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The latest medical research on Geriatric Medicine

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Vocal expression of emotions discriminates dementia with Lewy bodies from Alzheimer's disease.

Alzheimers Dementia Amsterdam

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), the two most common neurodegenerative dementias, both exhibit altered emotional processing. However, how vocal emotional expressions alter in and differ between DLB and AD remains uninvestigated. We collected voice data during story reading from 152 older adults comprising DLB, AD, and cognitively unimpaired (CU) groups and compared their emotional prosody in terms of valence and arousal dimensions. Compared with matched AD and CU participants, DLB patients showed reduced overall emotional expressiveness, as well as lower valence (more negative) and lower arousal (calmer), the extent of which was associated with cognitive impairment and insular atrophy. Classification models using vocal features discriminated DLB from AD and CU with an AUC of 0.83 and 0.78, respectively. Our findings may aid in discriminating DLB patients from AD and CU individuals, serving as a surrogate marker for clinical and neuropathological changes in DLB.

DLB showed distinctive reduction in vocal expression of emotions.Cognitive impairment was associated with reduced vocal emotional expression in DLB.Insular atrophy was associated with reduced vocal emotional expression in DLB.Emotional expression measures successfully differentiated DLB from AD or controls.

Trial of Thrombectomy for Stroke with a Large Infarct of Unrestricted Size.

N Engl J

The use of thrombectomy in patients with acute stroke and a large infarct of unrestricted size has not been well studied.

We assigned, in a 1:1 ratio, patients with proximal cerebral vessel occlusion in the anterior circulation and a large infarct (as defined by an Alberta Stroke Program Early Computed Tomographic Score of ≤5; values range from 0 to 10) detected on magnetic resonance imaging or computed tomography within 6.5 hours after symptom onset to undergo endovascular thrombectomy and receive medical care (thrombectomy group) or to receive medical care alone (control group). The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). The primary safety outcome was death from any cause at 90 days, and an ancillary safety outcome was symptomatic intracerebral hemorrhage.

A total of 333 patients were assigned to either the thrombectomy group (166 patients) or the control group (167 patients); 9 were excluded from the analysis because of consent withdrawal or legal reasons. The trial was stopped early because results of similar trials favored thrombectomy. Approximately 35% of the patients received thrombolysis therapy. The median modified Rankin scale score at 90 days was 4 in the thrombectomy group and 6 in the control group (generalized odds ratio, 1.63; 95% confidence interval [CI], 1.29 to 2.06; P<0.001). Death from any cause at 90 days occurred in 36.1% of the patients in the thrombectomy group and in 55.5% of those in the control group (adjusted relative risk, 0.65; 95% CI, 0.50 to 0.84), and the percentage of patients with symptomatic intracerebral hemorrhage was 9.6% and 5.7%, respectively (adjusted relative risk, 1.73; 95% CI, 0.78 to 4.68). Eleven procedure-related complications occurred in the thrombectomy group.

In patients with acute stroke and a large infarct of unrestricted size, thrombectomy plus medical care resulted in better functional outcomes and lower mortality than medical care alone but led to a higher incidence of symptomatic intracerebral hemorrhage. (Funded by Montpellier University Hospital; LASTE ClinicalTrials.gov number, NCT03811769.).

Recombinant ADAMTS13 for Immune Thrombotic Thrombocytopenic Purpura.

N Engl J

In patients with immune thrombotic thrombocytopenic purpura (iTTP), autoantibodies against the metalloprotease ADAMTS13 lead to catastrophic microv...

Association between retinal microvascular abnormalities and late-life brain amyloid-β deposition: the ARIC-PET study.

Journal Alzheimers Research Therapy

Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer's disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid.

Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-β (Aβ) by florbetapir PET were tested. Two different measures of Aβ burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures' association with Aβ burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aβ burden.

Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (β (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (β (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors.

Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.

Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in an Alzheimer's disease mouse model.

Journal Alzheimers Research Therapy

In Alzheimer's disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue.

Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113).

Treatment resulted in significant reductions in amyloid-beta (Aβ) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice.

This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

Video versus Direct Laryngoscopy for Urgent Intubation of Newborn Infants.

N Engl J

Repeated attempts at endotracheal intubation are associated with increased adverse events in neonates. When clinicians view the airway directly with a laryngoscope, fewer than half of first attempts are successful. The use of a video laryngoscope, which has a camera at the tip of the blade that displays a view of the airway on a screen, has been associated with a greater percentage of successful intubations on the first attempt than the use of direct laryngoscopy in adults and children. The effect of video laryngoscopy among neonates is uncertain.

In this single-center trial, we randomly assigned neonates of any gestational age who were undergoing intubation in the delivery room or neonatal intensive care unit (NICU) to the video-laryngoscopy group or the direct-laryngoscopy group. Randomization was stratified according to gestational age (<32 weeks or ≥32 weeks). The primary outcome was successful intubation on the first attempt, as determined by exhaled carbon dioxide detection.

Data were analyzed for 214 of the 226 neonates who were enrolled in the trial, 63 (29%) of whom were intubated in the delivery room and 151 (71%) in the NICU. Successful intubation on the first attempt occurred in 79 of the 107 patients (74%; 95% confidence interval [CI], 66 to 82) in the video-laryngoscopy group and in 48 of the 107 patients (45%; 95% CI, 35 to 54) in the direct-laryngoscopy group (P<0.001). The median number of attempts to achieve successful intubation was 1 (95% CI, 1 to 1) in the video-laryngoscopy group and 2 (95% CI, 1 to 2) in the direct-laryngoscopy group. The median lowest oxygen saturation during intubation was 74% (95% CI, 65 to 78) in the video-laryngoscopy group and 68% (95% CI, 62 to 74) in the direct-laryngoscopy group; the lowest heart rate was 153 beats per minute (95% CI, 148 to 158) and 148 (95% CI, 140 to 156), respectively.

Among neonates undergoing urgent endotracheal intubation, video laryngoscopy resulted in a greater number of successful intubations on the first attempt than direct laryngoscopy. (Funded by the National Maternity Hospital Foundation; VODE ClinicalTrials.gov number, NCT04994652.).

Gene Editing for CEP290-Associated Retinal Degeneration.

N Engl J

CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant).

We performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children).

EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.

The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1-2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.).

Prenatal Exposure to the 1944-45 Dutch Famine and Risk for Dementia up to Age 75: An Analysis of Primary Care Data.

Current Alzheimer Research

A poor prenatal environment adversely affects brain development. Studies investigating long-term consequences of prenatal exposure to the 1944-45 Dutch famine have shown that those exposed to famine in early gestation had poorer selective attention, smaller brain volumes, poorer brain perfusion, older appearing brains, and increased reporting of cognitive problems, all indicative of increased dementia risk.

In the current population-based study, we investigated whether dementia incidence up to age 75 was higher among individuals who had been prenatally exposed to famine.

We included men (n=6,714) and women (n=7,051) from the Nivel Primary Care Database who had been born in seven cities affected by the Dutch famine. We used Cox regression to compare dementia incidence among individuals exposed to famine during late (1,231), mid (1,083), or early gestation (601) with those unexposed (born before or conceived after the famine).

We did not observe differences in dementia incidence for those exposed to famine in mid or early gestation compared to those unexposed. Men and women exposed to famine in late gestation had significantly lower dementia rates compared to unexposed individuals (HR 0.52 [95%CI 0.30-0.89]). Sex-specific analyses showed a lower dementia rate in women exposed to famine in late gestation (HR 0.39 [95%CI 0.17-0.86]) but not in men (HR 0.68 [95%CI 0.33-1.41]).

Although prenatal exposure to the Dutch famine has previously been associated with measures of accelerated brain aging, the present population-based study did not show increased dementia incidence up to age 75 in those exposed to famine during gestation.

Culturally adapted cognitive assessment tool for Indigenous communities in Brazil: Content, construct, and criterion validity.

Alzheimers Dementia Amsterdam

Initial dementia prevalence estimates have revealed a significant burden of the disease in Indigenous communities in Amazonas, Brazil. However, the need for culturally adapted cognitive tools poses a critical challenge when assessing cognitive performance in these communities. This study addressed this issue by culturally adapting and providing validity indicators for the Brazilian Indigenous Cognitive Assessment (BRICA) tool in Manaus, Brazil's urban multiethnic Indigenous community.

Using a three-stage process and a stakeholder-engaged approach, the BRICA tool was culturally adapted in an urban multiethnic Indigenous community from Manaus, Brazil. The content validity index (CVI) examined inter-rater concordance between experts, while criterion and concurrent validity were performed using diagnostic consensus criteria in 141 Indigenous participants aged ≥ 50 years.

Findings showed evidence of content validity in terms of equivalence aspects (scale CVI [S-CVI] 0.93) and relevance ratings (S-CVI 0.85) between expert panels. The identified cut-off score of ≤ 33/39 on the BRICA demonstrated a sensitivity of 94.4%, specificity of 99.2%, positive predictive value of 94.4%, and negative predictive value of 99.2% for dementia diagnosis.

Using a stakeholder-engaged approach, we culturally adapted the BRICA tool for a Brazilian urban multiethnic Indigenous community. This comprehensive adaptation process resulted in favorable indicators of content, construct, and criteria validity for the BRICA tool. By addressing the existing bias in cognitive assessment within Indigenous communities, the BRICA tool represents a noteworthy breakthrough. Its implementation exhibits potential for improving the early detection and management of dementia among Indigenous groups.

Culturally sensitive tools are essential to assess cognition in Indigenous populations.An expert panel and stakeholders' perspectives were incorporated to design the Brazilian Indigenous Cognitive Assessment (BRICA) tool.A cognitive screening tool was adapted and validated using a stakeholder approach.BRICA is the first culturally sensitive cognitive tool for urban Brazilian Indigenous individuals.

The relation of a cerebrospinal fluid profile associated with Alzheimer's disease with cognitive function and neuropsychiatric symptoms in sporadic cerebral amyloid angiopathy.

Journal Alzheimers Research Therapy

Patients with sporadic cerebral amyloid angiopathy (sCAA) frequently report cognitive or neuropsychiatric symptoms. The aim of this study is to investigate whether in patients with sCAA, cognitive impairment and neuropsychiatric symptoms are associated with a cerebrospinal fluid (CSF) biomarker profile associated with Alzheimer's disease (AD).

In this cross-sectional study, we included participants with sCAA and dementia- and stroke-free, age- and sex-matched controls, who underwent a lumbar puncture, brain MRI, cognitive assessments, and self-administered and informant-based-questionnaires on neuropsychiatric symptoms. CSF phosphorylated tau, total tau and Aβ42 levels were used to divide sCAA patients in two groups: CAA with (CAA-AD+) or without a CSF biomarker profile associated with AD (CAA-AD-). Performance on global cognition, specific cognitive domains (episodic memory, working memory, processing speed, verbal fluency, visuoconstruction, and executive functioning), presence and severity of neuropsychiatric symptoms, were compared between groups.

sCAA-AD+ (n=31; mean age: 72 ± 6; 42%, 61% female) and sCAA-AD- (n=23; 70 ± 5; 42% female) participants did not differ with respect to global cognition or type of affected cognitive domain(s). The number or severity of neuropsychiatric symptoms also did not differ between sCAA-AD+ and sCAA-AD- participants. These results did not change after exclusion of patients without prior ICH.

In participants with sCAA, a CSF biomarker profile associated with AD does not impact global cognition or specific cognitive domains, or the presence of neuropsychiatric symptoms.

Clinical validity of the Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB) in Mild Cognitive Impairment and Alzheimer's Disease.

Journal Alzheimers Research Therapy

The identification and staging of Alzheimer's Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD.

One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses.

Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI.

Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD.

Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer's disease, suspected-LATE and frontotemporal dementia.

Journal Alzheimers Research Therapy

The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.

Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.

We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.

The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.