Objectives
Glymphatic function has not yet been explored in behavioral variant frontotemporal dementia (bvFTD). The spatial correlation between regional glymphatic function and bvFTD remains unknown.
...Method
A total of 74 patients with bvFTD and 67 age‐ and sex‐matched healthy controls (HCs) were selected from discovery dataset and replication dataset. All participants underwent neuropsychological assessment. Glymphatic measures including choroid plexus (CP) volume, diffusion tensor imaging along the perivascular (DTI‐ALPS) index, and coupling between blood‐oxygen‐level‐dependent signals and cerebrospinal fluid signals (BOLD‐CSF coupling), were compared between the two groups. Regional glymphatic function was evaluated by dividing DTI‐ALPS and BOLD‐CSF coupling into anterior, middle, and posterior regions. The bvFTD‐related metabolic pattern was identified using spatial covariance analysis based on l8F‐FDG‐PET.
Results
Patients with bvFTD showed higher CP volume (p < 0.001); anterior and middle DTI‐ALPS (p < 0.001); and weaker anterior BOLD‐CSF coupling (p < 0.05) than HCs after controlling for cortical gray matter volume in both datasets. In bvFTD from the discovery dataset, the anterior DTI‐ALPS was negatively associated with the expression of the bvFTD‐related metabolic pattern (r = −0.52, p = 0.034) and positively related with regional standardized uptake value ratios of l8F‐FDG‐PET in bvFTD‐related brain regions (r range: 0.49 to 0.62, p range: 0.017 to 0.047). Anterior and middle glymphatic functions were related to global cognition and disease severity.
Interpretation
Our findings reveal abnormal glymphatic function, especially in the anterior and middle regions of brain in bvFTD. Regional glymphatic dysfunction may contribute to the pathogenesis of bvFTD. ANN NEUROL 2023;94:442–456
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Given the importance of this public health issue, we wish to raise some methodological considerations limiting the interpretation of certain results, particularly the choice of the control group, the ...selection of the patients’ informant and the impact of the patients’ lifestyle on the findings. The authors don’t report how this person was chosen, if the patient and their spouse had the same informant, if they were close and had regular contact to be able to report a reliable opinion on the cognitive decline of the patient over the 6-month period. ...in the affected sample, 238 patients had severe covid and 1301 had non-severe covid. ...although this study claims to provide important insights regarding the impact of COVID-19 in cognition, our enthusiasm is tempered by these methodological shortcomings limiting the claims made in this manuscript.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
SARS‐CoV‐2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID‐19 neurological ...injury. This is a cross‐sectional exploratory prospective biomarker cohort study of 21 patients with COVID‐19 neurological syndromes (Guillain–Barre Syndrome GBS, encephalitis, encephalopathy, acute disseminated encephalomyelitis ADEM, intracranial hypertension, and central pain syndrome) and 23 healthy COVID‐19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor TNF ɑ, interleukin IL‐6, IL‐1β, IL‐8). Patients with COVID‐19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)‐ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10−8), Aβ42 (p = 3.5 × 10−7), and Aβ42/Aβ40 ratio (p = 0.005) compared to controls. Patients with COVID‐19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPβ. Conversely, GFAp was significantly reduced in COVID‐19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPβ. COVID‐19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPβ. A sensitivity analysis of COVID‐19‐associated GBS revealed a non‐significant trend toward greater impairment of amyloid processing in COVID‐19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID‐19‐associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.
SARS‐CoV‐2 can result in neurological conditions, but the mechanisms of COVID‐19‐associated nervous system injury remain unclear. Using cerebrospinal fluid (CSF) and blood biomarkers of amyloid processing collected from patients with COVID‐19‐associated neurological injury and healthy controls, we find COVID‐19 neurological patients display impaired amyloid processing characterized by decreased soluble amyloid precursor proteins and Amyloid β. Reductions in amyloid processing biomarkers correlated with increases in neuronal injury (NfL) and neuroinflammatory biomarkers but with decreases in astrocyte reactivity (GFAp). This supports the possibility that patients with COVID‐19‐associated neurological syndromes exhibit impaired amyloid processing during their acute illness.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The integrity and function of catecholamine neurotransmitter systems can be assessed using neuromelanin‐sensitive MRI (NM‐MRI). The relevance of this method to neurodegenerative and ...psychiatric disorders is becoming increasingly evident, and it has potential as a clinical biomarker.
Purpose
To support future application of NM‐MRI as a clinical biomarker by defining the normative range of NM‐MRI signal and volume metrics in cognitively normal older adults.
Study Type
Prospective.
Population
A total of 152 cognitively normal older adults aged 53–86 years old, including 41 participants who had follow‐up NM‐MRI data collected 9–16 months later.
Field Strength/Sequence
A 3.0 T; NM‐MRI turbo spin echo and T1‐weighted magnetization‐prepared rapid acquisition with gradient echo sequences.
Assessment
NM‐MRI images were processed to yield summary measures of volume and signal (contrast‐to‐noise ratio, CNR) for the substantia nigra (SN) and locus coeruleus (LC) using a recently developed software employing a fully automated algorithm. Change in these metrics over time was also assessed.
Statistical Tests
Mean and standard deviation of NM‐MRI metrics were calculated; change over time was tested for significance using 1‐sample t‐tests. P values < 0.05 were considered statistically significant.
Results
At baseline SN signal (CNR) was 10.02% (left) and 10.28% (right) and LC signal was 24.71% (left) and 20.42% (right). Baseline SN volume was 576 mm3 (left) and 540 mm3 (right) and LC volume was 6.31 mm3 (left) and 6.30 mm3 (right). The only NM‐MRI metric showing significant change was a decrease in left SN volume (t40 = −2.57, P = 0.014).
Data Conclusion
We report normative values for NM‐MRI signal and volume in the SN and LC of cognitively normal older adults and explore their change over time. These values may help future efforts to use NM‐MRI as a clinical biomarker by facilitating identification of patients with extreme NM‐MRI values.
Level of Evidence
2.
Technical Efficacy Stage
1.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Alzheimer's disease and related dementias is a major public health burden-compounding over upcoming years due to longevity. Recently, clinical evidence hinted at the experience of social isolation in ...expediting dementia onset. In 502,506 UK Biobank participants and 30,097 participants from the Canadian Longitudinal Study of Aging, we revisited traditional risk factors for developing dementia in the context of loneliness and lacking social support. Across these measures of subjective and objective social deprivation, we have identified strong links between individuals' social capital and various indicators of Alzheimer's disease and related dementias risk, which replicated across both population cohorts. The quality and quantity of daily social encounters had deep connections with key aetiopathological factors, which represent 1) personal habits and lifestyle factors, 2) physical health, 3) mental health, and 4) societal and external factors. Our population-scale assessment suggest that social lifestyle determinants are linked to most neurodegeneration risk factors, highlighting them as promising targets for preventive clinical action.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Introduction Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among ...others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. Methods We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). Results Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. Discussion When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.
Full text
Available for:
FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Within-person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined.
We included 467 subjects from the BIOMARKAPD study with at least two serial CSF ...samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow-up CSF levels of total tau (t-tau), phosphorylated tau (p-tau), YKL-40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years.
CSF levels of t-tau, p-tau, NfL, and YKL-40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t-tau levels were 1% lower (P <.001) and p-tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL-40 (P <.02) increased during the study period.
All four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau.
•In this large longitudinal multicenter cerebrospinal fluid (CSF) study each year of increase at baseline age was significantly associated with 2% higher mean CSF t-tau and p-tau levels in controls. Within the Alzheimer's disease group, each year of increase at baseline age was significantly associated with 1% lower mean CSF t-tau levels, and p-tau levels did not change with age.•Each year of increase at baseline age was significantly associated with 2% higher mean CSF neurofilament light (NfL) and YKL-40 levels in controls without differences among groups.•Longitudinally, after adjusting for baseline age, only NfL and YKL-40 levels significantly increased during the study period in all groups.•The pattern of change of CSF tau, NfL, and YKL-40 is different in Alzheimer's disease.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Following the development of magnetic resonance imaging (MRI) methods to assay the integrity of catecholamine nuclei, including the locus coeruleus (LC), there has been an effort to develop automated ...methods that can accurately segment this small structure in an automated manner to promote its widespread use and overcome limitations of manual segmentation. Here we characterize an automated LC segmentation approach (referred to as the funnel‐tip FT method) in healthy individuals and individuals with LC degeneration in the context of Alzheimer's disease (AD, confirmed with tau‐PET imaging using 18FMK6240). The first sample included n = 190 individuals across the AD spectrum from cognitively normal to moderate AD. LC signal assayed with FT segmentation showed excellent agreement with manual segmentation (intraclass correlation coefficient ICC = 0.91). Compared to other methods, the FT method showed numerically higher correlation to AD status (defined by presence of tau: Cohen's d = 0.64) and AD severity (Braak stage: Pearson R = −.35, cognitive function: R = .25). In a separate sample of n = 12 control participants, the FT method showed excellent scan–rescan reliability (ICC = 0.82). In another sample of n = 30 control participants, we found that the structure of the LC defined by FT segmentation approximated its expected shape as a contiguous line: <5% of LC voxels strayed >1 voxel (0.69 mm) from this line. The FT LC segmentation shows high agreement with manual segmentation and captures LC degeneration in AD. This practical method may facilitate larger research studies of the human LC‐norepinephrine system and has potential to support future use of neuromelanin‐sensitive MRI as a clinical biomarker.
The automated segmentation (funnel tip FT) method showed good agreement to manual segmentation in measuring LC signal and LC localization. FT method showed numerically higher correlation to Alzheimer's disease severity measures compared to other segmentation approaches. FT method demonstrated a high scan–rescan reliability and provided a practical method to segment the LC along its full rostrocaudal extent.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Introduction Recent literature proposes that amyloid-β and phosphorylated tau (p-tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this ...synergism is the driving force behind Alzheimer disease (AD) dementia. Methods We stratified 314 mild cognitive impairment individuals using 18 Fflorbetapir positron emission tomography amyloid-β imaging and cerebrospinal fluid p-tau. Regression and voxel-based logistic regression models with interaction terms evaluated 2-year changes in cognition and clinical status as a function of baseline biomarkers. Results We found that the synergism between 18 Fflorbetapir and p-tau, rather than their additive effects, was associated with the cognitive decline and progression to AD. Furthermore, voxel-based analysis revealed that temporal and inferior parietal were the regions where the synergism determined an increased likelihood of developing AD. Discussion Together, the present results support that progression to AD dementia is driven by the synergistic rather than a mere additive effect between amyloid-β and p-tau proteins.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
