Tormod Fladby

Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease.

We conducted a search for rare, functional variants altering susceptibility to Alzheimers disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimers disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10−13) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10−15).

EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia

The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimers disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinsons disease dementia, Huntingtons disease, prion diseases, normal‐pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer‐reviewed evidence‐based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance.

Mild cognitive impairment in Parkinson's disease.

Prospective studies conducted during the last decade have shown that the majority of patients with Parkinson’s disease (PD) develop dementia. In addition, using a variety of definitions and methods, more recent research suggests that approximately a quarter of PD patients without dementia have mild cognitive impairment (PD-MCI). Furthermore, several studies have shown that approximately 20% have MCI even at time of diagnosis of PD. The typical cognitive deficits include visuospatial, attentional, and executive deficits, but memory deficits have also been shown. The etiology of PD-MCI is not known, but it is likely that mechanisms known to contribute to dementia in PD (ie, limbic and cortical Lewy bodies, amyloid plaques, and cholinergic deficits) play a role, in addition to dysfunction of dopaminergic frontostriatal circuits. PD-MCI predicts a shorter time to dementia, and preliminary evidence suggests that this is particularly true for posterior cognitive deficits. There are currently no systematic clinical trials in PD-MCI.

Multimodal imaging in mild cognitive impairment: Metabolism, morphometry and diffusion of the temporal-parietal memory network.

This study compared sensitivity of FDG-PET, MR morphometry, and diffusion tensor imaging (DTI) derived fractional anisotropy (FA) measures to diagnosis and memory function in mild cognitive impairment (MCI). Patients (n=44) and normal controls (NC, n=22) underwent FDG-PET and MRI scanning yielding measures of metabolism, morphometry and FA in nine temporal and parietal areas affected by Alzheimers disease and involved in the episodic memory network. Patients also underwent memory testing (RAVLT). Logistic regression analysis yielded 100% diagnostic accuracy when all methods and ROIs were combined, but none of the variables then served as unique predictors. Within separate ROIs, diagnostic accuracy for the methods combined ranged from 65.6% (parahippocampal gyrus) to 73.4 (inferior parietal cortex). Morphometry predicted diagnostic group for most ROIs. PET and FA did not uniquely predict group, but a trend was seen for the precuneus metabolism. For the MCI group, stepwise regression analyses predicting memory scores were performed with the same methods and ROIs. Hippocampal volume and FA of the retrosplenial WM predicted learning, and hippocampal metabolism and parahippocampal cortical thickness predicted 5 minute recall. No variable predicted 30 minute recall independently of learning. In conclusion, higher diagnostic accuracy was achieved when multiple methods and ROIs were combined, but morphometry showed superior diagnostic sensitivity. Metabolism, morphometry and FA all uniquely explained memory performance, making a multi-modal approach superior. Memory variation in MCI is likely related to conversion risk, and the results indicate potential for improved predictive power by the use of multimodal imaging.

A Practical Guide to Immunoassay Method Validation

Biochemical markers have a central position in the diagnosis and management of patients in clinical medicine, and also in clinical research and drug development, also for brain disorders, such as Alzheimer’s disease. The enzyme-linked immunosorbent assay (ELISA) is frequently used for measurement of low-abundance biomarkers. However, the quality of ELISA methods varies, which may introduce both systematic and random errors. This urges the need for more rigorous control of assay performance, regardless of its use in a research setting, in clinical routine, or drug development. The aim of a method validation is to present objective evidence that a method fulfills the requirements for its intended use. Although much has been published on which parameters to investigate in a method validation, less is available on a detailed level on how to perform the corresponding experiments. To remedy this, standard operating procedures (SOPs) with step-by-step instructions for a number of different validation parameters is included in the present work together with a validation report template, which allow for a well-ordered presentation of the results. Even though the SOPs were developed with the intended use for immunochemical methods and to be used for multicenter evaluations, most of them are generic and can be used for other technologies as well.

Diffusion Tensor Imaging Surpasses Cerebrospinal Fluid as Predictor of Cognitive Decline and Medial Temporal Lobe Atrophy in Subjective Cognitive Impairment and Mild Cognitive Impairment

Neuropathological correlates of Alzheimers disease (AD) emerge years before dementia. Biomarkers preceding cognitive decline and reflecting the causative processes can potentially aid early intervention and diagnosis. Diffusion tensor imaging (DTI) indirectly reflects tissue microstructure. To answer whether DTI is an early biomarker for AD and to explore the relationship between DTI and the established biomarkers of medial temporal lobe atrophy and cerebrospinal fluid (CSF) Aβ(42), T-tau, and P-tau, we longitudinally studied normal controls and patients with subjective (SCI) or mild (MCI) cognitive impairment. 21 controls and 64 SCI or MCI cases recruited from a university-hospital based memory clinic were re-examined after two to three years. FreeSurfer was used for longitudinal processing of morphometric data, and DTI derived fractional anisotropy, radial diffusivity, and mean diffusivity were analyzed in Tract-Based Spatial Statistics. Using regression models, we explored and compared the predictive powers of DTI and CSF biomarkers in regard to cognitive change and atrophy of the medial temporal lobe. Both DTI and CSF biomarkers significantly predicted cognitive decline and atrophy in the medial temporal lobe. In this population, however, DTI was a better predictor of dementia and AD-specific medial temporal lobe atrophy than the CSF biomarkers. The case for DTI as an early biomarker for AD is strengthened, but further studies are needed to confirm these results.

Reduced cerebrospinal fluid BACE1 activity in multiple sclerosis.

Background Cell and animal experiments have shown that β-site APP-cleaving enzyme 1 (BACE1) may be involved in myelination. Objective Here, we assess the association of cerebrospinal fluid (CSF) BACE1 activity with multiple sclerosis (MS). Methods BACE1 activity and levels of secreted amyloid precursor protein (APP) and amyloid-β (Aβ) isoforms were analyzed in CSF from 100 patients with MS and 114 neurologically healthy controls. Patients with systemic lupus erythematosus (SLE), 26 with and 41 without cerebral engagement, were also included to enable comparisons with regards to another autoimmune disease. A subset of patients with MS and controls underwent a second lumbar puncture after 10 years. Results MS patients had lower CSF BACE1 activity than controls (P = 0.03) and patients with cerebral SLE (P < 0.001). Patients with cerebral SLE had higher BACE1 activity than any other group (P < 0.05 for all comparisons). BACE1 activity correlated with the different amyloid markers in all study groups. BACE1 activity decreased over 10 years in the MS group (P = 0.039) and correlated weakly with clinical disease severity scores in an inverse manner. Conclusions These results suggest an involvement of BACE1 in the MS disease process.

Morphometric Changes in the Episodic Memory Network and Tau Pathologic Features Correlate with Memory Performance in Patients with Mild Cognitive Impairment

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) may affect several cognitive domains, including attention and reasoning, but is often first characterized by memory deficits. The purpose of this study was to ask these 2 questions: 1) Can levels of CSF tau proteins and amyloid beta 42 peptide explain thinning of the cerebral cortex in patients with MCI? 2) How are brain morphometry, CSF biomarkers, and apolipoprotein E (APOE) allelic variation related to episodic memory function in MCI? MATERIALS AND METHODS: Hippocampal volume and cortical thickness were estimated by MR imaging and compared for patients with MCI (n = 18) and healthy controls (n = 18). In addition, regions of interest (ROIs) were selected in areas where the MCI group had atrophy and which overlapped with the episodic memory network (temporal, entorhinal, inferior parietal, precuneus/posterior cingulate, and frontal). Relationships among morphometry, CSF biomarkers, APOE, and memory were tested. The analyses were repeated with an independent sample of patients with MCI (n = 19). RESULTS: Patients with MCI and pathologic CSF values had hippocampal atrophy. However, both patients with pathologic and patients with nonpathologic CSF had a thinner cortex outside the hippocampal area. CSF pathology was related to hippocampal volume, whereas relationships with cortical thickness were found mainly in one of the samples. Morphometry correlated robustly with memory performance across MCI samples, whereas less stable results were found for tau protein. CONCLUSION: The differences in hippocampal volume between the MCI and the healthy control groups were only found in patients with pathologic CSF biomarkers, whereas differences in cortical thickness were also found for patients without such pathologic features. Morphometry in areas in the episodic memory network was robustly correlated with memory performance. It is speculated that atrophy in these areas may be associated with the memory problems seen in MCI.

Genetic overlap between Alzheimer's Disease and Parkinson's Disease at the MAPT locus

We investigated the genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10−7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer’s neurodegeneration.

Early and Presenting Symptoms of Dementia with Lewy Bodies

Background/Aims: To explore the presenting and early symptoms of dementia with Lewy bodies (DLB). Method: Patients with mild dementia fulfilling diagnostic criteria for DLB (n = 61) and Alzheimer’s disease (AD) (n = 109) were recruited from outpatient dementia clinics in western Norway. At diagnosis, caregivers were asked which symptom had been the presenting symptom of dementia. Results: Caregivers reported that memory impairment was the most common presenting symptom in DLB (57%), followed by visual hallucinations (44%), depression (34%), problem solving difficulties (33%), gait problems (28%), and tremor/stiffness (25%). In contrast, 99% of AD carers reported impaired memory as a presenting symptom, whereas visual hallucinations were a presenting symptom in 3% of the AD cases. Conclusion: DLB should be suspected in predementia cases with visual hallucinations.