Neurodegenerative diseases (NDD) such as Alzheimer's (AD) and Parkinson's disease (PD) are distinct clinical entities, however, the aggregation of key neuronal proteins, presumably leading to ...neuronal demise appears to represent a common mechanism. It has become evident, that advanced glycation end products (AGEs) trigger the accumulation of such modified proteins, which eventually contributes to pathological aspect of NDDs. Increased levels of AGEs are found in amyloid plaques in AD brains and in both advanced and early PD (incidental Lewy body disease). The molecular mechanisms by which AGE dependent modifications may modulate the susceptibility towards NDDs, however, remain enigmatic and it is unclear, whether AGEs may serve as biomarker of NDD. In the present study, we examined AGEs (CML: Carboxymethyllysine and CEL: Carboxyethyllysine), markers of oxidative stress and micronutrients in the plasma of PD and AD patients and controls. As compared to healthy controls, AD females displayed lower levels of CEL while higher levels of CML were found in AD and PD patients. A somewhat similar pattern was observed for protein carbonyls (PC), revealing lower values exclusively in AD females, whereas AD males displayed significantly higher values compared to healthy controls and PD. Sex-specific differences were also observed for other relevant markers such as malondialdehyde, 3-nitrotyrosine, γ -tocopherols, retinol, plasma proteins and α-carotene, while α-tocopherols, β-carotene, lutein/zeaxanthin, β-cryptoxanthin and lycopene showed no relevant association. Taken together, our study suggests yet unappreciated differences of the distribution of AGEs among the sexes in NDD. We therefore suggest to make a clear distinction between sexes when analyzing oxidative (AGEs)-related stress and carbonyl-related stress and vitamins.
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•As compared to healthy controls, AD females displayed lower levels of CEL (carboxyethyllysine) while higher levels of CML (carboxymethyllysine) were found in AD and PD patients.•A somewhat similar pattern was observed for protein carbonyls (PC), revealing lower values exclusively in AD females, whereas AD males displayed significantly higher values compared to healthy controls and PD. Presumed carbonlyated residues were identified the in the major proteins associated with neurodegenerative diseases.•Sex-specific differences were also observed for other relevant markers such as malondialdehyde, 3-nitrotyrosine, γ-tocopherols, retinol, plasma proteins and α-carotene, while α-tocopherols, β-carotene, lutein/zeaxanthin, β-cryptoxanthin and lycopene showed no relevant association.
Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now ...provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.
Within the elderly population, psychogeriatric patients may be particularly susceptible to negative mental health effects of the coronavirus crisis. Detailed information about the psychosocial ...well-being of psychogeriatric patients during the pandemic is still sparse. Here we examined which aspects of subjective experience of the COVID-19 pandemic especially affect levels of depression, anxiety and quality of life in psychogeriatric patients with and without cognitive impairment. A cross-sectional paper survey was conducted during the first German lockdown among patients with a diagnosed psychiatric disorder (≥ 60 years) or a diagnosed neurodegenerative disease (regardless of their age) from the department for neurodegenerative diseases and geriatric psychiatry at the University of Bonn. The WHO-5-, GAD-7- and WHOQOL-old score were used to determine levels of depression, anxiety and quality of life. The second part obtained information about the subjective experience of the COVID-19 pandemic. Statistical analysis included among others principal component analysis and multiple linear regression analysis. COVID-19-related, immediate distress was a strong predictor of elevated symptoms of depression, anxiety and a reduced quality of life. COVID-19-related concerns regarding health and financial security, however, were not significantly associated with negative mental health outcomes. The overall prevalence of symptoms of depression (50.8% 95% CI 43.8–57.6%) and anxiety (32.7% 95% CI 26.4–39.2%) among psychogeriatric patients was high. Our findings indicate that psychogeriatric patients are not significantly affected by COVID-19-related concerns but are primarily suffering from emotional consequences resulting from changed living conditions due to the pandemic.
Abstract Cognitive reserve (CR) is defined as the ability to maintain functionality despite accumulating pathology and education has been used as a proxy for CR. For example, by using PET imaging ...higher educated Alzheimer’s disease (AD) patients presented increased beta amyloid pathology than lower educated patients despite equal symptomatology. Whether similar associations exist for in vivo tau pathology remains elusive. We utilized 18 FAV-1451 PET imaging to examine whether high educated AD patients (n=12) present more severe tau pathology compared to low educated patients (n=12) despite equal clinical severity in regions of interest corresponding to the pathological disease stages defined by Braak & Braak. We report tau pathology in advanced Braak stages associated with parietal and frontal regions in high educated AD patients, whereas in low educated AD patients tau accumulation is still confined to lower Braak stages associated with temporal and cingulate regions. Highly educated AD patients seem to be able to tolerate more tau tangle pathology than lower educated patients with comparable cognitive impairment supporting the cognitive reserve hypothesis.
See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.
The stereotypical anatomical propagation of tau pathology is indicative of misfolded tau proteins spreading along ...neuronal networks. Hönig et al. report that tau pathology expands along independent pathways that correspond to functional networks known to be impaired in Alzheimer's disease, including the default mode network and the frontal control network.
Abstract
See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.
A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.
The objective of this preliminary study was to explore long-term changes in neurobehavioral parameters, brain morphology and electroencephalography of sepsis patients who received intensive care ...compared to non-septic intensive care unit (ICU) patients.
Two-centre follow-up study 6-24 months after discharge from hospital using published norms and existing databases of healthy controls for comparison. Patients included 25 septic and 19 non-septic ICU survivors who were recruited from two ICUs of a university and community hospital. Measurements used include brain morphology, standard electroencephalography, cognition and psychiatric health and health-related quality of life.
Sepsis survivors showed cognitive deficits in verbal learning and memory and had a significant reduction of left hippocampal volume compared to healthy controls. Moreover, sepsis and to some extent non-septic ICU patients had more low-frequency activity in the EEG indicating unspecific brain dysfunction. No differences were found in health-related quality of life, psychological functioning or depressive symptoms, and depression could be ruled out as a confounding factor.
This study demonstrates permanent cognitive impairment in several domains in both septic and non-septic ICU survivors and unspecific brain dysfunction. In the sepsis group, left-sided hippocampal atrophy was found compared to healthy controls. Further study is needed to clarify what contribution sepsis and other factors at the ICU make to these outcomes. Specific neuroprotective therapies are warranted to prevent persisting brain changes in ICU patients.
To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia ...(bvFTD).
Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes CDR-SOB, frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination MMSE) and brain volumetry.
At baseline, serum NfL level correlated with CSF NfL (bvFTD
= 0.706,
< 0.0001; AD/MCI
= 0.666,
= 0.0003). Highest serum levels were observed in bvFTD (
<0 0.0001 vs Con and MCI,
= 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (
= 0.0039 and
= 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB baseline
= 0.4157,
= 0.0006; follow-up
= 0.5629,
< 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe:
= -0.5857,
< 0.0001; 95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB baseline
= 0.6624,
< 0.0001; follow-up
= 0.5659,
= 0.0003) but not with regional brain volumes.
As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials.
This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia.
Abstract
Background and Objectives
Cognitive complaints are discussed as early signs of Alzheimer’s disease (AD). However, they are also very common in cognitively normal older adults and in patients ...with depression. Qualitative, interview-based approaches might be useful to identify those features of cognitive complaints specific for the experiences of cognitive decline in preclinical or prodromal AD versus those complaints typically reported by depressed patients.
Research Design and Methods
A semi-structured interview was administered to 21 cognitively normal older adults (HC), 18 nondemented memory clinic patients (MC), and 11 patients with a major depression (MD), all above 55 years. Interpretative phenomenological analysis (IPA) was applied to the interview transcripts to develop emerging complaint themes in each group. To identify thematic correspondence and possibly novel, hitherto unappreciated themes, the extracted complaint categories were compared with the neurocognitive domains in the DSM-5 and the content of the Everyday Cognition questionnaire (E-Cog).
Results
IPA yielded 18 cognitive complaint categories in MC, 10 in depressive patients, and 10 categories in the HC group. Several themes were common across groups, but some were group-specific, for example, spatial disorientation was only reported in MC patients. Some of these MC-specific themes were neither represented by DSM-5 domains nor by the E-Cog.
Discussion and Implications
We report a comprehensive qualitative description of cognitive complaints in old age which could help to develop questionnaires or structured interviews to better assess AD-related subjective cognitive decline. This may help to increase specificity in selecting high-risk subjects in research settings and improve clinical judgment of diverse cognitive complaints types mentioned by their patients.
Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if ...there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels.
Maps of fractional amplitude of low-frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 females) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 females). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of co-localization is associated with the observed clinical symptoms.
Patients displayed significantly reduced fALFF in frontotemporal and frontoparietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b and 5-HT2a) and γ-aminobutyric acid type A (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with NET was associated with cognitive symptoms and disease severity of bvFTD.
Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD.
This study has been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (BMBF; grant no. FKZ01GI1007A).
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