Functionally distinct pericyte subsets differently regulate amyloid-ß deposition in patients with Alzheimer's disease.

Although the concept that the blood-brain barrier (BBB) plays an important role in the etiology and pathogenesis of Alzheimer's disease (AD) has become increasingly accepted, little is known yet about how it actually contributes. We and others have recently identified a novel functionally distinct subset of BBB pericytes (PCs). In the present study, we sought to determine whether these PC subsets differentially contribute to AD-associated pathologies by immunohistochemistry and amyloid beta (Aß) peptidomics. We demonstrated that a disease-associated PC subset (PC2) expanded in AD patients compared to age-matched, cognitively unimpaired controls. Surprisingly, we found that this increase in the percentage of PC2 (%PC2) was correlated negatively with BBB breakdown in AD patients, unlike in natural aging or other reported disease conditions. The higher %PC2 in AD patients was also correlated with a lower Aß42 plaque load and a lower Aß42:Aß40 ratio in the brain as determined by immunohistochemistry. Colocalization analysis of multicolor confocal immunofluorescence microscopy images suggests that AD patient with low %PC2 have higher BBB breakdown due to internalization of Aß42 by the physiologically normal PC subset (PC1) and their concomitant cell death leading to more vessels without PCs and increased plaque load. On the contrary, it appears that PC2 can secrete cathepsin D to cleave and degrade Aß built up outside of PC2 into more soluble forms, ultimately contributing to less BBB breakdown and reducing Aß plaque load. Collectively our data shows functionally distinct mechanisms for PC1 and PC2 in high Aß conditions, demonstrating the importance of correctly identifying these populations when investigating the contribution of neurovascular dysfunction to AD pathogenesis.

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] ß = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] ß = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] ß = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] ß = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] ß = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] ß = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] ß = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.

Utility of amyloid PET Imaging in a Memory Clinic.

There is greater interest in amyloid biomarker for the diagnosis of Alzheimer disease (AD) with the recent Food and Drug Administration approval of amyloid-targeted therapy. The goal of this study was to assess the clinical utility of amyloid positron emission tomography (PET) in clinically ambiguous cases of cognitive impairment by examining outcomes of patients enrolled in the Imaging Dementia-Evidence of Amyloid Scanning study at 2 academic institutions. Of the 112 patients in the study, 66.1% (n=74) of patients had a positive amyloid PET scan, and 33.96% (n=38) had a negative amyloid PET scan. Lower cognitive test scores were predictive of positive amyloid PET scan ( P =0.001). Eighty-two percent (92/112) of the patients were seen for follow-up. Of the 30 patients with negative amyloid PET scan results, 90% had a diagnosis of non-AD etiology after receiving the negative results, suggesting a negative amyloid scan can be used to rule out AD diagnosis.

Atypical Case of VV1 Creutzfeldt-Jakob Disease Subtype: Case Report.

Creutzfeldt-Jakob disease (CJD) is a rare form of rapidly progressive, neurodegenerative disease that results from the misfolding and accumulation of an aberrant, disease-associated prion protein (PrPD). CJD affects 1-1.5 cases per million per year with the sporadic-type accounting for an estimated 85% of these cases. Sporadic CJD (sCJD) is further subdivided into five subtypes based on genetic polymorphisms; the rarest subtype, sCJDVV1, occurs at a rate of 1 case per one-hundredth million population per year. Clinical characteristics of the sCJDVV1 subtype have been reported to show, early age of onset (44 years), average disease duration of 21 months, absent PSWCs on electroencephalography (EEG), and MRI hyperintensities in the cerebral cortex with usual negative signal in the basal ganglia or thalamus. We present a case of the sCJDVV1 subtype with uncommon features. Contrary to current data on sCJDVV1, our patient presented with an unusual age at onset (61 years) and longer disease duration (32 months). The highly sensitive and specific real-time quaking-induced conversion (RT-QuIC) assay was negative. Presenting clinical symptoms included paranoid thoughts and agitation, rapidly progressive memory decline, prosopagnosia, and late development of myoclonus and mutism. Other findings showed positive antithyroid peroxidase antibodies (anti-TPO), and absent PSWCs on EEG. High-dose steroid therapy treatment was administered based on positive anti-TPO findings, which failed to elicit any improvement and the patient continued to decline. To our knowledge, only four cases with the sCJDVV1 subtype, including our patient, have been reported to have a negative result on RT-QuIC. This may suggest varied sensitivity across sCJD subtypes. However, given the rarity of our patient's subtype, and the relatively novel RT-QuIC, current data are based on a small number of cases and larger cohorts of confirmed VV1 cases with RT-QuIC testing need to be reported.

Sleep in Alzheimer's disease: a systematic review and meta-analysis of polysomnographic findings.

Polysomnography (PSG) studies of sleep changes in Alzheimer's disease (AD) have reported but not fully established the relationship between sleep disturbances and AD. To better detail this relationship, we conducted a systematic review and meta-analysis of reported PSG differences between AD patients and healthy controls. An electronic literature search was conducted in EMBASE, MEDLINE, All EBM databases, CINAHL, and PsycINFO inception to Mar 2021. Twenty-eight studies were identified for systematic review, 24 of which were used for meta-analysis. Meta-analyses revealed significant reductions in total sleep time, sleep efficiency, and percentage of slow-wave sleep (SWS) and rapid eye movement (REM) sleep, and increases in sleep latency, wake time after sleep onset, number of awakenings, and REM latency in AD compared to controls. Importantly, both decreased SWS and REM were significantly associated with the severity of cognitive impairment in AD patients. Alterations in electroencephalogram (EEG) frequency components and sleep spindles were also observed in AD, although the supporting evidence for these changes was limited. Sleep in AD is compromised with increased measures of wake and decreased TST, SWS, and REM sleep relative to controls. AD-related reductions in SWS and REM sleep correlate with the degree of cognitive impairment. Alterations in sleep EEG frequency components such as sleep spindles may be possible biomarkers with relevance for diagnosing AD although their sensitivity and specificity remain to be clearly delineated. AD-related sleep changes are potential targets for early therapeutic intervention aimed at improving sleep and slowing cognitive decline.

Discordance Between Cerebrospinal Fluid Biomarkers and Amyloid Positron Emission Tomography in Alzheimer's Sheds Light on Clinical Trial Exclusion Criteria.

Alzheimer's disease (AD) is the most common type of dementia and affects millions of adults over the age of 60 years. Accurate diagnosis relies on multiple modalities, including neuropsychological testing, cerebrospinal fluid (CSF) biomarkers, and amyloid positron emission tomography (PET) imaging. Discordant results between CSF biomarkers and amyloid PET can be seen in up to 15% of cases and can lead to exclusion from clinical trials along with anxiety and confusion for the patient and family. We present two cases of discordance (CSF+, amyloid PET-) that resulted in the exclusion of both patients from two large anti-amyloid monoclonal antibody trials.

Low-Frequency Transcranial Magnetic Stimulation (LF-TMS) in Treating Depression in Patients With Impaired Cognitive Functioning.

OBJECTIVE: Common methodologies for treating depressive symptoms have demonstrated decreased efficacy among individuals with impaired cognitive functioning. While transcranial magnetic stimulation (TMS) has been approved to treat major depressive disorder, few studies have analyzed the ability of TMS to treat depressive symptoms among individuals with cognitive impairments. The present study had two objectives: to determine whether low-frequency TMS (LF-TMS) might demonstrate efficacy in treating depressive symptoms among individuals with impaired cognitive functioning; and to determine whether LF-TMS might improve neurocognitive functioning above and beyond depressive symptom improvements. METHODS: Data were derived from a pre-existing database at Eastern Virginia Medical School. Fifty-three (N=53) participants completed LF-TMS treatment. The Beck Depression Inventory II (BDI-II) and CNS Vital Signs (CNS-VS) neurocognitive assessment were administered at multiple time points throughout treatment. Participants were classified as impaired cognitive functioning or average cognitive functioning based on baseline CNS-VS scores. Data were analyzed using restricted maximum likelihood (REML) measures-within-persons longitudinal hierarchical linear modeling (HLM) with time-varying covariates. RESULTS: LF-TMS produced significant reductions in depressive symptoms for individuals in both cognitive functioning groups; however, a significant group-by-time interaction indicates differential effects between these two groups. Low-frequency TMS produced significant improvements in three neurocognitive domains above and beyond improvements in depressive symptoms; however, the reliability of these changes may be questionable. CONCLUSIONS: This study adds to the growing body of empirical findings for LF-TMS treatment in improving neurocognitive functioning above and beyond other treatment-related effects.

A subtype of cerebrovascular pericytes is associated with blood-brain barrier disruption that develops during normal aging and simian immunodeficiency virus infection.

Lax phenotypic characterization of these morphologically distinct pericytes has delayed our understanding of their role in neurological disorders. We herein establish markers which uniquely distinguish different subpopulations of human brain microvascular pericytes and characterize them independently from cerebrovascular smooth muscle cells. Furthermore, we begin to elucidate the roles of these subsets in blood-brain barrier (BBB) breakdown by studying natural aging and simian immunodeficiency virus (SIV) infection in rhesus macaques. We demonstrate that the main type-1 pericyte subpopulation in the brain of young uninfected adults is positive for platelet-derived growth factor receptor-ß (PDGFRB) and negative for α-smooth muscle actin (SMA) and myosin heavy chain 11 (MYH11), whereas PDGFRB+/SMA+/MYH11- (type-2) pericytes are found more frequently in older adults and are associated with SIV infection and progression. Interestingly, we find a strong positive correlation between the degree of BBB breakdown and the percentage of type-2 pericytes regardless of age or SIV status. Taken together, our findings suggest that type-2 pericytes may be a cellular biomarker related to BBB disruption independent of disease status.

Perivascular macrophages in the neonatal macaque brain undergo massive necroptosis after simian immunodeficiency virus infection.

We previously showed that rhesus macaques neonatally infected with simian immunodeficiency virus (SIV) do not develop SIV encephalitis (SIVE) and maintain low brain viral loads despite having similar plasma viral loads compared to SIV-infected adults. We hypothesize that differences in myeloid cell populations that are the known target of SIV and HIV in the brain contribute to the lack of neonatal susceptibility to lentivirus-induced encephalitis. Using immunohistochemistry and immunofluorescence microscopy, we examined the frontal cortices from uninfected and SIV-infected infant and adult macaques (n = 8/ea) as well as adults with SIVE (n = 4) to determine differences in myeloid cell populations. The number of CD206+ brain perivascular macrophages (PVMs) was significantly greater in uninfected infants than in uninfected adults and was markedly lower in SIV-infected infants while microglia numbers were unchanged across groups. CD206+ PVMs, which proliferate after infection in SIV-infected adults, did not undergo proliferation in infants. While virtually all CD206+ cells in adults are also CD163+, infants have a distinct CD206 single-positive population in addition to the double-positive population commonly seen in adults. Notably, we found that more than 60% of these unique CD206+CD163- PVMs in SIV-infected infants were positive for cleaved caspase-3, an indicator of apoptosis, and that nearly 100% of this subset were concomitantly positive for the necroptosis marker receptor-interacting protein kinase-3 (RIP3). These findings show that distinct subpopulations of PVMs found in infants undergo programmed cell death instead of proliferation following SIV infection, which may lead to the absence of PVM-dependent SIVE and the limited size of the virus reservoir in the infant brain.

Evaluation of a clinically practical, ERP-based neurometric battery: Application to age-related changes in brain function.

OBJECTIVE: Event-related potentials (ERPs) show promise as markers of neurocognitive dysfunction, but conventional recording procedures render measurement of many ERP-based neurometrics clinically impractical. The purpose of this work was (a) to develop a brief neurometric battery capable of eliciting a broad profile of ERPs in a single, clinically practical recording session, and (b) to evaluate the sensitivity of this neurometric profile to age-related changes in brain function. METHODS: Nested auditory stimuli were interleaved with visual stimuli to create a 20-min battery designed to elicit at least eight ERP components representing multiple sensory, perceptual, and cognitive processes (Frequency & Gap MMN, P50, P3, vMMN, C1, N2pc, and ERN). Data were recorded from 21 younger and 21 high-functioning older adults. RESULTS: Significant multivariate differences were observed between ERP profiles of younger and older adults. Metrics derived from ERP profiles could be used to classify individuals into age groups with a jackknifed classification accuracy of 78.6%. CONCLUSIONS: Results support the utility of this design for neurometric profiling in clinical settings. SIGNIFICANCE: This study demonstrates a method for measuring a broad profile of ERP-based neurometrics in a single, brief recording session. These markers may be used individually or in combination to characterize/classify patterns of sensory and/or perceptual brain function in clinical populations.

Preventive health care in the elderly population: a guide for practicing physicians.

Preventive medicine provides important benefits to all persons, including older adults; however, these benefits may be seen more clearly in younger adults than in older persons. Smoking cessation, proper nutrition, exercise, and immunizations are important regardless of age. The prevalence of illness increases as we age; at the same time, life expectancy decreases. All physicians and patients should consider the potential benefits of screening and treatment vs conservative management. We discuss lifestyle recommendations such as smoking cessation, exercise, and good nutrition, as well as the role of screening for cardiovascular disease, cancer, and sensory and other disorders. These recommendations are derived from evidence-based guidelines when available; issues not associated with established guidelines are discussed on the basis of best current thinking.