Total and phosphorylated tau proteins: Evaluation as core biomarker candidates in frontotemporal dementia

An ever increasing number of patients with neurodegenerative disorders calls for the evaluation of potential diagnostic markers that allow an early diagnosis and an early initiation of specific therapy. Clinical diagnosis of Alzheimer's disease (AD), the most common neurodegenerative disorder, reaches 80-90% accuracy upon autopsy in specialized clinical centers. Diagnosis of AD in early clinical or preclinical stages is far less accurate, as is the differential diagnosis between AD and other primary dementias, such as frontotemporal dementia (FTD). Microtubule-associated tau protein is abnormally phosphorylated in AD and aggregates as paired helical filaments in neurofibrillary tangles. Recently, immunoassays have been developed detecting tau phosphorylated at specific epitopes in cerebrospinal fluid (CSF). Four years of clinical research consistently demonstrate that CSF phosphorylated tau (p-tau) is highly increased in AD compared to healthy controls and may differentiate AD from its most relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau(231)) shows excellent differentiation between AD and FTD, whereas serine 181 (p-tau(181)) enhances accurate differentiation between AD and dementia with Lewy bodies. Moreover, p-tau(231) levels decline with disease progression, correlating with cognitive performance at baseline. Total tau (t-tau) is regarded as a general marker of neurodegeneration for evaluation in future population-based studies. p-tau(231) and p-tau(181) yield excellent discrimination between AD and non-AD dementias including FTD, exceeding the differential diagnostic and prognostic accuracy of t-tau. Therefore, p-tau is a core biological marker candidate for future evaluation in large national and international multicenter networks. Copyright (C) 2004 S. Karger AG, Basel

Age-dependent differences in human brain activity using a face- and location-matching task: An fMRI study

Purpose: To evaluate the differences of cortical activation patterns in young and elderly healthy subjects for object and spatial visual processing using a face- and location-matching task. Materials and Methods: We performed a face- and a location-matching task in 15 young (mean age: 28 +/- 9 years) and 19 elderly (mean age: 71 +/- 6 years) subjects. Each experiment consisted of 7 blocks alternating between activation and control condition. For face matching, the subjects had to indicate whether two displayed faces were identical or different. For location matching, the subjects had to press a button whenever two objects had an identical position. For control condition, we used a perception task with abstract images. Functional imaging was performed on a 1.5-tesla scanner using an EPI sequence. Results: In the face-matching task, the young subjects showed bilateral (right 1 left) activation in the occipito-temporal pathway (occipital gyrus, inferior and middle temporal gyrus). Predominantly right hemispheric activations were found in the fusiform gyrus, the right dorsolateral prefrontal cortex (inferior and middle frontal gyrus) and the superior parietal gyrus. In the elderly subjects, the activated areas in the right fronto-lateral cortex increased. An additional activated area could be found in the medial frontal gyrus (right > left). In the location-matching task, young subjects presented increased bilateral (right > left) activation in the superior parietal lobe and precuneus compared with face matching. The activations in the occipito-temporal pathway, in the right fronto-lateral cortex and the fusiform gyrus were similar to the activations found in the face-matching task. In the elderly subjects, we detected similar activation patterns compared to the young subjects with additional activations in the medial frontal gyrus. Conclusion: Activation patterns for object-based and spatial visual processing were established in the young and elderly healthy subjects. Differences between the elderly and young subjects could be evaluated, especially by using a face-matching task. Copyright (c) 2007 S. Karger AG, Basel

Hippocampus and basal forebrain volumes modulate effects of anticholinergic treatment on delayed recall in healthy older adults

Introduction Volumes of hippocampus and cholinergic basal forebrain are associated with delayed recall performance and may modulate the effect of a muscarinic receptor antagonist on delayed recall in healthy volunteers Methods We studied 15 older adults before and after the oral administration of a single dose of 1 or 2 mg of the preferential M1 muscarinic receptor antagonist trihexyphenidyl (Artane™) or placebo in a double-blind randomized cross-over design. Hippocampus and basal forebrain volumes were measured using magnetic resonance imaging. Results We found a significant interaction between treatment and hippocampus volume and a trend level effect between treatment and anterior basal forebrain volume on task performance, with an attenuation of the association between volume size and performance with trihexyphenidyl. Discussion These findings suggest a reduction of delayed recall performance with increasing doses of the muscarinic antagonist that is related to an uncoupling of the association of task performance with cholinergic basal forebrain and hippocampus volume

Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder

BACKGROUND: Inflammatory mechanisms are believed to contribute to the manifestation of major depressive disorder (MDD). Central cholinergic activity may moderate this effect. Here, we tested if volume of the cholinergic basal forebrain is associated with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglial activation in people with late life MDD. METHODS: Basal forebrain volume was determined from structural MRI scans and levels of CSF sTREM2 with immunoassay in 29 people with late-life MDD and 20 healthy older controls at baseline and 3 years follow-up. Associations were determined using Bayesian analysis of covariance. RESULTS: We found moderate level of evidence for an association of lower CSF levels of sTREM2 at 3 years follow up with MDD (Bayes factor in favor of an effect = 7.9). This level of evidence prevailed when controlling for overall antidepressant treatment and CSF levels of markers of AD pathology, i.e., Aβ42/Aβ40, ptau181 and total tau. Evidence was in favor of absence of an effect for baseline levels of CSF sTREM2 in MDD cases and for baseline and follow up data in controls. LIMITATIONS: The sample size of repeated CSF examinations was relatively small. Therefore, we used Bayesian sequential analysis to assess if effects were affected by sample size. Still, the number of cases was too small to stratify effects for different antidepressive treatments. CONCLUSIONS: Our data agree with the assumption that central cholinergic system integrity may contribute to regulation of microglia activity in late-life MDD

Recent Advances in Cholinergic Imaging and Cognitive Decline—Revisiting the Cholinergic Hypothesis of Dementia

Purpose of Review Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis. Recent Findings Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD). Bidirectional changes in regional receptor expression may suggest the presence of compensatory responses to neurodegenerative injury. Cholinergic system changes are more complex in LBD because of additional subcortical degenerations compared to AD. Cholinergic-dopaminergic interactions affect attentional, verbal learning, and executive functions, and impairments in these two transmitter systems may jointly increase the risk of dementia in Parkinson’s disease. Summary The cholinergic hypothesis is evolving from a primary focus on memory toward expanded cognitive functions modulated by regionally more complex and interactive brain networks. Cholinergic network adaptation may serve as a novel research target in neurodegeneration

Association of plasma Aβ40/Aβ42 ratio and brain Aβ accumulation: testing a whole-brain PLS-VIP in individuals at risk of Alzheimer's disease

Molecular and brain regional/network-wise pathophysiological changes at preclinical stages of Alzheimer's disease (AD) have primarily been found through knowledge-based studies conducted in late-stage mild cognitive impairment/dementia populations. However, such an approach may compromise the objective of identifying the earliest spatial-temporal pathophysiological processes. We investigated 261 individuals with subjective memory complaints, a condition at increased risk of AD, to test a whole-brain, non-a-priori method based on partial least squares, in unraveling the association between plasma Aβ42/Aβ40 ratio and an extensive set of brain regions characterized through molecular imaging of Aβ accumulation and cortical metabolism. Significant associations were mapped onto large-scale networks, identified through an atlas and by knowledge, to elaborate on the reliability of the results. Plasma Aβ42/40 ratio was associated with Aβ-PET uptake (but not FDG-PET) in regions generally investigated in preclinical AD such as those belonging to the default mode network, but also in regions/networks normally not accounted - including the central executive and salience networks - which likely have a selective vulnerability to incipient Aβ accumulation. The present whole-brain approach is promising to investigate early pathophysiological changes of AD to fully capture the complexity of the disease, which is essential to develop timely screening, detection, diagnostic, and therapeutic interventions

The Primacy Effect in Amnestic Mild Cognitive Impairment: Associations with Hippocampal Functional Connectivity

Background: The “primacy effect,” i.e., increased memory recall for the first items of a series compared to the following items, is reduced in amnestic mild cognitive impairment (aMCI). Memory task-fMRI studies demonstrated that primacy recall is associated with higher activation of the hippocampus and temporo-parietal and frontal cortical regions in healthy subjects. Functional magnetic resonance imaging (fMRI) at resting state revealed that hippocampus functional connectivity (FC) with neocortical brain areas, including regions of the default mode network (DMN), is altered in aMCI. The present study aimed to investigate whether resting state fMRI FC between the hippocampus and cortical brain regions, especially the DMN, is associated with primacy recall performance in aMCI. Methods: A number of 87 aMCI patients underwent resting state fMRI and verbal episodic memory assessment. FC between the left or right hippocampus, respectively, and all other voxels in gray matter was mapped voxel-wise and used in whole-brain regression analyses, testing whether FC values predicted delayed primacy recall score. The delayed primacy score was defined as the number of the first four words recalled on the California Verbal Learning Test. Additionally, a partial least squares (PLS) analysis was performed, using DMN regions as seeds to identify the association of their functional interactions with delayed primacy recall. Results: Voxel-based analyses indicated that delayed primacy recall was mainly (positively) associated with higher FC between the left and right hippocampus. Additionally, significant associations were found for higher FC between the left hippocampus and bilateral temporal cortex, frontal cortical regions, and for higher FC between the right hippocampus and right temporal cortex, right frontal cortical regions, left medial frontal cortex and right amygdala (p < 0.01, uncorr.). PLS analysis revealed positive associations of delayed primacy recall with FC between regions of the DMN, including the left and right hippocampus, as well as middle cingulate cortex and thalamus (p < 0.04). In conclusion, in the light of decreased hippocampus function in aMCI, inter-hemispheric hippocampus FC and hippocampal FC with brain regions predominantly included in the DMN may contribute to residual primacy recall in aMCI

Neuronal correlates of serial position performance in amnestic mild cognitive impairment.

Objectives: Delayed recall of the first words of a list - the primacy position – is thought to be particularly dependent on intact memory consolidation. Hippocampal volume has been suggested as the primary neuronal correlate of delayed primacy recall in cognitively normal elderly individuals. Here, we studied the association of hippocampal volume with primacy recall in individuals with amnestic mild cognitive impairment (aMCI). Methods: We investigated serial position performance in 88 subjects with aMCI using a 16-word list (CVLT). Primacy and recency performance were measured during learning and delayed recall. Hippocampal volumes were automatically determined from structural MRI scans. We conducted regression analyses with bilateral hippocampal volumes as predictors and serial position indices as outcomes. Results: After controlling for age, gender, and total intracranial volume, bilateral hippocampal volume was not associated with primacy recall either during learning or delayed recall. Primacy performance during learning was associated with the right inferior and middle temporal gyrus as well as the right inferior parietal cortex and supramerginal gyrus. During delayed recall, primacy performance was related to the bilateral supramarginal gyri. Conclusions: Our findings suggest a reduced primacy effect in aMCI already during learning, contrasting previous findings in normal cognitive aging. This might indicate impaired encoding and consolidation processes at an early stage of episodic memory acquisition. Furthermore, our data indicates that hippocampal volume may not be a relevant determinant of residual primacy performance in the stage of aMCI, which may rather depend on temporal and parietal neocortical networks

Direct Imaging of Coexisting Ordered and Frustrated Sublattices in Artificial Ferromagnetic Quasicrystals

We have used scanning electron microscopy with polarization analysis and photoemission electron microscopy to image the two-dimensional magnetization of permalloy films patterned into Penrose P2 tilings (P2T). The interplay of exchange interactions in asymmetrically coordinated vertices and short-range dipole interactions among connected film segments stabilize magnetically ordered, spatially distinct sublattices that coexist with frustrated sublattices at room temperature. Numerical simulations that include long-range dipole interactions between sublattices agree with images of as-grown P2T samples and predict a magnetically ordered ground state for a two-dimensional quasicrystal lattice of classical Ising spins