ED reported widespread problems related to cognition, fatigue, and daily life functioning compared to the clinically recovered group. Furthermore, despite no longer fulfilling the clinical criteria, the recovered patients still reported more problems related to cognitive functioning and fatigue compared to healthy controls. Thus, this group appeared intermediary between the non-recovered group and healthy controls regarding self-reported cognitive functioning. To conclude, ED may have considerable negative long-term effects, and it is possible that some of these residual symptoms, particularly the cognitive problems and persistent fatigue, are permanent in some patients. Preventive measures should be the primary focus for all stakeholders, since the consequences of stress-related mental health problems seem to be extensive and long-lasting.

Altered thyroid hormone profile in patients with Alzheimer's disease.

BACKGROUND: Epidemiological studies have linked higher levels of thyroid hormones (THs) to increased risk of Alzheimer's disease (AD), whereas in advanced AD, THs have been unchanged or even decreased. In early AD dementia, little is known whether THs are related to AD neuropathology or brain morphology. METHODS: This was a cross-sectional study of 36 euthyroid AD patients and 34 healthy controls recruited at a single memory clinic. Levels of THs were measured in serum and cerebrospinal fluid (CSF). In addition, we determined AD biomarkers (amyloid-ß1-42, total tau and phosphorylated tau) in CSF and hippocampal and amygdalar volumes using magnetic resonance imaging. RESULTS: Serum free thyroxine (FT4) levels were elevated, whereas serum free triiodothyronine (FT3)/FT4 and total T3 (TT3)/total T4 (TT4) ratios were decreased, in AD patients compared to controls. In addition, serum TT4 was marginally higher in AD (p = 0.05 vs. the controls). Other TH levels in serum as well as CSF concentrations of THs were similar in both groups, and there were no correlations between THs and CSF AD biomarkers. However, serum FT3 correlated positively with left amygdalar volume in AD patients and serum TT3 correlated positively with left and right hippocampal volume in controls. CONCLUSIONS: Thyroid hormones were moderately altered in mild AD dementia with increased serum FT4, and in addition, the reduced T3/T4 ratios may suggest decreased peripheral conversion of T4 to T3. Furthermore, serum T3 levels were related to brain structures involved in AD development.

Evaluation of a screening program for iron overload and HFE mutations in 50,493 blood donors.

Early detection of individuals with hereditary hemochromatosis (HH) is important to manage iron levels and prevent future organ damage. Although the HFE mutations that cause most cases of HH have been identified, their geographic distribution is highly variable, and their contribution to iron overload is not fully understood. All new registered blood donors at the Sahlgrenska University hospital between 1998 and 2015 were included in the study. Donors with signs of iron overload at baseline and subsequent follow-up testing were recommended genotyping of the HFE gene. Of the 50,493 donors that were included in the study, 950 (1.9%) had signs of iron overload on both test occasions. Of the 840 donors with iron overload that performed HFE genotyping, 117 were homozygous for C282Y, and 97 were compound heterozygotes. The prevalence of C282Y homozygosity was 0.23%. Iron overload screening effectively detects individuals at risk of carrying the C282Y mutation of the HFE gene and enables early treatment to prevent HH complications.

Characteristic Biomarker and Cognitive Profile in Incipient Mixed Dementia.

BACKGROUND: Research has shown that mixed dementia is more common than previously believed but little is known of its early stages. OBJECTIVE: To examine if incipient mixed dementia can be differentiated from incipient Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SVD) using neuropsychological tests, cerebrospinal fluid (CSF) markers, and magnetic resonance imaging markers. METHODS: We included 493 patients and controls from the Gothenburg MCI study and used the dementia groups for marker selection (CSF total-tau (T-tau), phospho-tau (P-tau), and amyloid-ß42 (Aß42), 11 neuropsychological tests, and 92 regional brain volumes) and to obtain cut-off values which were then applied to the MCI groups. RESULTS: Incipient mixed dementia was best differentiated from incipient AD by the Word fluency F-A-S test and the Trail making test A. CSF T-tau, P-tau, and Aß42 differentiated incipient mixed dementia from incipient SVD. CONCLUSION: Incipient mixed dementia is characterized by an AD-like biomarker profile and an SVD-like cognitive profile. Incipient mixed dementia can be separated from incipient AD and incipient SVD using CSF markers and cognitive testing.

Latent Cognitive Profiles Differ Between Incipient Alzheimer's Disease and Dementia with Subcortical Vascular Lesions in a Memory Clinic Population.

BACKGROUND: It is unclear if latent cognitive profiles can distinguish between dementia with subcortical vascular lesions and Alzheimer's disease (AD) at the incipient stage, and if they differ in performance from the Petersen subtypes. OBJECTIVE: To identify latent cognitive profiles in a naturalistic population of patients from a memory clinic sample, and investigate the derived classes not only in terms of conversion to AD, but also in terms of conversion to dementia with subcortical vascular lesions. Another objective was to compare the derived classes to the Petersen subtypes. METHODS: We performed a latent profile analysis (LPA) on standardized neuropsychological test scores from 476 memory clinic patients (age 64±8) without dementia, and analyzed progression to dementia after 2 years. RESULTS: The LPA resulted in two classes with impaired cognition (Amnestic and Slow/Dysexecutive) and two classes with normal cognition (Normal-Low and Normal-High cognition). Belonging to the Amnestic class predicted progression to all-cause dementia and to AD; belonging to the Slow/Dysexecutive class predicted progression to all-cause dementia, AD, and dementia with subcortical vascular lesions. Of the Petersen MCI subtypes, only amnestic multi-domain MCI predicted progression to all-cause dementia, AD, and dementia with subcortical vascular lesions. CONCLUSION: Latent cognitive profiles separated between AD and dementia with subcortical vascular lesions, while the Petersen subtypes did not. However, similar to the Petersen subtypes, LPA classes work better for ruling out progression to dementia than for case finding.

MRI predictors of amyloid pathology: results from the EMIF-AD Multimodal Biomarker Discovery study.

BACKGROUND: With the shift of research focus towards the pre-dementia stage of Alzheimer's disease (AD), there is an urgent need for reliable, non-invasive biomarkers to predict amyloid pathology. The aim of this study was to assess whether easily obtainable measures from structural MRI, combined with demographic data, cognitive data and apolipoprotein E (APOE) ε4 genotype, can be used to predict amyloid pathology using machine-learning classification. METHODS: We examined 810 subjects with structural MRI data and amyloid markers from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, including subjects with normal cognition (CN, n = 337, age 66.5 ± 7.2, 50% female, 27% amyloid positive), mild cognitive impairment (MCI, n = 375, age 69.1 ± 7.5, 53% female, 63% amyloid positive) and AD dementia (n = 98, age 67.0 ± 7.7, 48% female, 97% amyloid positive). Structural MRI scans were visually assessed and Freesurfer was used to obtain subcortical volumes, cortical thickness and surface area measures. We first assessed univariate associations between MRI measures and amyloid pathology using mixed models. Next, we developed and tested an automated classifier using demographic, cognitive, MRI and APOE ε4 information to predict amyloid pathology. A support vector machine (SVM) with nested 10-fold cross-validation was applied to identify a set of markers best discriminating between amyloid positive and amyloid negative subjects. RESULTS: In univariate associations, amyloid pathology was associated with lower subcortical volumes and thinner cortex in AD-signature regions in CN and MCI. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.81 ± 0.07 in MCI and an AUC of 0.74 ± 0.08 in CN. In CN, selected features for the classifier included APOE ε4, age, memory scores and several MRI measures such as hippocampus, amygdala and accumbens volumes and cortical thickness in temporal and parahippocampal regions. In MCI, the classifier including demographic and APOE ε4 information did not improve after additionally adding imaging measures. CONCLUSIONS: Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE ε4 data can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.

Similar pattern of atrophy in early- and late-onset Alzheimer's disease.

INTRODUCTION: Previous research on structural changes in early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) have reported inconsistent findings. METHODS: In the present substudy of the Gothenburg MCI study, 1.5 T scans were used to estimate lobar and hippocampal volumes using FreeSurfer. Study participants (N = 145) included 63 patients with AD, (24 patients with EOAD [aged ≤65 years], 39 patients with LOAD [aged >65 years]), 25 healthy controls aged ≤65 years, and 57 healthy controls aged >65 years. RESULTS: Hippocampal atrophy is the most prominent feature of both EOAD and LOAD compared with controls. Direct comparison between EOAD and LOAD showed that the differences between the groups did not remain after correcting for age. DISCUSSION: Structurally, EOAD and LOAD does not seem to be different nosological entities. The difference in brain volumes between the groups compared with controls is likely due to age-related atrophy.

Delineation of two intracranial areas and the perpendicular intracranial width is sufficient for intracranial volume estimation.

OBJECTIVES: The aim of the present study is to determine if the delineation of one or two optimally chosen intracranial areas (ICA) is enough to achieve adequate estimates of intracranial volume (ICV) in magnetic resonance imaging. METHODS: The correlations of 62 fully delineated ICVs with four types of ICV estimates were calculated. The estimate types were: (1) a single midsagittal ICA, (2) single ICA multiplied by the intracranial width perpendicular to the ICA, (3) sum of two ICAs multiplied by the perpendicular intracranial width and (4) shape-preserving piecewise cubic interpolation using two ICAs. For methods 2-4, the fully delineated ICVs were randomly separated into an evaluation and a validation set of equal size. Method 1 was validated against all of the fully delineated ICVs. RESULTS: Estimates from method 1 had a Pearson correlation of 0.904 with fully delineated ICV. For method 2, the correlation was 0.986 when delineating the sagittal ICA at 31% of the sagittal intracranial width. For methods 3 and 4, the correlations were both 0.997 when delineating the sagittal ICAs at 17.5 and 64% and at 12 and 64% respectively. CONCLUSIONS: Delineation of two specific intracranial areas is sufficient for intracranial volume estimation. MAIN MESSAGES: • Delineation of two specific intracranial areas is sufficient for intracranial volume estimation. • The estimates had a Pearson correlation of 0.997 with intracranial volume. • The estimation should take no more than 5 min.

Longitudinal evaluation of criteria for subjective cognitive decline and preclinical Alzheimer's disease in a memory clinic sample.

INTRODUCTION: Subjective cognitive decline (SCD) and biomarker-based "at-risk" concepts such as "preclinical" Alzheimer's disease (AD) have been developed to predict AD dementia before objective cognitive impairment is detectable. We longitudinally evaluated cognitive outcome when using these classifications. METHODS: Memory clinic patients (n = 235) were classified as SCD (n = 122): subtle cognitive decline (n = 36) and mild cognitive impairment (n = 77) and subsequently subclassified into SCDplus and National Institute on Aging-Alzheimer's Association (NIA-AA) stages 0 to 3. Mean (standard deviation) follow-up time was 48 (35) months. Proportion declining cognitively and prognostic accuracy for cognitive decline was calculated for all classifications. RESULTS: Among SCDplus patients, 43% to 48% declined cognitively. Among NIA-AA stage 1 to 3 patients, 50% to 100% declined cognitively. The highest positive likelihood ratios (+LRs) for subsequent cognitive decline (+LR 6.3), dementia (+LR 3.4), and AD dementia (+LR 6.5) were found for NIA-AA stage 2. DISCUSSION: In a memory clinic setting, NIA-AA stage 2 seems to be the most successful classification in predicting objective cognitive decline, dementia, and AD dementia.

Subjective Cognitive Impairment Is a Predominantly Benign Condition in Memory Clinic Patients Followed for 6 Years: The Gothenburg-Oslo MCI Study.

BACKGROUND/AIMS: In the quest for prevention or treatment, there is a need to find early markers for preclinical dementia. This study observed memory clinic patients with subjective cognitive impairment (SCI) and normal cognitive function at baseline. The primary aim was to address SCI as a potential risk factor for cognitive decline. The secondary aim was to address a potential relation between (1) baseline cerebrospinal fluid biomarkers and (2) a decline in memory performance over the first 2 years of follow-up, with a possible cognitive decline after 6 years. METHODS: Eighty-one patients (mean age 61 years) were recruited from university memory clinics and followed up for 6 years. RESULTS: Eighty-six percent of the cohort remained cognitively stable or improved, 9% developed mild cognitive impairment, and only 5% (n = 4) developed dementia. Regression analysis revealed that low levels of Aß42 at baseline and memory decline during the first 2 years predicted dementia. When combined, these variables were associated with a 50% risk of developing dementia. CONCLUSIONS: Cognitive stability for 86% of the cohort suggests that SCI is predominantly a benign condition with regard to neuropathology. The low number of individuals who developed dementia limits the generalizability of the results and discussion of progression factors.

Alzheimer's disease--subcortical vascular disease spectrum in a hospital-based setting: Overview of results from the Gothenburg MCI and dementia studies.

The ability to discriminate between Alzheimer's disease (AD), subcortical vascular disease, and other cognitive disorders is crucial for diagnostic purposes and clinical trial outcomes. Patients with primarily subcortical vascular disease are unlikely to benefit from treatments targeting the AD pathogenic mechanisms and vice versa. The Gothenburg mild cognitive impairment (MCI) and dementia studies are prospective, observational, single-center cohort studies suitable for both cross-sectional and longitudinal analysis that outline the cognitive profiles and biomarker characteristics of patients with AD, subcortical vascular disease, and other cognitive disorders. The studies, the first of which started in 1987, comprise inpatients with manifest dementia and patients seeking care for cognitive disorders at an outpatient memory clinic. This article gives an overview of the major published papers (neuropsychological, imaging/physiology, and neurochemical) of the studies including the ongoing Gothenburg MCI study. The main findings suggest that subcortical vascular disease with or without dementia exhibit a characteristic neuropsychological pattern of mental slowness and executive dysfunction and neurochemical deviations typical of white matter changes and disturbed blood-brain barrier function. Our findings may contribute to better healthcare for this underrecognized group of patients. The Gothenburg MCI study has also published papers on multimodal prediction of dementia, and cognitive reserve.

The Gothenburg MCI study: Design and distribution of Alzheimer's disease and subcortical vascular disease diagnoses from baseline to 6-year follow-up.

There is a need for increased nosological knowledge to enable rational trials in Alzheimer's disease (AD) and related disorders. The ongoing Gothenburg mild cognitive impairment (MCI) study is an attempt to conduct longitudinal in-depth phenotyping of patients with different forms and degrees of cognitive impairment using neuropsychological, neuroimaging, and neurochemical tools. Particular attention is paid to the interplay between AD and subcortical vascular disease, the latter representing a disease entity that may cause or contribute to cognitive impairment with an effect size that may be comparable to AD. Of 664 patients enrolled between 1999 and 2013, 195 were diagnosed with subjective cognitive impairment (SCI), 274 with mild cognitive impairment (MCI), and 195 with dementia, at baseline. Of the 195 (29%) patients with dementia at baseline, 81 (42%) had AD, 27 (14%) SVD, 41 (21%) mixed type dementia (=AD + SVD = MixD), and 46 (23%) other etiologies. After 6 years, 292 SCI/MCI patients were eligible for follow-up. Of these 292, 69 (24%) had converted to dementia (29 (42%) AD, 16 (23%) SVD, 15 (22%) MixD, 9 (13%) other etiologies). The study has shown that it is possible to identify not only AD but also incipient and manifest MixD/SVD in a memory clinic setting. These conditions should be taken into account in clinical trials.

T-Tau is Associated with Objective Memory Decline Over Two Years in Persons Seeking Help for Subjective Cognitive Decline: A Report from the Gothenburg-Oslo MCI Study.

BACKGROUND: There is a need to find very early markers for pre-clinical Alzheimer's disease as interventions early in the disease process are thought to be most effective. OBJECTIVE: The present study aimed to address the potential relation between cerebrospinal fluid (CSF) biomarkers and reduced cognitive function in a relatively young cohort of memory clinic patients with subjective cognitive decline. METHODS: 122 patients (mean age 63 years) with subjective cognitive decline were recruited from two university memory clinics and followed for two years. RESULTS: The main finding was that the subgroup with objective memory decline during the study period had significantly higher T-tau at baseline than the group with improved memory. Baseline CSF variables showed a trend toward more pathological values in the patients with memory decline compared to those who improved or remained stable. The baseline memory score of those who declined was significantly better than the baseline score of those who improved over two years. The general trend for the whole group was improved memory and executive test scores. There were no differences in cognitive scores based on CSF quartiles at baseline, nor were there differences in cognitive outcome for patients with early amnestic mild cognitive impairment versus average cognitive function at baseline. CONCLUSIONS: The main finding that T-tau rather than amyloid-ß was associated with memory decline do not support the prevailing opinion about the chain of events assumed to take place in Alzheimer's disease. In addition, memory decline was not associated with poor baseline memory score. Thus, a memory cut-off indicating low baseline memory would not would have identified the declining group.