Background Neuronal and glial cell interaction is essential for synaptic homeostasis and may be affected in Alzheimer’s disease (AD). We measured cerebrospinal fluid (CSF) neuronal and glia markers along the AD continuum, to reveal putative protective or harmful stage-dependent patterns of activation. Methods We included healthy controls ( n = 36) and Aβ-positive (Aβ+) cases (as defined by pathological CSF amyloid beta 1-42 (Aβ42)) with either subjective cognitive decline (SCD, n = 19), mild cognitive impairment (MCI, n = 39), or AD dementia ( n = 27). The following CSF markers were measured: a microglial activation marker—soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of microglial inflammatory reaction—monocyte chemoattractant protein-1 (MCP-1), two astroglial activation markers—chitinase-3-like protein 1 (YKL-40) and clusterin, a neuron-microglia communication marker—fractalkine, and the CSF AD biomarkers (Aβ42, phosphorylated tau (P-tau), total tau (T-tau)). Using ANOVA with planned comparisons, or Kruskal-Wallis tests with Dunn’s pairwise comparisons, CSF levels were compared between clinical groups and between stages of biomarker severity using CSF biomarkers for classification based on amyloid pathology (A), tau pathology (T), and neurodegeneration (N) giving rise to the A/T/N score. Results Compared to healthy controls, sTREM2 was increased in SCD ( p < .01), MCI ( p < .05), and AD dementia cases ( p < .001) and increased in AD dementia compared to MCI cases ( p < .05). MCP-1 was increased in MCI ( p < .05) and AD dementia compared to both healthy controls ( p < .001) and SCD cases ( p < .01). YKL-40 was increased in dementia compared to healthy controls ( p < .01) and MCI ( p < .05). All of the CSF activation markers were increased in subjects with pathological CSF T-tau (A+T−N+ and A+T+N+), compared to subjects without neurodegeneration (A−T−N− and A+T−N−). Discussion Microglial activation as indicated by increased sTREM2 is present already at the preclinical SCD stage; increased MCP-1 and astroglial activation markers (YKL-40 and clusterin) were noted only at the MCI and AD dementia stages, respectively, and in Aβ+ cases (A+) with pathological T-tau (N+). Possible different effects of early and later glial activation need to be explored. Electronic supplementary material The online version of this article (10.1186/s12974-019-1399-2) contains supplementary material, which is available to authorized users.

Abstract. While APOE ε4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of A␤ 42 (pA␤) and APOE ε4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or * Correspondence to: Lene Pålhaugen, P.B. 1000, N-1478 Lørenskog, Norway. Tel.: +47 95832775; E-mail: lene. palhaugen@gmail.com. 98 T. Fladby et al. / Detecting At-Risk AD Casesmild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pA␤ and APOE ε4 frequency compared to NC. Also, NCFD had higher APOE ε4 frequencies without increased fraction of pA␤ compared to NC, and cases recruited from memory clinics had higher fractions of pA␤ and APOE ε4 frequency than self-referred. This study shows that memory clinic referrals are pA␤ enriched, whereas self-referred and NCFD cases more frequently are pA␤ negative but at risk (APOE ε4 positive), suitable for primary intervention.

Background/Objective: In recent years, several slightly younger cohorts have been established in order to study the preclinical and prodromal phases of dementia. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) wordlist memory test (WLT) is widely used in dementia research. However, culturally adapted and demographically adjusted test norms for younger ages are lacking. Method: This paper investigates effects of age, gender and years of education on test performance and offers demographically adjusted norms for the CERAD WLT using a regression-based norming procedure for the age span 40-80 years based on healthy controls (n ¼ 227) from the Norwegian "Dementia Disease Initiation" (DDI) (n ¼ 168) and "Trønderbrain" (n ¼ 59) cohorts. In order to evaluate normative performance, we apply the norms to an independent sample of persons diagnosed with mild cognitive impairment (MCI ¼ 168) and perform multiple regression analyses to evaluate adjustment of pertinent demographics. Results: CERAD WLT norms adjusted for effects of age, gender and educational level are proposed. The norms successfully adjusted for effects of age, gender and education in an independent sample of Norwegians with MCI. Conclusion: Demographically adjusted norms for the CERAD WLT for ages 40-80 years based on a Norwegian sample are proposed. To our knowledge, this is the first normative study of this test to offer demographically adjusted norms for this age span.

IntroductionThe cerebrospinal fluid neurogranin (Ng)/β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) ratio may reflect synaptic affection resulting from reduced beta-amyloid (Aβ) clearance. We hypothesize that increased Ng/BACE1 ratio predicts the earliest cognitive decline in Alzheimer's disease.MethodsWe compared Ng/BACE1 levels between cases with subjective cognitive decline (n = 18) and mild cognitive impairment (n = 20) both with amyloid plaques and healthy controls (APOE-ε4+, n = 16; APOE-ε4-, n = 20). We performed regression analyses between cerebrospinal fluid levels, baseline hippocampal and amygdala volumes, and pertinent cognitive measures (memory, attention, Mini Mental State Examination [MMSE]) at baseline and after 2 years.ResultsNg/BACE1 levels were elevated in both subjective cognitive decline and mild cognitive impairment compared to healthy controls. Higher Ng/BACE1 ratio was associated with lower hippocampal and amygdala volumes; lower baseline memory functions, attention, and MMSE; and significant decline in MMSE and memory function at 2-year follow-up.DiscussionHigh Ng/BACE1 ratio predicts cognitive decline also in preclinical cases with amyloid plaques.

Objective: The trail making test (TMT) is one of the most widely used neuropsychological tests. TMT-A provides measures of visual scanning/visuomotor speed and TMT-B involves additional demands on executive functions. Derived scores TMT B-A and TMT B/A enhance measures of executive functioning. However, simple B-A subtraction may lead to false estimates of executive dysfunction in clinical samples. Norms for TMT have been published in several countries but are currently lacking for Scandinavia. Methods: A total of 292 healthy controls between age 41 and 84 years were included from the Norwegian "Dementia Disease Initiation" (DDI) study (n ¼ 170) and the Gothenburg Mild Cognitive Impairment (MCI) study (n ¼ 122). We used a regression-based procedure to develop demographically adjusted norms for basic (TMT-A and TMT-B) and derived measures (TMT B-A and B/A). We also propose a regression-based alternative to the TMT B-A measure named "TMT-b". The proposed norms were compared to norms from Heaton et al. and Tombaugh. Results: Due to differences in the estimated normative effects of demographics on performance, the proposed norms for TMT were better suited in the Scandinavian sample compared with published non-Scandinavian norms. The proposed TMT-b measure was highly correlated to TMT B-A (r ¼ 0.969, p < 0.001). Conclusion: We here propose demographically adjusted norms for the TMT for ages 41 through 84 years based on a Scandinavian ARTICLE HISTORY

Background:Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning.Objective:We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants.Methods:We included 431 participants 40–80 years old. Participants were classified as controls (n = 132) or symptom group (n = 299). The symptom group comprised of subjective cognitive decline (SCD, n = 163) and mild cognitive impairment (MCI, n = 136). We compared cognitive performance and demographics in memory clinic-referrals (n = 86) to self-referred participants responding to advertisements and news bulletins (n = 179). Participants recruited by other means were excluded from analysis (n = 34).Results:At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group.Conclusion:Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type.

Background: In the care of persons with cognitive problems, it is important to use a valid mild cognitive impairment (MCI) criterion that discriminates well between normal and pathological aging. Objective: To find the brief neuropsychological screening criterion that best correlates with cerebrospinal fluid (CSF) biomarkers for cognitive decline and dementia in persons seeking help for cognitive problems. Methods: 452 consecutively recruited patients (age 40–80 years) from memory-clinics in the Norwegian national multicentre longitudinal study Dementia Disease Initiation were included. CSF data as well as full data from brief neuropsychological screening were available for all patients. Results: Amnestic MCI, including at least one memory test below T-score 40, outperformed the conventional US National Institute on Aging-Alzheimer’s Association (NIA-AA) MCI criterion. Only amnestic MCI was significantly associated with biomarker pattern of NIA-AA stage 2 (low CSF A β 42 concentrations and elevated tau) in multivariate regression analysis. Conclusions: The finding that amnestic MCI based on brief neuropsychological assessment is significantly associated with CSF biomarkers for cognitive decline and Alzheimer’s disease is in accordance with longitudinal studies that find memory impairment; both in itself and especially in combination with other cognitive deficit to constitute a risk factor for subsequent cognitive decline and dementia. The prevalence of pathological biomarkers for Alzheimer’s disease is common in the elderly and the clinical significance of present findings depend on longitudinal validation.

Background: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer's disease (AD). However, patients reporting SCD to their general practitioner are not always referred to a memory clinic. Objective: To investigate whether prior history of medical help-seeking is associated with AD biomarker abnormality, worse cognitive performance, and/or depressive symptoms in SCD. Methods: We compared levels of cerebrospinal fluid (CSF) A␤ 1-42 , cognitive performance, and depressive symptoms (15item Geriatric Depression Scale, GDS-15) between healthy controls (n = 88), SCD with a history of medical help seeking (SCD-HS, n = 67), and SCD non help-seekers (SCD-NHS, n = 44). Cases with evidence of amyloid plaques (CSF A␤ 1-42 ≤708 ng/l) and symptoms of depression (GDS-15≥6) were determined in both SCD groups. Results: The SCD-HS group had lower CSF A␤ 1-42 (p < 0.01), lower word list learning and memory recall (p < 0.0001), and an increased level of depressive symptoms (p < 0.0001) compared to controls and SCD-NHS cases. The SCD-HS group had more cases with symptoms of depression (n = 12, 18%) and amyloid plaques (n = 18, 27%) compared to SCD-NHS (n = 1, 2% and n = 7, 16%, respectively). None of the SCD-HS cases and only one SCD-NHS case had concurrent symptoms of depression and amyloid plaques. The SCD-HS cases showed equal word list learning and memory performance regardless of amyloid status or symptoms of depression. Conclusion: Medical help-seeking in SCD is associated with an increased risk of AD pathology or symptoms of depression. However, subtle memory deficits are seen in SCD help-seekers, also without amyloid plaques or symptoms of depression.