Differential Diagnosis Of Neurodegenerative Disorders Research Articles

A New Case of Mitochondrial RNA Helicase SUPV3L1-Associated Neurodegenerative Disease: Ataxia, Spasticity, Optic Atrophy, and Skin Hypopigmentation (ASOASH).

The SUPV3L1 gene encodes ATP-dependent RNA helicase SUPV3L1, which is a part of the mitochondrial degradosome complex or SUV3. SUPV3L1 unwinds secondary structures of mitochondrial RNA (mtRNA) and facilitates the degradation of mtRNA molecules. A nonsense homozygous variant in the SUPV3L1 gene was recently associated with mitochondrial disease. Our study presents the second documented case of SUPV3L1 pathology in humans. Whole-genome sequencing was performed on the NovaSeq 6000 platform using pair-end reading. Data analysis was performed with an in-house developed pipeline. The 17-year-old female patient exhibited a diverse array of symptoms, including ataxia, spastic paraparesis, cognitive deficit, optic atrophy, and horizontal gaze-evoked nystagmus. Early onset of symptoms, such as ataxic gait and nystagmus, was noted, with subsequent progression of neurological manifestations. At the time of the observation, the proband had extensive regions of hypopigmented skin patches on the body and extremities, which have progressed over time. Whole-genome sequencing revealed compound heterozygous variants in the SUPV3L1 gene: c.272-2A>G and c.1924A>C; p.(Ser642Arg). RNA analysis demonstrated splicing changes attributable to the c.272-2A>G variant. ELISA assay showed increased Complex I content in the patient's fibroblasts. This case underscores the phenotypic diversity associated with SUPV3L1 mutations, emphasizing the importance of considering mitochondrial RNA helicase dysfunction in the differential diagnosis of neurodegenerative disorders. Further elucidation of the molecular mechanisms underlying SUPV3L1-associated pathology may provide valuable insights into targeted therapeutic interventions.

Head-to-Head Comparison of Tau and Amyloid Positron Emission Tomography Visual Reads for Differential Diagnosis of Neurodegenerative Disorders: An International, Multicenter Study.

We compared the accuracy of amyloid and [18F]Flortaucipir (FTP) tau positron emission tomography (PET) visual reads for distinguishing patients with mild cognitive impairment (MCI) or dementia with fluid biomarker support of Alzheimer's disease (AD). Participants with FTP-PET, amyloid-PET, and diagnosis of dementia-AD (n = 102), MCI-AD (n = 41), non-AD diseases (n = 76), and controls (n = 20) were included. AD status was determined independent of PET by cerebrospinal fluid or plasma biomarkers. The mean age was 66.9 years, and 44.8% were women. Three readers interpreted scans blindly and independently. Amyloid-PET was classified as positive/negative using tracer-specific criteria. FTP-PET was classified as positive with medial temporal lobe (MTL) binding as the minimum uptake indicating AD tau (tau-MTL+), positive with posterolateral temporal or extratemporal cortical binding in an AD-like pattern (tau-CTX+), or negative. The majority of scan interpretations were used to calculate diagnostic accuracy of visual reads in detecting MCI/dementia with fluid biomarker support for AD (MCI/dementia-AD). Sensitivity of amyloid-PET for MCI/dementia-AD was 95.8% (95% confidence interval 91.1-98.4%), which was comparable to tau-CTX+ 92.3% (86.7-96.1%, p = 0.67) and tau-MTL+ 97.2% (93.0-99.2%, p = 0.27). Specificity of amyloid-PET for biomarker-negative healthy and disease controls was 84.4% (75.5-91.0%), which was like tau-CTX+ 88.5% (80.4-94.1%, p = 0.34), and trended toward being higher than tau-MTL+ 75.0% (65.1-83.3%, p = 0.08). Tau-CTX+ had higher specificity than tau-MTL+ (p = 0.0002), but sensitivity was lower (p = 0.02), driven by decreased sensitivity for MCI-AD (80.5% [65.1-91.2] vs. 95.1% [83.5-99.4], p = 0.03). Amyloid- and tau-PET visual reads have similar sensitivity/specificity for detecting AD in cognitively impaired patients. Visual tau-PET interpretations requiring cortical binding outside MTL increase specificity, but lower sensitivity for MCI-AD. ANN NEUROL 2024;96:476-487.

Neuropsychological Assessment for Early Detection and Diagnosis of Dementia: Current Knowledge and New Insights.

Dementia remains an underdiagnosed syndrome, and there is a need to improve the early detection of cognitive decline. This narrative review examines the role of neuropsychological assessment in the characterization of cognitive changes associated with dementia syndrome at different states. The first section describes the early indicators of cognitive decline and the major barriers to their identification. Further, the optimal cognitive screening conditions and the most widely accepted tests are described. The second section analyzes the main differences in cognitive performance between Alzheimer's disease and other subtypes of dementia. Finally, the current challenges of neuropsychological assessment in aging/dementia and future approaches are discussed. Essentially, we find that current research is beginning to uncover early cognitive changes that precede dementia, while continuing to improve and refine the differential diagnosis of neurodegenerative disorders that cause dementia. However, neuropsychology faces several barriers, including the cultural diversity of the populations, a limited implementation in public health systems, and the adaptation to technological advances. Nowadays, neuropsychological assessment plays a fundamental role in characterizing cognitive decline in the different stages of dementia, but more efforts are needed to develop harmonized procedures that facilitate its use in different clinical contexts and research protocols.

Characterisation of a novel [18F]FDG brain PET database and combination with a second database for optimising detection of focal abnormalities, using focal cortical dysplasia as an example

BackgroundBrain [18F]FDG PET is used clinically mainly in the presurgical evaluation for epilepsy surgery and in the differential diagnosis of neurodegenerative disorders. While scans are usually interpreted visually on an individual basis, comparison against normative cohorts allows statistical assessment of abnormalities and potentially higher sensitivity for detecting abnormalities. Little work has been done on out-of-sample databases (acquired differently to the patient data). Combination of different databases would potentially allow better power and discrimination. We fully characterised an unpublished healthy control brain [18F]FDG PET database (Marseille, n = 60, ages 21–78 years) and compared it to another publicly available database (MRXFDG, n = 37, ages 23–65 years). We measured and then harmonised spatial resolution and global values. A collection of patient scans (n = 34, 13–48 years) with histologically confirmed focal cortical dysplasias (FCDs) obtained on three generations of scanners was used to estimate abnormality detection rates using standard software (statistical parametric mapping, SPM12).ResultsRegional SUVs showed similar patterns, but global values and resolutions were different as expected. Detection rates for the FCDs were 50% for comparison with the Marseille database and 53% for MRXFDG. Simply combining both databases worsened the detection rate to 41%. After harmonisation of spatial resolution, using a full factorial design matrix to accommodate global differences, and leaving out controls older than 60 years, we achieved detection rates of up to 71% for both databases combined. Detection rates were similar across the three scanner types used for patients, and high for patients whose MRI had been normal (n = 10/11).ConclusionsAs expected, global and regional data characteristics are database specific. However, our work shows the value of increasing database size and suggests ways in which database differences can be overcome. This may inform analysis via traditional statistics or machine learning, and clinical implementation.

Dissociating nouns and verbs in temporal and perisylvian networks: Evidence from neurodegenerative diseases

Naming of nouns and verbs can be selectively impaired in neurological disorders, but the specificity of the neural and cognitive correlates of such dissociation remains unclear. Functional imaging and stroke research sought to identify cortical regions selectively recruited for nouns versus verbs, yet findings are inconsistent.The present study investigated this issue in neurodegenerative diseases known to selectively affect different brain networks, thus providing new critical evidence of network specificity. We examined naming performances on nouns and verbs in 146 patients with different neurodegenerative syndromes (Primary Progressive Aphasia – PPA, Alzheimer's disease – AD, and behavioral variant Frontotemporal Dementia – FTD) and 30 healthy adults. We then correlated naming scores with MRI-derived cortical thickness values as well as with performances in semantic and syntactic tasks, across all subjects.Results indicated that patients with the semantic variant PPA named significantly fewer nouns than verbs. Instead, nonfluent/agrammatic PPA patients named fewer verbs than nouns. Across all subjects, performance on nouns (adjusted for verbs) specifically correlated with cortical atrophy in left anterior temporal regions, and performance on verbs (adjusted for nouns) with atrophy in left inferior and middle frontal, inferior parietal and posterior temporal regions. Furthermore, lower lexical-semantic abilities correlated with deficits in naming both nouns and verbs, while lower syntactic abilities only correlated with naming verbs.Our results show that different neural and cognitive mechanisms underlie naming of specific grammatical categories in neurodegenerative diseases. Importantly, our findings showed that verb processing depends on a widespread perisylvian networks, suggesting that some regions might be involved in processing different types of action knowledge. These findings have important implications for early differential diagnosis of neurodegenerative disorders.

Comparison of magnetic resonance parkinsonism index between parkinson disease, progressive supranuclear palsy and spinocerebellar degeneration

Background: Imaging measurements, such as midsaggital area of the midbrain and pons and Magnetic Resonance Parkinsonism Index (MRPI) has been reported as useful tools for differential diagnosis of neurodegenerative disorders in neuroradiology. However, these measurements have not been used routinely in clinical neurology.

DIFFERENTIAL ROLE OF CSF FATTY ACID BINDING PROTEIN 3, α-SYNUCLEIN AND ALZHEIMER’S DISEASE CORE BIOMARKERS IN LEWY BODY DISORDERS AND ALZHEIMER’S DEMENTIA

Accumulation, in extra- or intracellular deposits, of aggregated and misfolded proteins characterizes Alzheimer disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). This reflects in an overlapping of clinical presentations, especially between AD and DLB. Here we evaluated the diagnostic performance of a panel of five cerebrospinal fluid (CSF) biomarkers in a cohort of patients diagnosed with AD, DLB, PDD and Parkinson's disease (PD). Here we measured CSF levels of fatty acid binding protein (FABP3), α-synuclein (α-syn) and classical AD biomarkers in a large cohort of patients diagnosed with PD (n= 54), AD (n=48), DLB (n=40), PDD (n=20) and control subjects (n=46). ELISA immunoassays were used to assess CSF levels of fatty acid binding protein (FABP3), α-synuclein (α-syn), amyloid β 1–42 (Aβ1–42), total tau (t-tau) and phosphorylated tau 181 (p-tau). Univariate and multivariate statistical analyses were applied to calculate the diagnostic performance of the five CSF biomarkers, as well as their association with clinical parameters. CSF t-tau, p-tau and α-syn levels were significantly higher in AD than in PDD, DLB, PD patients and controls. CSF FABP3 levels were significantly increased in AD and DLB patients compared to PD and controls (p<0.001). A combination of FABP3 and p-tau reached an optimal accuracy for discriminating AD and DLB (AUC=0.92), while the best performance for distinguishing AD and PDD was obtained using a combination of p-tau, FABP3 and α-syn (AUC = 0.96). CSF FABP3 levels were inversely associated with Mini Mental State Examination scores in the whole cohort (r = -0.42, p < 0.001). No correlation was found between CSF biomarkers and motor scores (UPDRS-III and H&Y). The combination of CSF biomarkers linked to different aspects of neurodegeneration may improve the differential diagnosis of neurodegenerative disorders. In this context FABP3 plays a key role when combined to CSF AD core biomarkers and α-synuclein.

Tau imaging with [18 F]THK-5351 in progressive supranuclear palsy.

Visualization of pathogenic protein aggregates is crucial to elucidate pathomechanisms and to make an accurate diagnosis in many neurodegenerative conditions. Aggregates of the microtubule-binding protein, tau, are one of the most important pathogenic molecules in neurodegenerative disorders. Progressive supranuclear palsy (PSP) is characterized by the deposition of tau proteins in some specific area such as the basal ganglia and brainstem. We tried to detect tau lesions in the brains of living patients with PSP with a novel positron emission tomography (PET) tracer, [18 F]THK-5351, which we have recently developed. Paraffin-embedded brain sections of the patients with PSP were used for autoradiography with [3 H]THK-5351 and immunohistochemistry. Nine healthy controls, 13 patients with Alzheimer's disease and three patients with PSP participated in this PET study with [18 F]THK-5351. To detect amyloid-β deposition, PET imaging with Pittsburgh compound B was also performed. Autoradiography in the brain sections of patients with PSP demonstrated [3 H]THK-5351 binding to tau deposits with a high selectivity. Although patients with PSP exhibited no remarkable [18 F]THK-5351 retention in the temporal cortex, significantly higher tracer retention was observed in the globus pallidus and midbrain. In contrast, amyloid imaging with Pittsburgh compound B showed no remarkable accumulation in the cerebral cortex of PSP. We conclude that [18 F]THK-5351 PET can potentially be used to detect the regional brain distribution of tau lesions in PSP, thereby facilitating the differential diagnosis of neurodegenerative disorders associated with tau protein.

COMBINATION OF CEREBROSPINAL FLUID H-FABP AND CORE ALZHEIMER'S DISEASE BIOMARKERS IMPROVES THE DIFFERENTIAL DIAGNOSIS OF NEURODEGENERATIVE DISORDERS

COMBINATION OF CEREBROSPINAL FLUID H-FABP AND CORE ALZHEIMER'S DISEASE BIOMARKERS IMPROVES THE DIFFERENTIAL DIAGNOSIS OF NEURODEGENERATIVE DISORDERS

Clusterin CSF levels in differential diagnosis of neurodegenerative disorders

IntroductionClusterin, a heterodimeric glycoprotein, is thought to be involved in many cellular functions, including cell–cell interaction, cell survival and apoptosis. In the brain, post-mortem analysis has found increased clusterin associated with the pathology of many other neurodegenerative diseases (ND) such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and multiple system atrophy (MSA). In vivo cerebrospinal fluid (CSF) levels of clusterin in ND diseases may reflect differences in the pathology and thus aid in the differential diagnosis. MethodsCSF levels of clusterin were assessed in 102 patients with clinical manifestations of neurodegenerative diseases (23 patients with PD, 18 with PDD, 15 with DLB, 18 with AD, 16 with PSP, 12 with MSA) and 21 subjects as a control group (CG). ResultsSignificantly higher CSF clusterin levels were found in PD compared to CG (median 6884 vs. 4484; p=0.012), DLB (median 6884 vs. 4192; p=0.023), MSA (median 6884 vs. 3606; p=0.001) and PSP (median 6884 vs. 4193; p=0.014). Significantly higher CSF clusterin levels were found in PDD compared to CG (median 8617 vs. 4484; p=0.045), DLB (median 8617 vs. 4192; p=0.025) and MSA (median 8617 vs. 3606; p=0.004). ConclusionThe results of the presented “feasibility” study support the role of clusterin in PD/PDD pathogenesis.Clusterin CSF levels could serve as a potential marker for PDD and DLB differentiation.

Glial fibrillar acidic protein in the cerebrospinal fluid of Alzheimer's disease, dementia with Lewy bodies, and frontotemporal lobar degeneration.

Biomarkers in the cerebrospinal fluid (CSF) are currently regarded as indispensable indicators for accurate differential diagnosis of neurodegenerative disorders. Although high levels of astrocyte-secreted glial fibrillar acidic protein (GFAP) in the CSF of patients with Alzheimer's disease (AD) have been reported, the levels of GFAP in the CSF have not been fully investigated in other neurological disorders that cause dementia, such as dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). In this study, we determined the levels of GFAP in the CSF of healthy control subjects and AD, DLB, and FTLD patients to address two questions: (i) Do the levels of GFAP differ among these disorders? and (ii) Can GFAP be used as a biomarker for the differential diagnosis of these neurodegenerative disorders? The levels of GFAP in AD, DLB, and FTLD patients were significantly higher than those in the healthy control subjects. Although the levels of GFAP were not significantly different between AD and DLB patients, a higher level of GFAP was observed in FTLD patients than in AD and DLB patients. It is concluded that representative neurological disorders causing dementia were associated with higher levels of GFAP in the CSF. We propose the following mechanism concerning the amount of glial fibrillar acidic protein (GFAP) in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). The increase in the release of GFAP into CSF is considered to reflect the sum of degeneration of astrocytes and astrocytosis. The sum of degeneration and astrocytosis or the GFAP release could be in the order of FTLD > DLB > AD > normal condition.

Quantification of CSF biomarkers using an electrochemiluminescence-based detection system in the differential diagnosis of AD and sCJD.

The identification of reliable diagnostic tools for the differential diagnosis between sporadic Creutzfeldt-Jakob Disease (sCJD) and Alzheimer's disease (AD) remains impeded by the existing clinical, neuropathological and molecular overlap between both diseases. The development of new tools for the quantitative measurement of biomarkers is gaining experimental momentum due to recent advances in high-throughput screening analysis and with the optimization of assays for their quantification in biological fluids, including cerebrospinal fluid (CSF). Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve clinical quality performance in a variety of sample types due to its high sensitivity and dynamic range. Here, we quantified the CSF levels of Tau-protein, β-amyloid 1-42 (Aβ42) and α-synuclein, as important biomarkers in CSF used in the differential diagnosis of neurodegenerative disorders in 12 AD, 12 sCJD and 12 control cases by singleplex ECL-based technology. Its performance has been compared to classical enzyme-linked immunosorbent assays (ELISA) to confront their clinical accuracy. ECL-based technology validates previous data obtained with ELISA and presents a higher performance in the discrimination of three analysed groups as determined by increased area under the curve (AUC) values for the three biomarkers. Importantly, α-synuclein levels detected by ECL allow an excellent discrimination between sCJD cases and AD and control cases, unveiling a new clinical approach for the differential diagnosis of sCJD.

Clusterin CSF Levels in Differential Diagnosis of Neurodegenerative Disorders (S27.007)

Clusterin CSF Levels in Differential Diagnosis of Neurodegenerative Disorders (S27.007)

Neuroimaging biomarkers of neurodegenerative diseases and dementia.

Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer's disease (AD) and prodromal stages, familial and atypical AD syndromes, frontotemporal dementia, amyotrophic lateral sclerosis with and without dementia, Parkinson's disease with and without dementia, dementia with Lewy bodies, Huntington's disease, multiple sclerosis, HIV-associated neurocognitive disorder, and prion protein associated diseases (i.e., Creutzfeldt-Jakob disease). The authors focus on neuroimaging findings of in vivo pathology in these disorders, as well as the potential for neuroimaging to provide useful information for differential diagnosis of neurodegenerative disorders.

Olfactory Dysfunction

Disturbances of smell and taste are common. About 5% of the general population have anosmia (absence of the sense of smell). Olfactory dysfunction can markedly impair the quality of life. Review of pertinent literature retrieved by a selective search. In recent years, simple and reliable tests of the sense of smell have been introduced in otorhinolaryngology. Olfactory testing has become a new focus of attention in neurology as well, mainly because many patients with neurodegenerative diseases-including the majority of those with Parkinson's or Alzheimer's disease-have olfactory loss early on in the course of their disorder. Olfactory dysfunction is thus regarded as an early sign of neurodegenerative disease that may allow a tentative diagnosis to be made years before the motor or cognitive disturbances become evident. As for the treatment of olfactory loss, anti-inflammatory drugs and surgery can help in some cases, and olfactory training can lead to significant improvement of post-viral olfactory deficits. Olfactory dysfunction is common and becomes more common with advancing age. It is increasingly receiving attention as an important sign for the early diagnosis and the differential diagnosis of neurodegenerative disorders.