LRP10 and α-synuclein transmission in Lewy body diseases.

Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.

What's in a score: A longitudinal investigation of scores based on item response theory and classical test theory for the Amsterdam Instrumental Activities of Daily Living Questionnaire in cognitively normal and impaired older adults.

OBJECTIVE: We aimed to investigate whether item response theory (IRT)-based scoring allows for a more accurate, responsive, and less biased assessment of everyday functioning than traditional classical test theory (CTT)-based scoring, as measured with the Amsterdam Instrumental Activities of Daily Living Questionnaire. METHOD: In this longitudinal multicenter study including cognitively normal and impaired individuals, we examined IRT-based and CTT-based score distributions and differences between diagnostic groups using linear regressions, and investigated scale attenuation. We compared change over time between scoring methods using linear mixed models with random intercepts and slopes for time. RESULTS: Two thousand two hundred ninety-four participants were included (66.6 ± 7.7 years, 54% female): n = 2,032 (89%) with normal cognition, n = 93 (4%) with subjective cognitive decline, n = 79 (3%) with mild cognitive impairment, and n = 91 (4%) with dementia. At baseline, IRT-based and CTT-based scores were highly correlated (r = -0.92). IRT-based scores showed less scale attenuation than CTT-based scores. In a subsample of n = 1,145 (62%) who were followed for a mean of 1.3 (SD = 0.6) years, IRT-based scores declined significantly among cognitively normal individuals (unstandardized coefficient [B] = -0.15, 95% confidence interval, 95% CI [-0.28, -0.03], effect size = -0.02), whereas CTT-based scores did not (B = 0.20, 95% CI [-0.02, 0.41], effect size = 0.02). In the other diagnostic groups, effect sizes of change over time were similar. CONCLUSIONS: IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior suitability for use in preclinical populations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Lessons Learned from 17 Years of Multidisciplinary Care for DSD Patients at A Single Indonesian Center.

BACKGROUND: Our Multidisciplinary Team (MDT) is a large specialized team based in Semarang, Indonesia that cares for a wide variety of pediatric and adult individuals with Differences of Sex Development (DSD) from across Indonesia. Here we describe our work over the last 17 years. METHODS: We analyzed phenotypic, hormonal and genetic findings from clinical records for all patients referred to our MDT during the period 2004 to 2020. RESULTS: Among 1184 DSD patients, 10% had sex chromosome DSD, 67% had 46,XY DSD and 23% had 46,XX DSD. The most common sex chromosome anomaly was Turner syndrome (45,X) (55 cases). For patients with 46,XY DSD under-masculinization was the most common diagnosis (311 cases) and for 46,XX DSD a defect of Müllerian development was most common (131 cases) followed by Congenital Adrenal Hyperplasia (CAH) (116 cases). Sanger sequencing, MLPA and targeted gene sequencing of 257 patients with 46,XY DSD found likely causative variants in 21% (55 cases), with 13 diagnostic genes implicated. The most affected gene coded for the Androgen Receptor. Molecular analysis identified a diagnosis for 69 of 116 patients with CAH, with 62 carrying variants in CYP21A2 including four novel variants, and seven patients carrying variants in CYP11B1. In many cases these genetic diagnoses influenced the clinical management of patients and families. CONCLUSIONS: Our work has highlighted the occurrence of different DSDs in Indonesia. By applying sequencing technologies as part of our clinical care, we have delivered a number of genetic diagnoses and identified novel pathogenic variants in some genes, which may be clinically specific to Indonesia. Genetics can inform many aspects of DSD clinical management, and whilst many of our patients remain undiagnosed, we hope that future testing may provide answers for even more.

Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia.

BACKGROUND & OBJECTIVES: Autoimmune encephalitis (AIE) may present with prominent cognitive disturbances without overt inflammatory changes in MRI and CSF. Identification of these neurodegenerative dementia diagnosis mimics is important because patients generally respond to immunotherapy. The objective of this study was to determine the frequency of neuronal antibodies in patients with presumed neurodegenerative dementia and describe the clinical characteristics of the patients with neuronal antibodies. METHODS: In this retrospective cohort study, 920 patients were included with neurodegenerative dementia diagnosis from established cohorts at 2 large Dutch academic memory clinics. In total, 1,398 samples were tested (both CSF and serum in 478 patients) using immunohistochemistry (IHC), cell-based assays (CBA), and live hippocampal cell cultures (LN). To ascertain specificity and prevent false positive results, samples had to test positive by at least 2 different research techniques. Clinical data were retrieved from patient files. RESULTS: Neuronal antibodies were detected in 7 patients (0.8%), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX, and anti-NMDAR. Clinical symptoms atypical for neurodegenerative diseases were identified in all 7 and included subacute deterioration (n = 3), myoclonus (n = 2), a history of autoimmune disease (n = 2), a fluctuating disease course (n = 1), and epileptic seizures (n = 1). In this cohort, no patients with antibodies fulfilled the criteria for rapidly progressive dementia (RPD), yet a subacute deterioration was reported in 3 patients later in the disease course. Brain MRI of none of the patients demonstrated abnormalities suggestive for AIE. CSF pleocytosis was found in 1 patient, considered as an atypical sign for neurodegenerative diseases. Compared with patients without neuronal antibodies (4 per antibody-positive patient), atypical clinical signs for neurodegenerative diseases were seen more frequently among the patients with antibodies (100% vs 21%, p = 0.0003), especially a subacute deterioration or fluctuating course (57% vs 7%, p = 0.009). DISCUSSION: A small, but clinically relevant proportion of patients suspected to have neurodegenerative dementias have neuronal antibodies indicative of AIE and might benefit from immunotherapy. In patients with atypical signs for neurodegenerative diseases, clinicians should consider neuronal antibody testing. Physicians should keep in mind the clinical phenotype and confirmation of positive test results to avoid false positive results and administration of potential harmful therapy for the wrong indication.

Effects of the DICE Method to Improve Timely Recognition and Treatment of Neuropsychiatric Symptoms in Early Alzheimer's Disease at the Memory Clinic: The BEAT-IT Study.

BACKGROUND: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD) and are associated with negative outcomes. However, NPS are currently underrecognized at the memory clinic and non-pharmacological interventions are scarcely implemented. OBJECTIVE: To evaluate the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) method™ to improve the care for NPS in AD at the memory clinic. METHODS: We enrolled sixty community-dwelling people with mild cognitive impairment or AD dementia and NPS across six Dutch memory clinics with their caregivers. The first wave underwent care as usual (n = 36) and the second wave underwent the DICE method (n = 24). Outcomes were quality of life (QoL), caregiver burden, NPS severity, NPS-related distress, competence managing NPS, and psychotropic drug use. Reliable change index was calculated to identify responders to the intervention. A cost-effectiveness analysis was performed and semi-structured interviews with a subsample of the intervention group (n = 12). RESULTS: The DICE method did not improve any outcomes over time compared to care as usual. Half of the participants of the intervention group (52%) were identified as responders and showed more NPS and NPS-related distress at baseline compared to non-responders. Interviews revealed substantial heterogeneity among participants regarding NPS-related distress, caregiver burden, and availability of social support. The intervention did not lead to significant gains in quality-adjusted life years and well-being years nor clear savings in health care and societal costs. CONCLUSION: The DICE method showed no benefits at group-level, but individuals with high levels of NPS and NPS-related distress may benefit from this intervention.

Biweekly fluctuations of neuropsychiatric symptoms according to the Neuropsychiatric Inventory: Erratic symptoms or scores?

OBJECTIVES: This study investigates the stability of neuropsychiatric symptoms (NPS) assessed biweekly using the Neuropsychiatric Inventory (NPI) in a memory clinic population during a 6 week period. METHODS: Twenty-three spousal caregivers (mean [SD] age = 69.7 [8.8], 82.6% female) of 23 patients (43.5% had dementia) completed all assessments. The NPI was assessed four times during 6 weeks. We examined whether NPI domains were present during all four assessments, studied within-person variation for each NPI domain, and calculated Spearman's correlations between subsequent time-points. Furthermore, we associated repeated NPI assessments with repeated measures of caregiver burden to examine the clinical impact of changes in NPI scores over time. RESULTS: The course of NPS was highly irregular according to the NPI, with only 35.8% of the NPI domains that were present at baseline persisted during all 6 weeks. We observed large within-person variation in the presence of individual NPI domains (61.3%, range 37.5%-83.9%) and inconsistent correlations between NPI assessments (e.g., range rs  = 0.20-0.57 for agitation, range rs  = 0.29-0.59 for anxiety). Higher NPI total scores were related to higher caregiver burden (rs  = 0.60, p < 0.001), but changes in NPI total scores were unrelated to changes in caregiver burden (rs  = 0.16, p = 0.20). CONCLUSIONS: We observed strong fluctuations in NPI scores within very short time windows raising the question whether this represents erratic symptoms and/or scores. Further studies are needed to investigate the origins of these fluctuations.

CYP11B1 variants influence skeletal maturation via alternative splicing.

We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders. The joint meta-analysis (N = 4557) in two multiethnic cohorts of school-aged children identified one locus, CYP11B1 (expression confined to the adrenal gland), robustly associated with SA (rs6471570-A; ß = 0.14; P = 6.2 × 10-12). rs6410 (a synonymous variant in the first exon of CYP11B1 in high LD with rs6471570), was prioritized for functional follow-up being second most significant and the one closest to the first intron-exon boundary. In 208 adrenal RNA-seq samples from GTEx, C-allele of rs6410 was associated with intron 3 retention (P = 8.11 × 10-40), exon 4 inclusion (P = 4.29 × 10-34), and decreased exon 3 and 5 splicing (P = 7.85 × 10-43), replicated using RT-PCR in 15 adrenal samples. As CYP11B1 encodes 11-ß-hydroxylase, involved in adrenal glucocorticoid and mineralocorticoid biosynthesis, our findings highlight the role of adrenal steroidogenesis in SA in healthy children, suggesting alternative splicing as a likely underlying mechanism.

Autoimmune Encephalitis Resembling Dementia Syndromes.

OBJECTIVE: As autoimmune encephalitis (AIE) can resemble neurodegenerative dementia syndromes, and patients do not always present as encephalitis, this study evaluates how frequently AIE mimics dementia and provides red flags for AIE in middle-aged and older patients. METHODS: In this nationwide observational cohort study, patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), anti-gamma-aminobutyric acid B receptor (GABABR), or anti-contactin-associated protein-like 2 (CASPR2) encephalitis were included. They had to meet 3 additional criteria: age ≥45 years, fulfillment of dementia criteria, and no prominent seizures early in the disease course (≤4 weeks). RESULTS: Two-hundred ninety patients had AIE, of whom 175 were 45 years or older. Sixty-seven patients (38%) fulfilled criteria for dementia without prominent seizures early in the disease course. Of them, 42 had anti-LGI1 (48%), 13 anti-NMDAR (52%), 8 anti-GABABR (22%), and 4 anti-CASPR2 (15%) encephalitis. Rapidly progressive cognitive deterioration was seen in 48 patients (76%), whereas a neurodegenerative dementia syndrome was suspected in half (n = 33). In 17 patients (27%; 16/17 anti-LGI1), subtle seizures had been overlooked. Sixteen patients (25%) had neither inflammatory changes on brain MRI nor CSF pleocytosis. At least 1 CSF biomarker, often requested when dementia was suspected, was abnormal in 27 of 44 tested patients (61%), whereas 8 had positive 14-3-3 results (19%). Most patients (84%) improved after immunotherapy. CONCLUSIONS: Red flags for AIE in patients with suspected dementia are: (1) rapidly progressive cognitive decline, (2) subtle seizures, and (3) abnormalities in ancillary testing atypical for neurodegeneration. Physicians should be aware that inflammatory changes are not always present in AIE, and that biomarkers often requested when dementia was suspected (including 14-3-3) can show abnormal results. Diagnosis is essential as most patients profit from immunotherapy.

Levoketoconazole, the 2S,4R Enantiomer of Ketoconazole, a New Steroidogenesis Inhibitor for Cushing's Syndrome Treatment.

INTRODUCTION: Racemic ketoconazole (RK) is a steroidogenesis inhibitor used for treatment of Cushing's syndrome. Levoketoconazole (COR-003), the pure 2S,4R enantiomer, is potentially more potent and safe compared to RK. We compared in vitro effects of levoketoconazole and RK on adrenocortical and pituitary adenoma cells. MATERIALS AND METHODS: HAC15 cells and 15 primary human neoplastic adrenocortical cultures (+/- ACTH), and murine (AtT20) and human corticotroph adenoma cultures were incubated with levoketoconazole or RK (0.01-10 µM). Cortisol and ACTH were measured using a chemiluminescence immunoassay system, and steroid profiles by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: In HAC15, levoketoconazole inhibited cortisol at lower concentrations (IC50: 0.300 µM) compared to RK (0.611 µM; P < 0.0001). IC50 values of levoketoconazole for basal cortisol production in primary adrenocortical cultures varied over a 24-fold range (0.00578-0.140 µM), with 2 patients having a higher sensitivity for levoketoconazole vs RK (2.1- and 3.7-fold). LC-MS/MS analysis in selected cases revealed more potent inhibition of cortisol and other steroid profile components by levoketoconazole vs RK. In AtT20, levoketoconazole inhibited cell growth and ACTH secretion (10 µM: -54% and -38%, respectively), and levoketoconazole inhibited cell number in 1 of 2 primary human corticotroph pituitary adenoma cultures (-44%, P < 0.001). CONCLUSION: Levoketoconazole potently inhibits cortisol production in adrenocortical cells, with a variable degree of suppression between specimens. Levoketoconazole inhibits adrenal steroid production more potently compared to RK and might also inhibit ACTH secretion and growth of pituitary adenoma cells. Together with previously reported potential advantages, this indicates that levoketoconazole is a promising novel pharmacotherapy for Cushing's syndrome.

The maturity of sovereign debt issuance in the euro area.

We use information on new sovereign debt issues in the euro area to explore the drivers behind the debt maturity decisions of governments. We set up a theoretical model for the maturity structure that trades off the preference for liquidity services provided by short-term debt, roll-over risk and price risk. The average debt maturity is negatively related to both the level and the slope of the yield curve. A panel VAR analysis shows that positive shocks to risk aversion, the probability of non-repayment and the demand for the liquidity services of short-term debt all have a positive effect on the yield curve level and slope, and a negative effect on the average maturity of new debt issues. These results are partially in line with our theoretical framework. A forecast error variance decomposition suggests that changes in the probability of non-repayment as captured by the expected default frequency extracted from credit default spreads are the most important source of shocks.

Anterior insular network disconnection and cognitive impairment in Parkinson's disease.

BACKGROUND: The insula is a central brain hub involved in cognition and affected in Parkinson's disease (PD). The aim of this study was to assess functional connectivity (FC) and betweenness centrality (BC) of insular sub-regions and their relationship with cognitive impairment in PD. METHODS: Whole-brain 3D-T1, resting-state functional MRI and a battery of cognitive tests (CAMCOG) were included for 53 PD patients and 15 controls. The insular cortex was segmented into ventral (vAI) and dorsal (dAI) anterior and posterior sub-regions. Connectivity between insular sub-regions and resting-state networks was assessed and related to cognition; BC was used to further explore nodes associated with cognition. RESULTS: Cognitive performance was significantly lower in PD patients compared to controls (p < 0.01) and was associated with FC of the dAI with default mode network (DMN) (adjusted R2 = 0.37, p < 0.001). In controls, cognitive performance was positively related to FC of the dAI with the fronto-parietal network (FPN) only (adjusted R2 = 0.5, p = 0.003). Regionally, FC of the dAI with the anterior cingulate cortex (ACC) was significantly reduced in PD (F(1,65) = 11, p = 0.002) and correlated with CAMCOG (r = 0.4, p = 0.001). DMN and FPN showed increased BC in PD which correlated with cognition and reduced connectivity of dAI with the ACC (rs = -0.33, p = 0.014 and rs = -0.44, p = 0.001 respectively). CONCLUSIONS: These results highlight the relevance of the insula in cognitive dysfunction in PD. Disconnection of the dAI with ACC was related to altered centrality in the DMN and FPN only in patients. Disturbance in this network triad appears to be particularly relevant for cognitive impairment in PD.

LRP10 variants in progressive supranuclear palsy.

The aim of this study was to explore whether variants in LRP10, recently associated with Parkinson's disease and dementia with Lewy bodies, are observed in 2 large cohorts (discovery and validation cohort) of patients with progressive supranuclear palsy (PSP). A total of 950 patients with PSP were enrolled: 246 patients with PSP (n = 85 possible (35%), n = 128 probable (52%), n = 33 definite (13%)) in the discovery cohort and 704 patients with definite PSP in the validation cohort. Sanger sequencing of all LRP10 exons and exon-intron boundaries was performed in the discovery cohort, and whole-exome sequencing was performed in the validation cohort. Two patients from the discovery cohort and 8 patients from the validation cohort carried a rare, heterozygous, and possibly pathogenic LRP10 variant (p.Gly326Asp, p.Asp389Asn, and p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554∗, p.Arg661Cys). In conclusion, possibly pathogenic LRP10 variants occur in a small fraction of patients with PSP and may be overrepresented in these patients compared with controls. This suggests that possibly pathogenic LRP10 variants may play a role in the development of PSP.

Clinical and Pathological Phenotypes of LRP10 Variant Carriers with Dementia.

BACKGROUND: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10) have recently been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). OBJECTIVE: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies. METHODS: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank. RESULTS: Rare, possibly pathogenic heterozygous LRP10 variants were present in three patients: p.Gly453Ser in a patient with mixed Alzheimer's disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD. CONCLUSION: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum.

Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach.

BACKGROUND: Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer's disease (AD) diagnosis. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach. METHODS: We applied liquid chromatography/tandem mass spectrometry with label-free quantification to identify biomarker candidates to individual CSF samples from a well-characterized cohort comprising patients with DLB (n = 20) and controls (n = 20). Validation was performed using (1) the identical proteomic workflow in an independent cohort (n = 30), (2) proteomic data from patients with related neurodegenerative diseases (n = 149) and (3) orthogonal techniques in an extended cohort consisting of DLB patients and controls (n = 76). Additionally, we utilized random forest analysis to identify the subset of candidate markers that best distinguished DLB from all other groups. RESULTS: In total, we identified 1995 proteins. In the discovery cohort, 69 proteins were differentially expressed in DLB compared to controls (p < 0.05). Independent cohort replication confirmed VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N as candidate biomarkers for DLB. The downregulation of the candidate biomarkers was somewhat more pronounced in DLB in comparison with related neurodegenerative diseases. Using random forest analysis, we identified a panel of VGF, SCG2 and PDYN to best differentiate between DLB and other clinical groups (accuracy: 0.82 (95%CI: 0.75-0.89)). Moreover, we confirmed the decrease of VGF and NPTX2 in DLB by ELISA and SRM methods. Low CSF levels of all biomarker candidates, except PCSK1N, were associated with more pronounced cognitive decline (0.37 < r < 0.56, all p < 0.01). CONCLUSION: We identified and validated six novel CSF biomarkers for DLB. These biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy and strengthen the importance of synaptic dysfunction in the pathophysiology of DLB.

The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: Longitudinal findings from the Catch-Cog study cohort.

INTRODUCTION: In an attempt to capture clinically meaningful cognitive decline in early dementia, we developed the Cognitive-Functional Composite (CFC). We investigated the CFC's sensitivity to decline in comparison to traditional clinical endpoints. METHODS: This longitudinal construct validation study included 148 participants with subjective cognitive decline, mild cognitive impairment, or mild dementia. The CFC and traditional tests were administered at baseline, 3, 6, and 12 months. Sensitivity to change was investigated using linear mixed models and r 2 effect sizes. RESULTS: CFC scores declined over time (ß = -.16, P < .001), with steepest decline observed in mild Alzheimer's dementia (ß = -.25, P < .001). The CFC showed medium-to-large effect sizes at succeeding follow-up points (r 2 = .08-.42), exhibiting greater change than the Clinical Dementia Rating scale (r 2 = .02-.12). Moreover, change on the CFC was significantly associated with informant reports of cognitive decline (ß = .38, P < .001). DISCUSSION: By showing sensitivity to decline, the CFC could enhance the monitoring of disease progression in dementia research and clinical practice.

Differential insular cortex sub-regional atrophy in neurodegenerative diseases: a systematic review and meta-analysis.

The insular cortex is proposed to function as a central brain hub characterized by wide-spread connections and diverse functional roles. As a result, its centrality in the brain confers high metabolic demands predisposing it to dysfunction in disease. However, the functional profile and vulnerability to degeneration varies across the insular sub-regions. The aim of this systematic review and meta-analysis is to summarize and quantitatively analyze the relationship between insular cortex sub-regional atrophy, studied by voxel based morphometry, with cognitive and neuropsychiatric deficits in frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). We systematically searched through Pubmed and Embase and identified 519 studies that fit our criteria. A total of 41 studies (n = 2261 subjects) fulfilled the inclusion criteria for the meta-analysis. The peak insular coordinates were pooled and analyzed using Anatomic Likelihood Estimation. Our results showed greater left anterior insular cortex atrophy in FTD whereas the right anterior dorsal insular cortex showed larger clusters of atrophy in AD and PD/DLB. Yet contrast analyses did not reveal significant differences between disease groups. Functional analysis showed that left anterior insular cortex atrophy is associated with speech, emotion, and affective-cognitive deficits, and right dorsal atrophy with perception and cognitive deficits. In conclusion, insular sub-regional atrophy, particularly the anterior dorsal region, may contribute to cognitive and neuropsychiatric deficits in neurodegeneration. Our results support anterior insular cortex vulnerability and convey the differential involvement of the insular sub-regions in functional deficits in neurodegenerative diseases.

Dementia With Lewy Bodies: A Clinicopathologic Series of False-positive Cases.

Diagnosing dementia with Lewy bodies (DLB) is challenging as symptoms are heterogenous and not specific to the disease. Here we present a clinicopathologic series of false-positive DLB cases. Patients were enrolled retrospectively from the Netherlands Brain Bank when they met the clinical criteria of probable DLB, but with a pathologic diagnosis other than DLB or Parkinson's disease dementia. Twenty-two false-positive cases were selected. Alzheimer disease with or without copathology was the most common (64%) pathologic diagnosis. Other pathologic diagnoses, such as frontotemporal dementia, multiple-system atrophy, Creutzfeldt-Jakob disease, and autoimmune encephalitis, were also encountered. Atypical clinical signs for DLB were present in almost half of the cases and could be a trigger to consider other diagnoses than DLB. Additional diagnostic examinations, feedback of pathologic diagnosis, and the creation of a set of clinical features that are indicative of other conditions, could reduce the amount of false-positive DLB cases.

Family History is Associated with Phenotype in Dementia with Lewy Bodies.

It is currently unknown whether patients with dementia with Lewy bodies (DLB) with relatives with dementia or Parkinson's disease (familial DLB patients) have a different phenotype than sporadic DLB patients. In this study, we aimed to examine disease onset, rate of cognitive decline, survival, and Alzheimer's disease (AD) biomarkers in patients with familial DLB (n = 154) and sporadic DLB (n = 137), using linear mixed model analysis and Cox regression analysis, among others. Familial patients had a shorter survival (8.0 years) and more often elevated cerebrospinal fluid AD biomarkers (47%) than sporadic patients (9.0 years; p≤0.001; 30%, p = 0.037). Our findings suggest that genetic factors are important in DLB and that the identification of new genetic factors will probably improve the prediction of prognosis.

Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study.

BACKGROUND: Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia. METHODS: We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia. FINDINGS: We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; p<0·0001) and non-carriers (8 pg/mL [6-11]; p<0·0001), and was higher in converters than in non-converting carriers (19 pg/mL [17-28] vs 8 pg/mL [6-11]; p=0·0007; adjusted for age). During follow-up, NfL increased in converters (b=0·097 [SE 0·018]; p<0·0001). In symptomatic mutation carriers overall, NfL did not change during follow-up (b=0·017 [SE 0·010]; p=0·101) and remained elevated. Rates of NfL change over time were associated with rate of decline in Mini Mental State Examination (b=-94·7 [SE 33·9]; p=0·003) and atrophy rate in several grey matter regions, but not with change in Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale score (b=-3·46 [SE 46·3]; p=0·941). INTERPRETATION: Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker. FUNDING: ZonMw and the Bluefield project.