Correction:Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes (Human Genomics, (2023), 17, 1, (55), 10.1186/s40246-023-00499-z)

Following publication of the original article [1], the authors reported an error in Table 1. The correct Table 1 has been provided in this Correction. (Table presented.) Basic clinical and genetic characteristics of all 60 EOD patients ID Diagnosis AAO (years) Sex FH APOE Gene Variant Position Transcript CADD ClinVar Significance for disease EOD-1 EOD-2 c.184G &gt; A; p.R62C chr6:41129208-41129208 NM_001271821.1 25.5 n.r Risk modifier Risk modifier EOD-3 AD 45 f 2 E3/E3 EOD-4 AD 51 f 4 E4/E3 Risk modifier EOD-5 nfPPA 58 f 2 E3/E2 EOD-6 AD 56 f 3 E3/E3 EOD-7 AD/PCA 56 f 4 E3/E3 EOD-8 bvFTD 56 m 4 E3/E3 c.1427T &gt; C; p.M476T chr11:117160361-117160361 NM_012104.3 26.4 n.r Unknown c.9757A &gt; G; p.S3253G chr15:62173781-62173781 NM_020821.2 29.5 n.r Unknown EOD-9 AD 55 f 3,5 E4/E3 Risk modifier EOD-10 AD 58 f 3,5 E3/E3 EOD-11 AD 63 m 4 E3/E3 EOD-12 mixed dementia (AD + VD) 55 m 3,5 E4/E3 Risk modifier EOD-13 AD 61 m 4,5 E3/E3 EOD-14 AD/lpPPA 61 m 4 E4/E3 Risk modifier c.4300C &gt; T; p.V1434I chr15:62244179-62244179 NM_020821.2 24.8 n.r Unknown EOD-15 nfPPA 64 m 2 E3/E3 c.2218C &gt; T; p.E740K chr2:74594514-74594514 NM_004082.4 24.0 n.r Unknown EOD-16 AD 56 f 4 E3/E3 EOD-17 AD (PD) 60 m 1 E4/E3 Risk modifier g.chr16:1816528 A &gt; G; c.2817-2A &gt; G chr16:1816528-1816528 NM_015133.3 22.3 n.r Unknown EOD-18a c.2914C &gt; T; p.P972S chr19:1051537-1051537 NM_019112.3 25.3 n.r Potential risk modifier EOD-19 EOD-19 (2)b EOD-20 AD 57 m 4,5 E3/E3 c.7397T &gt; A; p.L2466H chr12:40760814-40760814 NM_198578.3 25.7 VUS Unknown EOD-21 EOD-22 EOD-23 EOD-24 EOD-25 EOD-26 AD 56 f 4 E3/E3 c.2980G &gt; C; p.P994A chr2:74590268-74590268 NM_023019.3 17.3 VUS Unknown c.2087G &gt; A; p.R696H chr16:1814180-1814180 NM_015133.3 31.0 n.r Unknown EOD-27 AD 57 f 4 E4/E3 Risk modifier EOD-28 AD 54 m 4 E3/E3 EOD-29 AD 54 m 4 E3/E3 EOD-30 AD 64 m 4 E3/E3 EOD-31 mixed dementia (AD + VD) 58 m 3,5 E3/E3 EOD-32 FTD/svPPA 61 m 4 E3/E3 EOD-33 AD 62 f 4,5 E4/E3 Risk modifier c.521G &gt; A; p.S174L chr2:74598788-74598788 NM_004082.4 24.4 VUS Unknown EOD-34 AD 59 f 2 E4/E3 Risk modifier EOD-35 AD 55 m 3,5 E4/E3 Risk modifier EOD-36c AD 64 m 2 E4/E3 c.140G &gt; A; p.R47H chr6:41129252-41129252 NM_018965.3 9.7 LB Risk modifier Risk modifier EOD-37 AD 52 f 3,5 E3/E3 c.7397T &gt; A; p.L2466H chr12:40760814-40760814 NM_198578.3 25.7 VUS Unknown EOD-38 AD 52 f 3,5 E4/E3 Risk modifier EOD-39 AD 63 f 3 E4/E3 Risk modifier EOD-40 AD 55 f 4 E4/E3 Risk modifier EOD-41 AD 58 m 3,5 E3/E3 EOD-42 AD 39 m 4 E3/E2 EOD-43 AD 63 m 4 E3/E3 c.3148A &gt; G; p.I1050V chr15:62256964-62256964 NM_020821.2 0.001 VUS Unknown EOD-44 AD/lpPPA 58 f 3,5 E3/E3 c.3014T &gt; G; p.M1005R chr11:121430331-121430331 NM_003105.5 27.9 n.r Potential risk modifier EOD-45 AD 65 m 4 E3/E3 EOD-46 CBS + AD 51 f 3,5 E3/E3 c.4606G &gt; A; p.G1536S chr11:121474988-121474988 NM_003105.5 25.2 B Risk modifier EOD-47 AD 54 f 4 E3/E3 EOD-48 bvFTD 57 m 4 E3/E3 EOD-49 FTD/nfPPA + ALS 58 m 4 E3/E3 c.986T &gt; C; p.L276P chr12:64875636-64875636 NM_013254.3 n.r Potential risk modifier c.7436T &gt; C; p.I2429T chr15:62212307-62212307 NM_020821.2 n.r Unknown EOD-50 Risk modifier EOD-51 FTD/svPPA 62 f 4 E3/E3 EOD-52 AD 57 m 4 E4/E3 Risk modifier EOD-53 c.7377G &gt; A; p.M2459I chr12:40758839-40758839 NM_198578.3 17.7 n.r Unknown EOD-54 AD 59 m 1 E4/E3 Risk modifier EOD-55 AD 49 m 4 E3/E3 EOD-56 AD 61 m 3,5 E3/E3 EOD-57 AD/lpPPA 57 f 4 E3/E3 EOD-58 AD + VD 64 f 3 E3/E3 c.823C &gt; T; p.R141C chr2:74598126-74598126 NM_004082.3 29.3 VUS Unknown EOD-59 bvFTD 52 m 4 E4/E3 Risk modifier EOD-60 a, EOD-18: The APP duplication of was confirmed to be 'de novo'. Both parents did not show this duplication b, EOD-19 (2) is the brother of EOD19. He was also affected by AD and carrier of the same duplication. EOD 19 (2) was not included in the analyses of AAO and FH c, EOD-36: ClinVar assessment of TREM2 p.R47H of LB (likely benign) refers to Nasu-Hakola disease. However, p.R47H is an established risk variant for dementia (Ref. 15) The original article [1] has been corrected.</p

HLA dependency and possible clinical relevance of intrathecally synthesized anti-IgLON5 IgG4 in anti-IgLON5 disease

BackgroundAnti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance.MethodsIgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method.ResultsThe median age at onset was 66 years (range: 54–75), disease duration 10 years (range: 15–156 months), and follow-up 25 months (range: 0–83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab.ConclusionOur findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease

Differences regarding the five-factor personality model in patients with subjective cognitive decline and mild cognitive impairment

Persönlichkeitsveränderung und Demenz sind miteinander assoziiert. Wissen über Persönlichkeitsveränderungen bei prodromalen Stadien der Demenz könnte hilfreich sein, um Demenz früher zu erkennen. Anhand einer Querschnittsstudie wurden Persönlichkeitsunterschiede zwischen drei kognitiv beeinträchtigten Gruppen anhand der Selbsteinschätzung von Persönlichkeitsmerkmalen untersucht. Des Weiteren wurden Zusammenhänge zwischen Persönlichkeit und kognitiver Funktion untersucht. Die Stichprobe bestand aus kognitiv beeinträchtigten Patienten (N=133) im Alter von 50 Jahren und älter, die aufgrund kognitiver Beschwerden eine Gedächtnisklinik aufsuchten. Die Untersuchung umfasste ein kognitives Screening, die Neuropsychologische Testbatterie Wien (NTBV) und das Big Five Plus One Persönlichkeitsinventar (B5PO). Während sich Patienten mit subjektivem kognitivem Abbau (SCD) nicht von denen mit nicht-amnestischer leichter kognitiver Beeinträchtigung (naMCI) bezüglich der verschiedenen Persönlichkeitsmerkmale unterschieden, zeigten Patienten mit amnestischer leichter kognitiver Beeinträchtigung (aMCI) signifikant niedrigere Werte für Extraversion (p<0,05), Offenheit (p<0,001) und Empathie (p<0,001) als Patienten mit SCD sowie Patienten mit naMCI. Kognitiv beeinträchtigte Gruppen unterschieden sich hinsichtlich Persönlichkeitseigenschaften in Abhängigkeit davon, ob Gedächtnisbeeinträchtigungen vorlagen oder nicht.Personality and dementia are connected in different ways. A broad knowledge about personality and prodromal stages of dementia might be helpful to identify dementia as early as possible. Hence, personality differences between three cognitively impaired groups on the basis of patients self-assessments of personality traits and connections between personality and cognitive functioning were examined via a cross-sectional study. The sample consisted of cognitively impaired patients (N=133), aged 50 and older, who came to a memory clinic due to cognitive complaints. The test procedure encompassed a cognitive screening, the Neuropsychological Test Battery Vienna (NTBV), and self-assessment questionnaires such as the Big Five Plus One Persönlichkeitsinventar (B5PO). While patients with subjective cognitive decline (SCD) did not differ from those with non-amnestic mild cognitive impairment (naMCI) concerning the different personality traits, patients with amnestic mild cognitive impairment (aMCI) showed significantly lower scores for extraversion (p<0.05), openness (p<0.001), and empathy (p<0.001) than patients with SCD as well as patients with naMCI. Thus, cognitively impaired groups mainly differ concerning personality traits depending on whether they do show memory decline or not.(VLID)365859

Naunyn-Schmiedeberg's Archives of Pharmacology / In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin

Extrusion of chemotherapeutics by ATP-binding cassette (ABC) transporters like ABCB1 (P-glycoprotein) represents a crucial mechanism of multidrug resistance in cancer therapy. We have previously shown that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin directly inhibits ABCB1, alters the glycosylation of the transporter, and enhances the intracellular accumulation of doxorubicin with subsequent anti-cancer action. Here, we show that simvastatin reduces endogenous dolichol levels and ABCB1 in human neuroblastoma SH-SY5Y cells. Coapplication with dolichol prevents the downregulation of the ABCB1 transporter. Importantly, dolichol also attenuated simvastatin-induced apoptosis, unmasking involvement of unfolded protein response. Direct monitoring of the fluorescent fusion protein YFP-ABCB1 further confirms concentration-dependent reduction of ABCB1 in HEK293 cells by simvastatin. In simvastatin-treated murine xenografts, ABCB1 was also reduced in the liver and rhabdomyosarcoma but did not reach significance in neuroblastoma. Nevertheless, the in vivo anti-cancer effects of simvastatin are corroborated by increased apoptosis in tumor tissues. These findings provide experimental evidence for usage of simvastatin in novel chemotherapeutic regimens and link dolichol depletion to simvastatin-induced anti-cancer activity.P 22385-B11(VLID)308385

Analysis of inflammatory markers and tau deposits in an autopsy series of nine patients with anti-IgLON5 disease

Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with a specific tauopathy. Only a few post-mortem neuropathological studies have been reported so far. Little is known about the pathogenic mechanisms that result in neurodegeneration. We investigated the neuropathology of anti-IgLON5 disease and characterized cellular and humoral inflammation. We included nine cases (six of them previously published). Median age of patients was 71&nbsp;years (53-82&nbsp;years), the median disease duration was 6&nbsp;years (0.5-13&nbsp;years), and the female to male ratio was 5:4. Six cases with a median disease duration of 9&nbsp;years presented a prominent tauopathy. Five of them had a classical anti-IgLON5-related brainstem tauopathy and another presented a prominent neuronal and glial 4-repeat tauopathy, consistent with progressive supranuclear palsy (PSP). Three cases with short disease duration (median 1.25&nbsp;years) only showed a primary age-related neurofibrillary pathology. Inflammatory infiltrates of T and B cells were mild to moderate and did not significantly differ between anti-IgLON5 disease cases with or without tauopathy. In contrast, we found an extensive neuropil deposition of IgG4 in the tegmentum of the brainstem, olivary nucleus, and cerebellar cortex that was most prominent in two patients with short disease duration without the typical IgLON5-related tauopathy. The IgG4 deposits were particularly prominent in the cerebellar cortex and in these regions accompanied by mild IgG1 deposits. Activated complement deposition (C9neo) was absent. Our study indicates that IgLON5-related tau pathology occurs in later disease stages and may also present a PSP-phenotype with exclusively 4-repeat neuronal and glial tau pathology. The prominent deposition of anti-IgLON5 IgG4 at predilection sites for tau pathology suggests that anti-IgLON5 antibodies precede the tau pathology. Early start of immunotherapy might prevent irreversible neuronal damage and progression of the disease, at least in a subgroup of patients

Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease

Background and Objectives Anti-IgLON5 disease is a recently described neurologic disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are underreported. We describe the frequency and types of movement disorders in a series of consecutive patients with this disease. Methods In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by 3 experts in movement disorders. Results Seventy-two patients were included. In 41 (57%), the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least 1 movement disorder with a median of 3 per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients [72%]), chorea (24 [33%]), bradykinesia (20 [28%]), dystonia (19 [26%]), abnormal body postures or rigidity (18 [25%]), and tremor (15 [21%]). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients [32%]) including dystonia (13), myorhythmia (6), chorea (4), or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31 (43%) patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only 7 (13%) cases. Discussion Movement disorders are a frequent and leading cause of initial neurologic consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment