TAR DNA binding protein-43 (TDP-43) immunoreactive neuronal inclusions are detected in 20–30% of Alzheimer disease (AD) brains, but the distribution of this pathology has not been rigorously studied. ...In this report, we describe region-specific distribution and density of TDP-43 positive neuronal cytoplasmic inclusions (NCIs) in clinically demented individuals with high probability AD pathology, all with Braak neurofibrillary tangle stages of V or VI. Sections of hippocampus, amygdala, as well as temporal, frontal, and parietal neocortex, were analyzed with TDP-43 immunohistochemistry, and the density of NCIs was assessed using a semiquantitative scoring method. Of the 29 cases, six had TDP-43 positive NCIs in the amygdala only and seven had TDP-43 inclusions restricted to amygdala and hippocampus. In 16 cases, TDP-43 immunoreactivity was more widespread, affecting temporal, frontal or parietal neocortex. These findings indicate that medial temporal lobe limbic structures are vulnerable to TDP-43 pathology in advanced AD, and that the amygdala appears to be the most susceptible region. The distribution of the lesions in this cross-sectional analysis may suggest a progression of TDP-43 pathology in AD, with limbic structures in the medial temporal lobe affected first, followed by higher order association cortices.
Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, ...dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.
The Washington University School of Medicine Knight Alzheimer Disease Research Center's “African American Participation in Alzheimer Disease Research: Effective Strategies” Workshop convened to ...address a major limitation of the ongoing scientific progress regarding Alzheimer's disease and related dementias (ADRD): participants in most ADRD research programs overwhelmingly have been limited to non‐Hispanic white persons, thus precluding knowledge as to how ADRD may be represented in non‐white individuals. Factors that may contribute to successful recruitment and retention of African Americans into ADRD research were discussed and organized into actionable next steps as described within this report.
IMPORTANCE An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility are necessary. ...OBJECTIVE To develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS. DESIGN, SETTING, AND PARTICIPANTS A case-control study including 51 individuals with ALS and 23 individuals with a disorder associated with a 4-repeat tauopathy was conducted at an academic medical center. MAIN OUTCOMES AND MEASURES The CSF level of tau phosphorylated at threonine 181 (ptau) and ratio of ptau to total tau (ttau). RESULTS Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and the ptau:ttau ratio in ALS relative to 4-repeat tauopathy and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS with 4-repeat tauopathy showed 92.0% sensitivity and 91.7% specificity. Correct classification based on a low CSF ptau:ttau ratio was confirmed in 18 of 21 cases (86%) with autopsy-proved or genetically determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity, such as the Mini-Mental State Examination (n = 51) and ALS Functional Rating Scale–Revised (n = 42), and regression analyses related the ptau:ttau ratio to magnetic resonance imaging (n = 10) evidence of disease in the corticospinal tract and white matter projections involving the prefrontal cortex. CONCLUSIONS AND RELEVANCE The CSF ptau:ttau ratio may be a candidate biomarker to provide objective support for the diagnosis of ALS.
The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials ...must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Aβ), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Aβ clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Aβ degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE-precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans.
Background YKL-40 (Chitinase 3-like I) is increased in CSF of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) patients and is therefore considered a potential neuroinflammatory ...biomarker. Whether changed YKL-40 levels in the CSF reflect dysregulation of YKL-40 in the brain is not completely understood yet. We aimed to extensively analyze YKL-40 levels in the brain of AD and different FTLD pathological subtypes. The direct relationship between YKL-40 levels in post-mortem brain and ante-mortem CSF was examined in a small set of paired brain-CSF samples. Method YKL-40 was analyzed in post-mortem temporal and frontal cortex of non-demented controls and patients with AD and FTLD (including FTLD-Tau and FTLD-TDP) pathology by immunohistochemistry (temporal cortex: 51 controls and 56 AD and frontal cortex: 7 controls and 24 FTLD patients), western blot (frontal cortex: 14 controls, 5 AD and 67 FTLD patients), or ELISA (temporal cortex: 11 controls and 7 AD and frontal cortex: 14 controls, 5 AD and 67 FTLD patients). YKL-40 levels were also measured in paired post-mortem brain and ante-mortem CSF samples from dementia patients (n = 9, time-interval collection: 1.4 years) by ELISA. Results We observed that YKL-40 post-mortem brain levels were similar between AD, FTLD, and controls as shown by immunohistochemistry, western blot, and ELISA. Interestingly, strong YKL-40 immunoreactivity was observed in AD cases with cerebral amyloid angiopathy (CAA; n = 6). In paired CSF-brain samples, YKL-40 concentration was 8-times higher in CSF compared to brain. Conclusion Our data suggest that CSF YKL-40 changes may not reflect YKL-40 changes within AD and FTLD pathological brain areas. The YKL-40 reactivity associated with classical CAA hallmarks indicates a possible relationship between YKL-40, neuroinflammation, and vascular pathology. Keywords: YKL-40, Chitinase 3-like I, Alzheimer's disease, Frontotemporal lobar degeneration, Neuroinflammation, Brain
Low enrollment in U.S. biomedical research by non-White adults has historically been attributed to mistrust, but few studies have simultaneously examined dimensions of trust in three or more ...racial/ethnic groups. Leveraging the racial/ethnic diversity of New Jersey, we prospectively recruited 293 adults (72% women, 38% older than 54 years of age) between October 2020 and February 2022 to complete two anonymous surveys in English or one of the common languages (e.g., Spanish, Mandarin Chinese). The first consisted of 12 Likert Scale questions related to trust in biomedical researchers (according to safety, equity, transparency), and the second assessed willingness to consider participation in eight common research activities (health-related survey, blood collection, genetic analysis, medication study, etc). Participants self-reported as Hispanic (n=102), Black (n=49), Chinese (n=48), other Asian (n=53), or White (n=41) race/ethnicity. Factor analysis showed three aspects related to trust in researchers: researchers as fiduciaries for research participants, racial/ethnic equity in research, and transparency. Importantly, we observed differences in the relationship between mistrust and willingness to participate. Whereas Chinese respondents' low trust in researchers mediated their low interest in research involving more than health-related surveys, Hispanic respondents' low trust in research equity did not deter high willingness to participate in research involving blood and genetic analysis. We caution that a generic association between trust and research participation should not be broadly assumed, and biomedical researchers should prospectively assess this relationship within each minoritized group to avoid hasty generalization.
Older African Americans are more likely to develop Alzheimer's disease (AD) than older Caucasians, and this difference cannot be readily explained by cerebrovascular and socioeconomic factors alone. ...We previously showed that mild cognitive impairment and AD dementia were associated with attenuated increases in the cerebrospinal fluid (CSF) levels of total and phosphorylated tau in African Americans compared to Caucasians, even though there was no difference in beta-amyloid 1-42 level between the two races.
We extended our work by analyzing early functional magnetic resonance imaging (fMRI) biomarkers of the default mode network in older African Americans and Caucasians. We calculated connectivity between nodes of the regions belonging to the various default mode network subsystems and correlated these imaging biomarkers with non-imaging biomarkers implicated in AD (CSF amyloid, total tau, and cognitive performance).
We found that race modifies the relationship between functional connectivity of default mode network subsystems and cognitive performance, tau, and amyloid levels.
These findings provide further support that race modifies the AD phenotypes downstream from cerebral amyloid deposition, and identifies key inter-subsystem connections for deep imaging and neuropathologic characterization.
Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer’s disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal ...levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of Aβ42, tau and p-tau
181
). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Aβ42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1α), but not in cognitively normal subjects. A multi-prong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1α, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1α and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.
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