Fragile X-associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the ...clinical, neurophysiologic, and morphologic characteristics of FXTAS.
Clinical, morphologic (brain MRI, (123)I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women.
A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal (123)I-ioflupane SPECT. Unified Parkinson's Disease Rating Scale motor score was correlated to abnormal (123)I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04).
We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.
GRN mutations are frequent causes of familial frontotemporal degeneration. Although there is no clear consensual threshold, plasma progranulin levels represent an efficient biomarker for predicting ...GRN mutations when decreased. We evaluated plasma levels to determine whether it could also predict age at onset, clinical phenotype, or disease progression in 160 GRN carriers. Importantly, progranulin levels were influenced by gender, with lower levels in male than in female patients in our study. Although we found no correlation with age at onset or with clinical phenotype, we confirmed that decreased level predicts GRN mutations, even in presymptomatic carriers more than four decades before disease onset. We also provided first evidence for the stability of levels throughout longitudinal trajectory in carriers, over a 4-year time span. Finally, we confirmed that progranulin levels constitute a reliable, cost-effective marker, suitable as a screening tool in patients with familial frontotemporal degeneration, and more broadly in patients without family history or with atypical presentations who are less likely to be referred for molecular diagnosis.
•Plasma progranulin levels were analyzed in 293 GRN carriers and controls.•Progranulin levels were stable in carriers and controls over a 4-year time span.•Plasma progranulin did not correlate with age at onset and FTD phenotypes.•Different thresholds were suggested for male and female carriers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
OBJECTIVETo determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic ...correlates. METHODSPatients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. RESULTSAmong the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). CONCLUSIONSThis study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.
Very-early-onset Alzheimer's disease (young-AD) differentiates from late-onset AD (old-AD) by a predominant involvement of the parietal neocortex leading to atypical presentations. The diagnosis of ...AD is often not the first to be mentioned in such young patients.
We retrospectively reviewed the initial complaint and care pathways of 66 sporadic young-AD (age < 62) and 30 old-AD patients (age > 65) and compared their neuropsychological profiles at the time of diagnosis (based on clinical-biological criteria) with 44 amyloid-negative controls.
The initial complaint of young-AD was non-cognitive and mimicked a burnout in 32% of cases. Their main cognitive complaints were memory (38% vs 87% in old-AD) and language (17% vs 13%) impairment. The referral to a psychiatrist prior to AD diagnosis was more frequent in young-AD than in old-AD (26% vs 0%). At the time of diagnosis, young-AD were at a more severe stage of dementia than old-AD (24% vs 10% with CDR ≥ 1) but had less anosognosia.
Better identifying the initial signs of very-early-onset AD is crucial to improve the early diagnosis and develop new treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
In early 2020, COVID‐19 outbreak struck France leading to a national lockdown between March 17th and May 11th. While standard in‐person medical consultation was complicated, telemedicine ...dramatically expanded. In order to evaluate the impact of this unpreceded situation on clinical practice and use of psychoactive drug in dementia care, we conducted a nationwide clinical prospective and retrospective study.
Method
During the lockdown period, telemedicine patients’ demographic and clinical data were retrospectively collected from 7 French memory clinics (telemedicine cohort). Clinical diagnoses, treatment changes, cognitive modifications since last consultations and living conditions during the lockdown were systematically retrieved.
In Rouen site, we also included patients only reached by a secretary to propose a postponed visit after lockdown (no‐telemedicine cohort) and patients seen in 2019 during the same period of the year (Rouen‐2019).
The primary outcome was any change in psychoactive drug and a specific analysis on sedative treatment increase was the secondary outcome, defined as any increase in the prescriptions of antipsychotics or benzodiazepines.
Result
The telemedicine cohort included 874 patients (73 from Rouen), while no‐telemedicine control cohort and Rouen‐2019 cohorts included respectively 86 and 234 patients (table 1). In the telemedicine cohort, treatments were modified for 10.7% of the patients with more treatment modification among the patients living with a relative (+5.8% (CI95% 0.2%; 11.4% p=0.04) and among the patients with Alzheimer’s disease (+12.2% (CI95% 7.1%; 17.3% p<0.001). When comparing therapeutic strategies in 2020 and 2019 for Rouen site, 24.6% of the patients had their treatment modified in 2020 and 12.4% in 2019. That difference was however not statically significant with an adjusted percentage difference of ‐4% (CI95% ‐10.8%; 3.4% p=0.27, including the telemedicine and no‐telemedicine cohorts for 2020.
Conclusion
Telemedicine seems to have had only minor negative impacts on clinical practice in memory clinics.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
GRN null mutations are among the main genetic causes of frontotemporal dementia through progranulin haploinsufficiency. Most missense mutations are considered not pathogenic. The p.Trp7Arg ...substitution is localized within the signal peptide domain and no formal evidence for its pathogenicity has yet been provided. We identified the p.Trp7Arg substitution in 3 carriers with low plasma progranulin levels. This evidences that this missense mutation leads to functional haploinsufficiency and should thus be considered pathogenic. Assessing the pathogenicity of variants of unknown significance has significant implications for clinical practice, genetic counseling, and future therapeutic interventions.
•The GRN missense p.Trp7Arg mutation has been considered a variant of unknown significance so far.•The p.Trp7Arg variant determines low plasma progranulin levels indicating it leads to progranulin haploinsufficiency.•This study evidences that the p.Trp7Arg mutation is pathogenic and should be included among the frontotemporal dementia–causing mutations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This multicenter study was conducted in French memory clinics during the first COVID-2019 lockdown (March-May 2020). The objective was to evaluate the effect of a telemedicine consultation on ...treatment modification in dementia care. Among 874 patients who had a telemedicine consultation, 103 (10.7%) had treatment modifications, in particular those living with a relative or diagnosed with Alzheimer's disease. A control group of patients referred March-May 2019 was also included. Treatment modification rate was similar between periods with an adjusted percentage difference of -4% (p = 0.27). Telemedicine consultations allowed treatment modifications with only a minor short-term negative impact on therapeutic strategies.
GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids ...(lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases.
We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography.
Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers.
This study evidences an age-dependent increase of β-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases.
•GRN mutation carriers display increased plasma levels of lysosphingolipids (lysoSPL).•Lysosphingomyelins are elevated in presymptomatic (PS) and symptomatic carriers.•Glucosylsphingosine displays an age-dependent increase in GRN-associated FTD patients.•In PS carriers, LSM18:1 and LGL1 increase over time, in association with NfL changes.•Lysosomal biomarker dosages contribute to monitor disease progression in GRN carriers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Late-onset Niemann-Pick type C (NP-C) is a rare, underdiagnosed lysosomal disease with neurological manifestations. A specific treatment, miglustat, can stabilize the disease if given early. ...Recently, three plasma screening biomarkers (PSBs) were developed cholestane3β,5α,6βtriol (C-triol), 7-ketocholesterol (7-KC), and lysosphingomyelin-509 (LSM-509), allowing a simpler and quite robust screening of patients suitable for genetic testing. The objective of our study was to evaluate practical utility and feasibility of large-scale PSB screening for NP-C in selected adult patients. Patients were prospectively enrolled if they showed, starting from 12 years of age, at least one of the three initial neuro-psychiatric manifestations described in NP-C: (1) gait disorder (cerebellar and/or dystonic); (2) cognitive decline with frontal lobe syndrome; (3) atypical psychosis. PSBs were measured in plasma of all patients and, if positive (LSM-509 and/or C-triol + 7-KC elevated), sequencing of
NPC1
and
NPC2
genes was performed. A total of 251 patients 136 males, 115 females; median age 42.1 (range 12.2–85.6) years were screened. Six patients had positive PSBs. Two were confirmed to have NP-C (0.8% diagnostic yield, both with all three PSBs highly increased, especially LSM-509). False-positive rate was 1.2%, which was identical if only considering LSM-509. By contrast, false-positive rates were 8.1% and 5.7% for 7-KC and C-triol, respectively. We showed that selecting patients with neurologic and/or psychiatric symptoms consistent with NP-C for large-scale PSB screening is a simple and valid strategy to identify new adult NP-C patients, and would probably lead to earlier diagnosis and treatment administration if widely applied.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
ABSTRACTWe report a case of Gayet-Wernicke encephalopathy, revealed by an F-FDG PET/MRI performed in a patient with memory impairment. Metabolism showed no pattern of neurodegenerative disease, but a ...severe decrease in hippocampus and mammillary bodies (MBs). MRI images analyzed in light of PET findings revealed MB atrophy coupled with signal-intensity alterations, suggestive of a Gayet-Wernicke encephalopathy. Patient was known for alcohol use disorders, and all previous MRI scans were considered as inconclusive. Symptoms improved with correction of thiamine (vitamin B1) deficiency. This report highlights ability of hybrid PET/MRI to investigate small neuronal structures, such as the MBs involved in Gayet-Wernicke disease.
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