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Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations., Competing Interests: A.C.B. is site PI for the Alector INFRONT-3 trial. A.L.B. receives research support from NIH (R01AG038791, R01AG073482, and U24AG057437), Rainwater Charitable Foundation, Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Alzheimer’s Drug Discovery Foundation, and the Alzheimer’s Association. He has served as a consultant for Alector, AGTC, Arkuda, Arvinas, AZTherapies, GSK, Oligomerix, Ono, Roche, Samumed, Stealth, Third Rock, Transposon, TrueBinding, and Wave and received research support from Biogen, Eisai, and Regeneron. B.F.B. has served as an investigator for clinical trials sponsored by Biogen, Alector, and EIP Pharma. He receives royalties from a published book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009, 2017), serves on the Tau Consortium Scientific Advisory Board, and receives research support from the NIH. B.C.D. consults for Acadia, Arkuda, Axovant, Lilly, Biogen, Merck, Novartis, and Wave LifeSciences; has Elsevier editorial duties with payment (Neuroimage: Clinical and Cortex); and receives royalties from Oxford University Press and Cambridge University Press. K.D.-R. has research funding from Biogen and Lawson Health Research Institute and receives consultant fees from Biogen and educational fees from MedBridge. D.R.G. consults for Biogen, Fujirebio, and Amprion and is on the DSMB for Cognition Therapeutics. M.G. is participating in treatment trials sponsored by Alector, Prevail, and Passage Bio and is a consultant to Takeda, Passage Bio, and Biogen. N.G. has or is participating in clinical trials of anti-dementia drugs sponsored by Bristol Myers Squibb, Lilly/Avid Radiopharmaceuticals, Janssen, Novartis, Pfizer, and Wyeth. N.R.G.-R. has taken part in multicenter studies funded by Biogen, AbbVie, and Lilly. G.-Y.R.H. has received research support from Anavax, Biogen, and Roche. I.L. received support from Roche, Abbvie, Biogen, EIP-Pharma, and Biohaven Pharmaceuticals; was member of a Lundbeck Advisory Board; and receives salary from the University of California, San Diego and as Chief Editor of Frontiers in Neurology. J.C.M. participates on a speaker forum for Biogen and receives research support from Biogen, Eisai, Eli Lilly, Green Valley, and Novartis. C.U.O. is a consultant with Alector and Acadia and receives research funding from Alector. L.P. is a consultant for Expansion Therapeutics. E.D.R. receives funding from NIH, Alzheimer’s Drug Discovery Foundation, Bluefield Project, and Alector; consults for Biogen, AVROBIO, and AGTC; and owns intellectual property related to tau. J.C.R. is a site PI for Eli Lilly and Eisai clinical trials and receives research support from NIH K23AG059888. M.C.T. participates in clinical trials with Biogen, Avanex, UCB, and Janssen. Z.K.W. is supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, the gifts from The Sol Goldman Charitable Trust, the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson’s Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301); Neuraly, Inc. (NLY01-PD-1); and Vigil Neuroscience, Inc. (VGL101–01.001) grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for Vigil Neuroscience, Inc. All other authors report no competing interests., (© 2022 The Author(s).)

Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with cerebrospinal fluid/positron emission tomography biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/amyloid-β42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Depression and circadian rhythm disruptions are non-cognitive neuropsychiatric symptoms (NPS) that can appear at any stage of the Alzheimer's disease (AD) continuum. Evidence suggests that NPS are linked to AD pathophysiology and hippocampal dysfunction. Objective: To examine structural white matter (WM) connectivity and its association with gray matter (GM) atrophy and to identify specific AD-related neural networks linked to NPS in individuals with mild cognitive impairment (MCI). Methods: Ninety-six older adults participants were divided into three groups based on the Global Depression Scale, Neuropsychiatric Inventory, Clinical Dementia Rating, and Mini-Mental Status Examination. Twelve individuals with MCI and NPS (MCI+) and 49 without NPS (MCI-) were classified, along with 35 age and gender-matched healthy individuals. Voxel-based morphometry and tract-based spatial statistics were employed to identify structural and microstructural alterations. Network-based statistics analyzed structural WM connectivity differences between MCI groups and healthy controls. Results: Significant structural WM connectivity and GM loss were exclusively observed in MCI+ individuals compared to controls. The hippocampus, amygdala, and sensory cortex showed GM atrophy (p < 0.05), while the thalamus, pallidum, putamen, caudate, hippocampus, and sensory and frontal cortices exhibited structural WM connectivity loss (p < 0.01). These data indicate early limbic system involvement even without GM atrophy. Conclusions: Structural WM connectivity loss within the Papez circuit may precede and potentially predict GM atrophy in the temporal lobe of individuals with MCI+. These findings highlight the importance of investigating structural WM alterations in the prodromal phase of AD, which may inform diagnostic and therapeutic strategies in early AD. [ABSTRACT FROM AUTHOR]

The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses. Synopsis: In the early phase of Alzheimer's disease, astrocytes are the primary source of APOE in the brain. This study examined the effects of astrocyte-derived human APOE isoforms in APOE-deficient mouse brains on amyloid pathology and related cellular responses. Apoe-deficient mouse brains: Displayed no fibrillar amyloid plaques and had increased levels of soluble Aβ aggregates. Human APOE isoforms in astrocytes: Expression in astrocytes alone induced formation of fibrillar amyloid plaques (APOE4 > APOE2 > APOE3) and reduced soluble Aβ aggregates (APOE2 > APOE4 ≈ APOE3). Astrocyte transcriptomics: APOE isoforms caused differential changes, suggesting possible impairment of proteostasis and autophagy in APOE4 astrocytes. Microglial response: Apoe-deficient microglia exhibited clustering and a DAM-like response to amyloid pathology induced by astrocyte-secreted APOE. Astrocyte-derived APOE and microglia: Astrocyte-derived APOE could induce fibrillar amyloid plaques even without the presence of microglia, although to a lesser extent. In the early phase of Alzheimer's disease, astrocytes are the primary source of APOE in the brain. This study examined the effects of astrocyte-derived human APOE isoforms in APOE-deficient mouse brains on amyloid pathology and related cellular responses. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) and mild behavioral impairment (MBI) are both considered potential prodromal stages of dementia, especially Alzheimer's disease. Previous literature has lacked specific information about MBI in individuals with MCI and associations of several aspects of both, MBI and MCI. Objective: Our aim was to investigate whether associations exist between aspects of MBI and aspects of cognitive performance in certain dimensions of the Montreal Cognitive Assessment (MoCA). Methods: We used baseline data from the double-blind randomized controlled intervention MCI-CCT-study. Current cognitive performance of individuals with MCI was measured with the MoCA. MBI was assessed with the MBI Shortscale (MBI short), which was administered through a self-report interview. Associations were assessed with Pearson correlations. Sensitivity analyses were conducted for gender and cognition. Group differences were examined with independent samples t-tests or Welch test. Significant correlations were considered in binary logistic regressions under control of covariates. Results: There was no significant correlation between the current MoCA and MBI short scores in the total sample or in the gender-related analysis. Using dichotomized cognitive performance, significant correlations between MCI and MBI were revealed for individuals with lower MoCA scores. On the task level, several significant associations were identified between MoCA dimensions and MBI dimensions in the total sample and in the sensitivity analyses, also under control of covariates. Conclusions: Our findings support the hypothesis that with increasing cognitive decline, the association between MCI and MBI becomes stronger. Furthermore, a certain cut-off on the MoCA must be reached to identify a correlation. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is classically characterized by alterations in memory consolidation. With the advent of diagnostic biomarkers, some patients clinically diagnosed with AD display biomarkers inconsistent with the diagnosis. Objective: We aimed to explore differences in memory consolidation and neurodegeneration of the temporal and parietal lobes as a function of amyloid-β status in amnestic mild cognitive impairment (aMCI). Methods: We examined differences in memory consolidation and neurodegeneration between patients diagnosed with amyloid-β positive aMCI (Aβ+ N = 78), amyloid-β negative aMCI (Aβ− N = 48), and healthy participants (HP; N = 41), within a well-characterized clinical cohort. Results: Aβ+ exhibited more pronounced consolidation impairments compared to Aβ−, while Aβ− faced more consolidation challenges than HP. Both Aβ+ and Aβ− were similar in hippocampal volume and entorhinal thickness, but Aβ+ had thinner inferior parietal cortex than Aβ−. Using 18F-fluoro-deoxyglucose-positron emission tomography, metabolism in both temporal and parietal regions was lower in Aβ+ relative to Aβ−. Conclusions: These findings suggest pathologies other than AD likely contribute to memory consolidation difficulties in aMCI, and neurodegeneration of the parietal cortex in combination with hypometabolism may contribute to more pronounced consolidation problems in Aβ+. [ABSTRACT FROM AUTHOR]

A conundrum in Alzheimer's disease (AD) is why the long-term use of acetylcholinesterase (AChE) inhibitors, intended for treatment of dementia, results in slowing neurodegeneration in the cholinergic basal forebrain, hippocampus, and cortex. The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only the onset of dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein, early should be a high priority as a strategy to help reduce dementia and its associated widespread social and economic suffering. [ABSTRACT FROM AUTHOR]

Selective vulnerability of neuronal populations occurs in both Down syndrome (DS) and Alzheimer's disease (AD), resulting in disproportional degeneration of pyramidal neurons (PNs) affecting memory and executive function. Elucidating the cellular mechanisms underlying the selective vulnerability of these populations will provide pivotal insights for disease progression in DS and AD. Single population RNA-sequencing analysis was performed on neurons critical for executive function, prefrontal cortex Brodmann area 9 (BA9) layer III (L3) and layer V (L5) excitatory PNs in postmortem human DS and age- and sex-matched control (CTR) brains. Data mining was performed on differentially expressed genes (DEGs) from PNs in each lamina with DEGs divergent between lamina identified and interrogated. Bioinformatic inquiry of L3 PNs revealed more unique/differentially expressed DEGs (uDEGs) than in L5 PNs in DS compared to CTR subjects, indicating gene dysregulation shows both spatial and cortical laminar projection neuron dependent dysregulation. DS triplicated human chromosome 21 (HSA21) comprised a subset of DEGs only dysregulated in L3 or L5 neurons, demonstrating partial cellular specificity in HSA21 expression. These HSA21 uDEGs had a disproportionally high number of noncoding RNAs, suggesting lamina specific dysfunctional gene regulation. L3 uDEGs revealed overall more dysregulation of cellular pathways and processes, many relevant to early AD pathogenesis, while L5 revealed processes suggestive of frank AD pathology. These findings indicate that trisomy differentially affects a subpopulation of uDEGs in L3 and L5 BA9 projection neurons in aged individuals with DS, which may inform circuit specific pathogenesis underlying DS and AD. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) are common in hereditary ataxias as a part of the cerebellar cognitive affective syndrome. In Friedreich ataxia (FRDA), one of the most common hereditary ataxias, depressive symptoms were previously reported, but little is known about other NPS. We aimed to study the presence and severity of a broad range of NPS in individuals with FRDA and assess the relationship between the NPS and the disease severity, cognition, and quality of life and to examine the concordance between the NPS reported by the patients and by their informants. Mild Behavioral Impairment Checklist (MBI-C), a questionnaire designed for screening NPS in the early stages of neurodegenerative diseases, was administered to informants of individuals with FRDA and healthy controls and to people with FRDA themselves. Compared to healthy controls, patients with FRDA scored significantly higher in the total MBI-C score, emotion dysregulation domain (corresponding to depression and anxiety), and decreased motivation domain. When assessed by caregiver, the total MBI-C score and several NPS domains correlated with activities of daily living. Only psychotic symptoms were related to ataxia severity and general cognition. When endorsed by patients, only the relation between few MBI-C domains and quality of life was observed. We found slight to moderate agreement between informant-rated and patient-rated scores. NPS, particularly emotion dysregulation and decreased motivation, are common and clinically relevant in FRDA and should receive more attention due to their potential impact on quality of life and the possibility of therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Optical coherence tomography (OCT) enables high-resolution imaging of ocular structures in health and disease. Choroid thickness (CT) is a key vascular retinal parameter that can be assessed by OCT and might be relevant in the evaluation of the vascular component of cognitive decline. We aimed to investigate CT changes in a large cohort of individuals cognitive unimpaired (CU), with mild cognitive impairment due to Alzheimer's (MCI-AD), mild cognitive impairment due to cerebrovascular disease (MCI-Va), Alzheimer's disease dementia (ADD), and vascular dementia (VaD). Methods: Clinical, demographical, ophthalmological and OCT data from the Neuro-ophthalmological Research at Fundació ACE (NORFACE) project were analyzed. CT was assessed in the macula across nine Early Treatment Diabetic Retinopathy Study (ETDRS) quadrants, average thickness, total volume, and subfoveal choroidal thickness. Differences of CT among the five diagnostic groups were assessed in a multivariate regression model, adjusting for demographic and cardiovascular risk factors and OCT image quality. A comparison between manual and automatic CT measurements in a subset of participants was also performed. Results: The study cohort comprised 1,280 participants: 301 CU, 196 MCI-AD, 112 MCI-Va, 578 ADD, and 93 VaD. CT was significantly increased in individuals with cognitive impairment compared to those CU, particularly in the VaD and MCI-Va groups and in the peripheral ETDRS regions. No significant differences were found in inner superior, center and subfoveal choroidal thickness. The interaction of sex and diagnosis had no effect in differentiating CT. Mini-Mental State Examination (MMSE) scores were not correlated to CT. Manual and automated CT measurements showed good reliability. Discussion: Our findings indicated that peripheral choroidal thickening, especially in patients with cerebrovascular disease, may serve as a potential choroidal biomarker for cognitive decline and suggest different pathogenic pathways in AD and VaD. Further research is required to explore CT as a reliable ocular biomarker for cognitive impairment. [ABSTRACT FROM AUTHOR]

This review is an attempt to compile existing hypotheses on the mechanisms underlying the initiation and progression of Alzheimer's disease (AD), starting from sensory impairments observed in AD and concluding with molecular events that are typically associated with the disease. These events include spreading of amyloid plaques and tangles of hyperphosphorylated tau and formation of Hirano and Biondi bodies as well as the development of oxidative stress. We have detailed the degenerative changes that occur in several neuronal populations, including the cholinergic neurons in the nucleus basalis of Meynert, the histaminergic neurons in the tuberomammillary nucleus, the serotonergic neurons in the raphe nuclei, and the noradrenergic neurons in the locus coeruleus. Furthermore, we discuss the potential role of iron accumulation in the brains of subjects with AD in the disease progression which served as a basis for the idea that iron chelation in the brain may mitigate oxidative stress and decelerate disease development. We also draw attention to possible role of sympathetic system and, more specifically, noradrenergic neurons of the superior cervical ganglion in triggering of the disease. We also explore the alternative possibility of compensatory protective changes that may occur in these neurons to support cholinergic function in the forebrain of subjects with AD. [ABSTRACT FROM AUTHOR]

The frequency of behavioral and psychological symptoms of dementia (BPSD) is high, and it is a challenge to elucidate its neural substrates underlying their development. In recent years, many findings have been reported on the relationship between BPSD and brain volume in dementia patients. However, the results are not fully conclusive. Furthermore, there have been few population-based studies. Therefore, the relationship between BPSD and brain volume was investigated as an exploratory study. Of the 927 older persons who participated in the fifth Nakayama study, 90 were included in this analysis, consisting of 52 patients with mild cognitive impairment and 38 patients with dementia, with head MRI and the Neuropsychiatric Inventory (NPI) data. Multiple regression analysis was used to examine the association between the total score of each BPSD score on the NPI and brain volume estimated by FreeSurfer. On multivariate adjustment, even after false discovery rate correction, insular cortical volumes decreased significantly as total scores for apathy/indifference increased (p value = 0.002, q-value = 0.01). Similarly, total brain volume decreased significantly as total scores for appetite and eating disturbance increased (p value = 0.03), and parietal, temporal, and hippocampal cortical volumes also decreased significantly as total scores for appetite and eating disturbance increased (all p and q values < 0.05). This study's results suggest that apathy is negatively correlated with insular cortical volume, and that appetite and eating disturbance are also correlated with brain regions, including parietal, temporal, and hippocampal volume in a community-dwelling older population. [ABSTRACT FROM AUTHOR]

Background: Dementia preventive interventions targeting multiple modifiable risk factors are a promising approach. However, the impact of modifiable risk factors in the presence of beta-amyloid or phosphorylated-tau (p-tau) pathology is unclear. Methods: The objective of the study was to examine the role of modifiable risk factors (vascular factors, depression, and smoking) in the progression to mild cognitive impairment (MCI) or dementia among 434 cognitively unimpaired (CU) and 611 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Vascular risk factors were summarized with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, dichotomized into higher versus lower risk. Depression and smoking (yes/no) were categorised according to medical history or current symptoms. Analyses were stratified by beta-amyloid negative (A-) and positive (A +), p-tau negative (T-) and positive (T +), or beta-amyloid and p-tau negative (A-T-) and positive (A + T +) biomarker status. Cox proportional hazard models were adjusted for age, sex, education, baseline MMSE score, baseline hippocampal volume and ApoE4 carrier status. Results: Higher CAIDE score was associated with increased risk of progression to all-cause dementia in most MCI subgroups: adjusted hazard ratios (aHR) [95% CI] were 3.1 [1.43; 6.53] in the A- subgroup, 1.7 [1.20–2.27] in T + , 2.6 [1.06–6.59] in A-T-, and 1.6 [1.15–2.22] in the A + T + subgroup. Smoking (yes/no) was associated with increased dementia aHR in the A + MCI subgroup: 1.6 [1.07–2.34]. Depression increased dementia aHR in the T + MCI subgroup: 1.5 [1.06–2.02]. No significant associations were found in the CU biomarker subgroups. Conclusion: Addressing modifiable risk factors carries an important potential for reducing the risk of dementia even after the onset of Alzheimer's pathology. Knowledge of biomarker status can further optimize prevention strategies. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms are prevalent in patients with mild cognitive impairment (MCI) and are predictive of the conversion to dementia. Fortasyn Connect, a medical food, has shown efficacy in managing cognitive and behavioral symptoms associated with MCI. Early diagnosis and intervention in primary care are essential for managing MCI. However, real-world prospective studies assessing Fortasyn Connect in MCI are still limited. Methods: This observational, multicenter, prospective study will enroll 150 patients recently diagnosed with MCI by primary care physicians across several regions in Spain. Participants will be followed-up over a 12-month period, with assessments at baseline, 6 months, and 12 months, as per clinical practice. The study aims to evaluate the impact of Fortasyn Connect on neuropsychiatric symptoms, cognition, and health-related quality of life (HRQoL) using validated neuropsychological tests and machine learning (ML) techniques. The primary outcome measure will be changes in neuropsychiatric symptoms using the Neuropsychiatric Inventory Questionnaire (NPI-Q) at 6 months. Secondary outcome measures include further changes in the NPI-Q at 12 months, and changes in cognition (Fototest, and clock-drawing test) and HRQoL (EQ-5D-5L) at 6 and 12 months. Exploratory outcomes will assess speech using an artificial intelligence (AI)-enhanced ML tool, with a correlation analysis of these findings with traditional neuropsychological test results. Conclusion: This study will provide evidence of the effectiveness of Fortasyn Connect in a real-world setting, exploring its potential to stabilize or improve neuropsychiatric symptoms, cognition, and HRQoL in MCI patients. Results will also contribute to the understanding of AI and ML in identifying early biomarkers of cognitive decline, supporting the timely management of MCI. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Mild neurocognitive disorder is mild reduction in cognitive abilities than a previous level, requiring compensatory strategies that help maintain independence, and is associated with behavioral and psychiatric symptoms. This cross-sectional comparative study aimed to evaluate prevalence of mild neurocognitive disorder, its risk factors, and associated neuropsychiatric symptoms. It included a sample of 156 elderly people ≥ 60 years old in Suez Canal Area from geriatric homes and primary health care centers. Study tools included a semi-structured clinical interview to assess sociodemographic, clinical, and lifestyle risk factors, DSM-5 criteria for diagnosis of neurocognitive disorders, the Montreal Cognitive Assessment Scale, and the Neuropsychiatric Inventory Questionnaire. Results: Prevalence of mild neurocognitive disorder was 37.2% in total sample with mean total score of 22.7 ± 6.1 by Montreal Cognitive Assessment Scale. The most common subtype was amnestic multiple domain subtype (72.4%). Its predicting factors included advanced age, lower education, physical work, non-adherence to treatment, less physical activity, bone and joint disorders, and family history of cognitive impairment. The neuropsychiatric symptoms with highest scores were sleep/nighttime behavior, depression, irritability, and eating/appetite, respectively. Among the two study groups, geriatric home residents had highly significant lower cognitive scores (p < 0.001) and higher Neuropsychiatric Inventory Questionnaire scores. Conclusion: Mild neurocognitive disorder is common among elderly people and is associated with neuropsychiatric symptoms that need screening and management. Modifiable risk factors should be identified to provide interventions. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the dementia risk associated with mild behavioral impairment (MBI) and its domains in older community‐dwelling individuals. A total 4803 community‐dwelling individuals aged over 55 years were followed for 4.5 years (ZARADEMP study). MBI was assessed according to the International Society to Advance Alzheimer's Research and Treatment (ISTAART) diagnostic criteria using the Geriatric Mental State (GMS). Odds ratios (OR) for incident dementia and Alzheimer's disease (AD) were determined using logistic regression models adjusted for potential confounders (such as age, disability, or vascular disease). In cognitively normal individuals, decreased motivation was the only MBI domain that was associated with an increased risk of all‐cause dementia (OR: 2.30 [95% confidence interval {CI}: 1.16‐4.61]) in multivariable analyses, although the increase in the risk of AD was not statistically significant. Our findings suggest that decreased motivation may be a phenotypic marker for individuals at risk of dementia. Further research is required to evaluate the association between MBI domains and different types of dementia. [ABSTRACT FROM AUTHOR]

Introduction: Sleep disorders, particularly insomnia and obstructive sleep apnea, are associated with dyslipidemia in the general population. The study's aim was to explore the association between pathological Cholesterol and Triglyceride levels, and sleep and nighttime behavior disorders (SNBD) in older adults, whether they might predict SNBD onset, and to emphasize the role of body mass index (BMI) in this association. Methods: Alzheimer's Disease Neuroimaging Initiative (ADNI) population with complete Cholesterol, Triglyceride, SNBD, and neurocognitive data were included. Logistic regression was performed to study the association between hypercholesterolemia, hypertriglyceridemia, and SNBD at baseline and at 12 months. Relevant confounders, particularly BMI, were adjusted for. Results: Among the 2,216 included cases, 1,045 (47%) were females, and the median age was 73 years (IQR: 68, 78). At baseline, 357 (16%) had SNBD and 327 (18%) at 12 months; 187 of them were incident cases. There were more cases of baseline SNBD in the hypertriglyceridemia group than in those without (19% vs. 14%, P-value = 0.003). Similarly, more follow-up SNBD cases had hypertriglyceridemia at baseline (21% vs. 16%, P-value = 0.025). SNBD cases at baseline had significantly higher serum Triglyceride levels than those without (132 vs. 118mg/dL, P-value < 0.001). Only hypertriglyceridemia was significantly associated with baseline SNBD (crude OR = 1.43, 95%CI: 1.13,1.80, P-value = 0.003), even after adjustment for confounding factors (adj. OR = 1.36, 95%CI: 1.06,1.74, P-value = 0.016) and (BMI-adj. OR = 1.29, 95%CI: 1.00,1.66, P-value = 0.048). None of the dyslipidemia forms did predict incident cases at 12 months. Conclusions: Hypertriglyceridemia, but not hypercholesterolemia, was associated with higher odds of SNBD. The association was independent of BMI. None of the dyslipidemia forms did predict incident SNBD over 12 months. Sleep disorders should motivate a systematic screening of dyslipidemia in older adults and vice versa. [ABSTRACT FROM AUTHOR]

Context: Aging and increasing comorbidities in the population are leading to more complex care for patients and primary healthcare providers. Community organizations (COs) may play a role in the services offered to support patients with chronic diseases (PCDs) but there are currently no clear guidelines to support primary healthcare providers in linking patients to COs. Objectives: The aim of this study was to describe the role of primary healthcare providers regarding linking PCDs to COs by: (1) describing linking activities; and (2) identifying the main facilitators and barriers associated with these activities. Methods: This scoping review was based on the Arksey and O'Malley method, completed by Levac, Colquhoun, and O'Brien. Related keywords were used in 7 databases to search relevant studies. After the initial screening, 135 full texts were assessed for eligibility by 2 reviewers using inclusion/exclusion criteria. Empirical studies describing activities performed by primary healthcare providers in linking PCDs to COs or describing facilitators or barriers to linking activities were included. Studies describing activities linking to other services than COs or located in emergency departments were excluded. Results: In total, 28 studies were included. Information reported in the studies was classified into 8 main linking activities: capacity development, patient identification, assessment, information, planning, referral, follow-up, and collaboration. Facilitators and barriers to these activities were related to intrapersonal characteristics of providers and patients, professional practice, work environment, relationships, and external influences. Healthcare providers' involvement was often adapted according to their field of practice. Conclusion: This scoping review details the role of primary healthcare providers when linking PCDs to COs in a collaborative and interdisciplinary context, which can be adapted to clinical practice by providers, experts, or stakeholders to support improvement in chronic care management. [ABSTRACT FROM AUTHOR]

Background: Brain MRI with volumetric quantification, MRI volumetry, can improve diagnostic delineation of patients with neurocognitive disorders by identifying brain atrophy that may not be evident on visual assessments. Objective: To investigate diagnostic utility of MRI volumetry in traumatic brain injury (TBI), early-onset Alzheimer disease (EOAD), late-onset Alzheimer disease, and behavioral variant frontotemporal dementia (bvFTD). Method: We utilized 137 participants of TBI (n = 40), EOAD (n = 45), LOAD (n = 32), and bvFTD (n = 20). Participants had 3D T1 brain MRI imaging amendable to MRI volumetry. Scan volumes were analyzed with Neuroreader. One-way ANOVA compared brain volumes across diagnostic groups. Discriminant analysis was done with leave-one-out cross validation on Neuroreader metrics to determine diagnostic delineation across groups. Result: LOAD was the oldest compared to other groups (F = 27.5, p <.001). There were no statistically significant differences in sex (p =.58) with women comprising 54.7% of the entire cohort. EOAD and LOAD had the lowest Mini-Mental State Exam (MMSE) scores compared to TBI (p =.04 for EOAD and p =.01 for LOAD). LOAD had lowest hippocampal volumes (Left Hippocampus F = 13.1, Right Hippocampus F = 7.3, p <.001), low white matter volume in TBI (F = 5.9, p <.001), lower left parietal lobe volume in EOAD (F = 9.4, p <.001), and lower total gray matter volume in bvFTD (F = 32.8, p <.001) and caudate atrophy (F = 1737.5, p <.001). Areas under the curve ranged from 92.3 to 100%, sensitivity between 82.2 and 100%, specificity of 78.1-100%. TBI was the most accurately delineated diagnosis. Predictive features included caudate, frontal, parietal, temporal lobar and total white matter volumes. Conclusion: We identified the diagnostic utility of regional volumetric differences across multiple neurocognitive disorders. Brain MRI volumetry is widely available and can be applied in distinguishing these disorders. [ABSTRACT FROM AUTHOR]

Background: Brain network dysfunction has been characterized by resting-state electroencephalography (EEG) and magnetic resonance imaging (MRI) in the prodromal stage. This study aimed to identify multi-modal electrophysiological and neuroimaging biomarkers for differential diagnosis in synucleinopathies and phenoconversion in isolated rapid eyemovement sleep behavior disorder (iRBD). Methods: We enrolled 35 patients with multiple system atrophy (MSA), 32 with Parkinson's disease (PD), 30 with iRBD and 30 matched healthy controls (HC). Power spectral density (PSD) was calculated in different frequency bands. EEG functional connectivity (FC) was calculated using the weighted Phase Lag Index (wPLI) after source localization. Significant network disruptions were further confirmed by MRI FC analysis. Results: Quantitative EEG analysis demonstrated that delta and theta power spectral density significantly differed among MSA, PD and HC. The increased PSD was correlated with cognitive decline and olfactory dysfunction in PD. Band-specific FC profiles were observed in theta, alpha, and gamma bands. The hypoconnected alpha network significantly correlated with motor dysfunction, while the gamma FC distinguished PD from MSA. By integrating EEG and MRI network analyses, we found that FC between the olfactory cortex and dorsolateral prefrontal cortex was significantly different between MSA and PD. A multimodal discriminative model for MSA and PD, integrating spectral and FC attributes of EEG and MRI, yielded an area under the receiver operating characteristic curve of 0.900. Simultaneously, we found the FC abnormalities were more prominent than spectral features in iRBD indicating prodromal dysfunction. The decreased FC between the angular gyrus and striatum was identified in a-synucleinopathies. This hypoconnectivity was associated with dopaminergic degeneration in iRBD examined by dopamine transporter imaging. Discussion: Our study demonstrated EEG spectral and functional profiles in prodromal and clinical-defined synucleinopathies. Multimodal EEG and MRI provided a novel approach to discriminate MSA and PD, and monitor neurodegenerative progression in the preclinical phase. [ABSTRACT FROM AUTHOR]

Background: Multi-component CS programs incorporating practice of activities of daily living (ADL) into intervention have reported benefits for ADL outcomes in individuals living with mild-to-moderate dementia. A randomised controlled trial (RCT) within community occupational therapy services in Ireland, is planned to evaluate the effects of CS-ADL, an ADL-focused, multi-component CS program, on ADL outcomes for individuals living with mild-to-moderate dementia. Method: A single-blind RCT with a calculated sample size of 34 participants has been planned to compare the effects of CS-ADL versus treatment as usual on the outcomes of basic ADLs and instrumental ADLs. Cognition, mood, communication, and quality of life will also be evaluated as secondary outcomes. CS-ADL sessions will run once weekly for a total of seven weeks, lasting approximately two hours each. Outcome data will be collected at baseline, within sessions and post-intervention at week eight. Descriptive statistics will be used to analyse the data. This study has been registered at clinicaltrials.gov (NCT06147479). Discussion: CS programs are commonly conducted by occupational therapists working with individuals living with mild-to-moderate dementia. This study aims to demonstrate the effectiveness of a multi-component CS program delivered through an occupational therapy lens, potentially influencing the approach to CS and ADL interventions undertaken by occupational therapists. [ABSTRACT FROM AUTHOR]

Background: Lewy body dementia (LBD) is the second most common neurodegenerative dementia in the US, presenting unique end-of-life challenges. Objective: This study examined healthcare utilization and care continuity in the last year of life in LBD. Methods: Medicare claims for enrollees with LBD, continuously enrolled in the year preceding death, were examined from 2011–2018. We assessed hospital stays, emergency department (ED) visits, intensive care unit (ICU) admissions, life-extending procedures, medications, and care continuity. Results: We identified 45,762 LBD decedents, predominantly female (51.8%), White (85.9%), with average age of 84.1 years (SD 7.5). There was a median of 2 ED visits (IQR 1–5) and 1 inpatient stay (IQR 0–2). Higher age was inversely associated with ICU stays (Odds Ratio [OR] 0.96; 95% Confidence Interval [CI] 0.96–0.97) and life-extending procedures (OR 0.96; 95% CI 0.95–0.96). Black and Hispanic patients experienced higher rates of ED visits, inpatient hospitalizations, ICU admissions, life-extending procedures, and in-hospital deaths relative to White patients. On average, 15 (7.5) medications were prescribed in the last year. Enhanced care continuity correlated with reduced hospital (OR 0.72; 95% CI 0.70–0.74) and ED visits (OR 0.71; 95% CI 0.69–0.87) and fewer life-extending procedures (OR 0.71; 95% CI 0.64–0.79). Conclusions: This study underscored the complex healthcare needs of people with LBD during their final year, which was influenced by age and race. Care continuity may reduce hospital and ED visits and life-extending procedures. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms are common in dementia and linked to adverse outcomes. Inflammation is increasingly recognized as playing a role as a driver of early disease progression in Alzheimer's disease (AD) and related dementias. Inflammation has also been linked to primary psychiatric disorders, however its association with neuropsychiatric symptoms in neurodegenerative dementias remains uncertain. Methods: We conducted a systematic literature review investigating associations between inflammation and neuropsychiatric symptoms in neurodegenerative dementias, including AD, Lewy body, Frontotemporal, Parkinson's (PD) and Huntington's disease dementias. Results: Ninety-nine studies met our inclusion criteria, and the majority (n = 59) investigated AD and/or mild cognitive impairment (MCI). Thirty-five studies included PD, and only 6 investigated non-AD dementias. Inflammation was measured in blood, CSF, by genotype, brain tissue and PET imaging. Overall, studies exhibited considerable heterogeneity and evidence for specific inflammatory markers was inconsistent, with lack of replication and few longitudinal studies with repeat biomarkers. Depression was the most frequently investigated symptom. In AD, some studies reported increases in peripheral IL-6, TNF-a associated with depressive symptoms. Preliminary investigations using PET measures of microglial activation found an association with agitation. In PD, studies reported positive associations between TNF-a, IL-6, CRP, MCP-1, IL-10 and depression. Conclusion: Central and peripheral inflammation may play a role in neuropsychiatric symptoms in neurodegenerative dementias; however, the evidence is inconsistent. There is a need for multi-site longitudinal studies with detailed assessments of neuropsychiatric symptoms combined with replicable peripheral and central markers of inflammation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifactorial neuron-degenerative old age disease which has no cure. AD causes degeneration of the neuronal cells in the brain which is the main reason of dementia, characterized by a decline in the thinking and independence in daily routine activities. In most of the cases, AD is suspected to be caused by a combination of genetic, lifestyle and environmental factors, affecting the brain over time. The currently approved therapy, which includes cholinesterase inhibitors, NMDA-receptor antagonists and their combinations provides only temporary symptomatic relief. Nowadays, the clinical research is targeting on understanding of Alzheimer pathology¹. These are targeting the abnormal tau protein metabolism, removal of beta-amyloid, inflammatory response, cholinergic neuron and free radical damage treatments which can either that stop or modify the course of Alzheimer. Global efforts are continued to identify new targets to develop novel therapeutic agents for the treatment of AD. [ABSTRACT FROM AUTHOR]

Introduction: With the advent of anti-ß-amyloid therapies, clinical distinction between Aß + and Aß- in cognitive impairment is becoming increasingly important for stratifying referral and better utilization of biomarker assays. Methods: Cognitive profile, rate of decline, neuropsychiatric inventory questionnaire (NPI-Q), and imaging characteristics were collected from 52 subjects with possible/probable AD. Results: Participants with Aß+ status had lower baseline MMSE scores (24.50 vs. 26.85, p = 0.009) and higher total NPI-Q scores (2.73 vs. 1.18, p < 0.001). NPI-Q score was found to be the only independent predictor for ß-amyloid positivity (p = 0.008). A simple scoring system, namely Clinical ß-Amyloid Positivity Prediction Score (CAPS), was developed by using the following parameters: NPI-Q, rapidity of cognitive decline, and white matter microangiopathy. Data from 48 participants were included in the analysis of accuracy of CAPS. CAP Score of 3 or 4 successfully classified Aß+ individuals in 86.7% cases. Discussion: Clinical ß-Amyloid Positivity Prediction Score is a simple clinical tool for use in primary care and memory clinic settings to predict ß-amyloid positivity in individuals with clinical Alzheimer Syndrome can potentially facilitate referral for Anti Aß therapies. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias, but research on end-of-life experiences for people with DLB and their caregivers is limited. Method: Dyads of individuals with moderate-advanced DLB and their primary informal caregivers were recruited from specialty clinics, advocacy organizations, and research registries and followed prospectively every 6 months. The current study examines results of caregiver study visits 3 months after the death of the person with DLB. These visits included the Last Month of Life survey, study-specific questions, and a semi-structured interview querying end-of-life experiences. Results: Individuals with DLB (n = 50) died 3.24 ± 1.81 years after diagnosis, typically of disease-related complications. Only 44% of caregivers reported a helpful conversation with clinicians regarding what to expect at the end of life in DLB. Symptoms commonly worsening prior to death included: cognition and motor function, ADL dependence, behavioral features, daytime sleepiness, communication, appetite, and weight loss. Almost 90% of participants received hospice care, but 20% used hospice for <1 week. Most caregivers reported overall positive experiences in the last month of life, but this was not universal. Having information about DLB and what to expect, access to support, and hospice care were healthcare factors associated with positive and negative end of life experiences. Hospice experiences were driven by communication, care coordination, quality care, and caregiver education. Conclusion: Most caregivers of individuals who died with DLB reported positive end-of-life experiences. However, the study identified multiple opportunities for improvement relating to clinician counseling of patients/families, support/hospice referrals, and monitoring individuals with DLB to identify approaching end of life. Future research should quantitatively identify changes that herald end of life in DLB and develop tools that can assist clinicians in evaluating disease stage to better inform counseling and timely hospice referrals. Trial registration: Trial registration information: NCT04829656. [ABSTRACT FROM AUTHOR]

Background: Studies that assess cognition prospectively and study in detail anxiety history in the participants' medical records within the context of brain aging and Alzheimer's disease are limited. Objective: To examine the associations of anxiety and unspecified emotional distress (UED) acquired throughout a person's life with prospectively collected cognitive outcomes. Methods: Mayo Clinic Study of Aging participants who were cognitively unimpaired at baseline were included. Anxiety and UED data were abstracted from the medical record using the Rochester Epidemiology Project (REP) resources and were run separately as predictors in our models. The data were analyzed using Cox proportional hazards models for the outcomes of incident mild cognitive impairment (MCI) and dementia and using linear mixed effects models for the outcomes of global and domain specific cognitive z-scores and included key covariates. Results: The study sample (n = 1,808) had a mean (standard deviation) age of 74.5 (7.3) years and 51.4% were male. Anxiety was associated with increased risk of MCI and dementia and was associated with lower baseline cognitive z-scores and accelerated decline over time in the global, memory, and attention domains. UED was associated with faster decline in all domains except visuospatial but did not show evidence of association with incident cognitive outcomes. These results varied by medication use and timing of anxiety. Conclusions: Anxiety and UED both showed inverse associations with cognition. Utilization of anxiety and UED data from across the life course, as available, from the REP system adds robustness to our results. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms are a robust risk factor for caregiver burden in family dementia caregivers. By grouping these symptoms, clinical interpretations regarding neuropsychiatric symptoms may facilitated because different groups of symptoms may require a different approach for intervention, thereby reducing caregiver burden. Objective: As clustering of neuropsychiatric symptoms could be clinically relevant, we aimed to explore the effects of these clusters on burden in family dementia caregivers. Methods: 152 family dementia caregivers were included. Caregiver burden was measured using the Ervaren Druk door Informele Zorg (EDIZ)/Self-Perceived Pressure from Informal Care, a Dutch questionnaire. Caregivers also reported the neuropsychiatric symptoms and functional impairments in daily activities of the people with dementia they cared for. Multiple regression analyses were used in this cross-sectional study. Results: Adjusted for functional impairments and sociodemographic variables, neuropsychiatric symptoms were associated with more caregiver burden (p < 0.001). However, this association did not differ between the three neuropsychiatric symptom clusters (p = 0.745). Conclusions: Neuropsychiatric symptoms were associated with more family caregiver burden, but no conclusive evidence was found that this association differed for the three clusters. Clustering of neuropsychiatric symptoms is, however, worth exploring further in future studies with more participants. If specific links are found, these could be targeted in clinical practice in order to prevent, reduce and/or postpone caregiver burden. [ABSTRACT FROM AUTHOR]

Dementia is characterized by a progressive decline in cognition, behavioral and psychological symptoms (BPSD), and quality of life (QoL). The lack of curative therapies has led to a psychosocial discourse prioritizing QoL of people thriving with dementia (PTD). Group reminiscence therapy (RT) is a relatively inexpensive intervention, with music prompts being a preferred choice, owing to robust musical memory in the early disease stage. However, a synthesis of current evidence is needed to inform research and clinical use of group music RT in dementia care. Therefore, we conducted a systematic review on PubMed, Scopus, CINAHL, APA PsycInfo, and APA PsycArticles to critically appraise published randomized controlled trials examining group music RT to improve cognition, BPSD, and QoL in PTD. Of 14,725 articles, two RCTs involving 102 PTD were included. All studies used prerecorded music for group music RT. All studies were deemed of good quality, adhering to intention‐to‐treat analysis and assessor blinding. Based on the American Academy of Neurology guidelines, we assigned a Level C recommendation for group music RT for cognition and Level B recommendations for BPSD and QoL (ineffective). In conclusion, group music RT may be useful for symptomatic management in PTD. However, heterogeneous study designs, disease severity, dementia subtype, and outcome measures are likely barriers to meaningful clinical translation. Therefore, the rating of recommendations only serves as a point of reference. Future avenues include live performances as prompts for group music RT. [ABSTRACT FROM AUTHOR]

Background: Cognitive dysfunction is a non-motor manifestation of Parkinson's disease (PD). We aimed to determine the frequency and patterns of cognitive dysfunction in treated patients with PD and their predictors. Research design and methods: This study included 80 patients (male = 48; female = 32) and 30 healthy individuals. They underwent neuropsychiatric evaluations. Measurements included Beck's depression inventory – II (BDI-II), mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). Results: Patients had mean age of 55.56 ± 9.06 yrs, duration of PD of 4.86 ± 2.71 yrs and Hoehn and Yahr Scoring of 2.19 ± 0.89. They were on levodopa/carbidopa therapy and adjuvant therapy with benztropine mesylate, an anticholinergic drug, (n = 51) or amantadine sulfate, a dopaminergic drug, (n = 29). Sixteen (20%) had moderate depressive symptoms. Mild and moderate cognitive impairments were reported in 38.8% and 28.8% (by MMSE) and 46.3% and 31.3% (by MoCA). Patients had lower global cognitive scoring (p = 0.0001) and scorings of different cognitive functions (naming, attention, language, abstraction, memory and orientation) than controls. Patients treated with benztropine had lower cognition than with amantadine. Correlation analyses showed that lower cognition was only associated with chronic PD and its treatment (p = 0.0001). Conclusions: Cognitive dysfunction is common with PD (77.5%) particularly with anticholinergic drugs. De-prescription of anticholinergics is recommended for patients with PD. [ABSTRACT FROM AUTHOR]