Diagnosis Of Neurodegenerative Dementias Research Articles

Diagnostic value of isolated plasma biomarkers and its combination in neurodegenerative dementias: A multicenter cohort study

BackgroundPlasma amyloid-β (Aβ), phosphorylated tau-181 (p-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) potentially aid in the diagnosis of neurodegenerative dementias. We aim to conduct a comprehensive comparison between different biomarkers and their combination, which is lacking, in a multicenter Chinese dementia cohort consisting of Alzheimer’s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). MethodsWe enrolled 92 demented patients [64 AD, 16 FTD, and 12 PSP with dementia] and 20 healthy controls (HC). Their plasma Αβ, p-tau181, NfL, and GFAP were detected by highly sensitive-single molecule immunoassays. Αβ pathology in patients was measured by cerebrospinal fluid or/and amyloid positron emission tomography. ResultsAll plasma biomarkers tested were significantly altered in dementia patients compared with HC, especially Aβ42/Aβ40 and NfL showed significant performance in distinguishing AD from HC. A combination of plasma Aβ42/Aβ40, p-tau181, NfL, and GFAP could discriminate FTD or PSP well from HC and was able to distinguish AD and non-AD (FTD/PSP). ConclusionsOur results confirmed the diagnostic performance of individual plasma biomarkers Aβ42/Aβ40, p-tau181, NfL, and GFAP in Chinese dementia patients and noted that a combination of these biomarkers may be more accurate in identifying FTD/PSP patients and distinguishing AD from non-AD dementia.

New knowledge on anti-IgLON5 disease.

Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported. Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects. Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease.

Combination Functional and Structural Imaging for the Diagnosis of Neurodegenerative Dementias – A Suggested Imaging Strategy

Combination Functional and Structural Imaging for the Diagnosis of Neurodegenerative Dementias – A Suggested Imaging Strategy

The Parietal Atrophy Score on Brain Magnetic Resonance Imaging is a Reliable Visual Scale.

AimsThe purpose of the study was to evaluate the reliability of our new visual scale for a quick atrophy assessment of parietal lobes on brain Magnetic Resonance Imaging (MRI) among different professionals. A good agreement would justify its use for differential diagnosis of neurodegenerative dementias, especially early-onset Alzheimer’s Disease (AD), in clinical settings.MethodsThe visual scale named the Parietal Atrophy Score (PAS) is based on a semi-quantitative assessment ranging from 0 (no atrophy) to 2 (prominent atrophy) in three parietal structures (sulcus cingularis posterior, precuneus, parietal gyri) on T1-weighted MRI coronal slices through the whole parietal lobes. We used kappa statistics to evaluate intra-rater and inter-rater agreement among four raters who independently scored parietal atrophy using PAS. Rater 1 was a neuroanatomist (JM), rater 2 was an expert in MRI acquisition and analysis (II), rater 3 was a medical student (OP) and rater 4 was a neurologist (DS) who evaluated parietal atrophy twice in a 3-month interval to assess intra-rater agreement. All raters evaluated the same 50 parietal lobes on brain MRI of 25 cognitively normal individuals with even distribution across all atrophy degrees from none to prominent according to the neurologist’s rating.ResultsIntra-rater agreement was almost perfect with the kappa value of 0.90. Inter-rater agreement was moderate to substantial with kappa values ranging from 0.43-0.86.ConclusionThe Parietal Atrophy Score is the reliable visual scale among raters of different professions for a quick evaluation of parietal lobes on brain MRI within 1-2 minutes. We believe it could be used as an adjunct measure in differential diagnosis of dementias, especially early-onset AD.

18F-FDG in the differential diagnosis of neurodegenerative dementias

The diagnostic workflow of patients with cognitive decline needs an extensive clinical evaluation. The use of FDG-PET can be helpful because the finding of a rather specific pattern of hypometabolism could point to specific neurodegenerative disorders. In patients with memory impairment and visuo-spatial deficits, FDG-PET may reveal a pattern of temporo-parietal hypometabolism that is associated with Alzheimer’s disease or a more extended area of hypometabolism that spreads to the occipital cortex, as in posterior cortical atrophy indicating signs of neurodegeneration in the associative visual cortex. In the spectrum of fronto-temporal lobe degeneration, FDG-PET is used to support the diagnosis by excluding AD and to identify areas of hypometabolism that are associated with the behavioural variant of FTD or with progressive primary aphasia. When cognitive impairment develops along with parkinsonism, FDG-PET can be used to differentiate among the different forms of disorders, such as dementia with Lewy bodies, progressive supranuclear palsy and cortico-basal degeneration, occurring with different specific pattern of altered metabolism. In this pictorial essay, we present a series of clinical cases in which the use of FDG-PET contributed to the final diagnosis.

Diagnosis of neurodegenerative dementia: where do we stand, now?

After many years of large efforts made for understanding the pathogenesis of dementias, the early diagnosis of these degenerative diseases remains an open challenge. Alzheimer's disease (AD) represents the most common form of dementia, followed by Lewy body disease and frontotemporal degeneration. Actually, different pathological processes can determine similar and overlapping clinical syndrome. To detect in vivo the pathological process underlying progressive cognitive and behavior impairment, the Internationals guidelines recommend the use of biological and topographical markers, which can reflect neuropathological modifications in brain. In cerebrospinal fluid (CSF), decrease of amyloid beta 1-42 (Aβ42) and a low ratio of Aβ42 with amyloid beta 1-40 (Aβ42/Aβ40), together with the increase of both total tau protein (t-tau) and phosphorylated tau (p-tau), contribute to define the "Alzheimer's signature". This review points out on the evolution of the concept for early diagnosis of AD, and on the current use of CSF proteins for research purposes and in clinical setting. Then, we discuss the limitations and drawbacks in wide application of CSF biomarkers for diagnosing degenerative dementias, and on the role of laboratory medicine to convey these biomarkers from "research" toward "clinical practice".

Alzheimer's Disease and the Routine Clinical Use of CSF Biomarkers.

Amyloid based hypothesis led to develop biomarkers oriented diagnosis of neurodegenerative dementias. Among them biomarkers for AD, the most diffuse form of dementia, are currently the unique available for scientific and diagnostic purposes. CSF biomarkers like Amyloid beta 42, total tau and phosphorylated tau levels can be easily evaluated in individuals suffering from cognitive decline, to diagnose or exclude AD type dementia, since early stages. Moreover, their analysis gave the opportunity to better understand cognitive decline patho-physiology during aging. Experience from their use and analysis however showed a high degree of variability due to the great heterogeneity of AD on one hand, the presence of isolated CSF biomarker changes that are not to be considered of AD type and deserve a clinico-pathological classification on the other. Aim of this review is to offer the knowledge about CSF biomarker's use in clinics.

Magnetic resonance imaging and positron emission tomography in the diagnosis of neurodegenerative dementias.

Neuroimaging, both with magnetic resonance imaging (MRI) and positron emission tomography (PET), has gained a pivotal role in the diagnosis of primary neurodegenerative diseases. These two techniques are used as biomarkers of both pathology and progression of Alzheimer's disease (AD) and to differentiate AD from other neurodegenerative diseases. MRI is able to identify structural changes including patterns of atrophy characterizing neurodegenerative diseases, and to distinguish these from other causes of cognitive impairment, e.g. infarcts, space-occupying lesions and hydrocephalus. PET is widely used to identify regional patterns of glucose utilization, since distinct patterns of distribution of cerebral glucose metabolism are related to different subtypes of neurodegenerative dementia. The use of PET in mild cognitive impairment, though controversial, is deemed helpful for predicting conversion to dementia and the dementia clinical subtype. Recently, new radiopharmaceuticals for the in vivo imaging of amyloid burden have been licensed and more tracers are being developed for the assessment of tauopathies and inflammatory processes, which may underlie the onset of the amyloid cascade. At present, the cerebral amyloid burden, imaged with PET, may help to exclude the presence of AD as well as forecast its possible onset. Finally PET imaging may be particularly useful in ongoing clinical trials for the development of dementia treatments. In the near future, the use of the above methods, in accordance with specific guidelines, along with the use of effective treatments will likely lead to more timely and successful treatment of neurodegenerative dementias.

A comparison of FDG‐PET and blood flow SPECT in the diagnosis of neurodegenerative dementias: a systematic review

Perfusion single photon emission computed tomography (SPECT) and 18F fluorodeoxyglucose positron emission tomography (FDG-PET) both have clinical utility for the differential diagnosis of dementia. Although PET is often viewed by some as more accurate and therefore preferential, the extent to which published evidence supports this is not clear. The aim of this review was to address the question by reviewing studies of SPECT and PET imaging in dementia diagnosis, with a particular focus on all published head-to-head studies. A MEDLINE search was carried out using the following keywords: "PET" and "SPECT" and "dementia" or "Mild Cognitive Impairment," together with "alzheimers" or "DLB" or "lewy body" or "frontotemporal" or "FTD" or "Picks." Articles were included up to February 2013, limited to human studies and in English language. Published studies of SPECT accuracy show that it is a useful tool for differential diagnosis, with sensitivities of 65-85% for diagnosing Alzheimer's disease (AD) and specificities (for other neurodegenerative dementias) of 72-87%. PET studies generally report higher accuracy, with sensitivities of 75-99% for AD and specificities of 71-93%. However, there have been few direct head-to-head comparisons, with some indicating SPECT and PET to be equally useful in dementia diagnosis and others favouring PET. Many of these studies are limited with respect to numbers and methodically with poorly matched control groups. Overall, although studies suggest superiority of PET over SPECT, the evidence base for this is actually quite limited. We suggest that further direct comparative studies, including health economic and patient preference evaluations, are needed to help direct future service provision.

TEP/IRM hybride en neuro-imagerie

The hybrid Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) is a newly available imaging modality combining the molecular and metabolic PET information with the morphological and functional data provided by MRI. Integrated PET/MRI tomographs were conceived in analogy to the current PET/Computed Tomography (PET/CT) technology, with specific properties linked to the intrinsic differences of MRI and CT imaging. In the field of neuro-imaging, in particular, MRI provides a larger panel of information, as compared with CT, and is already systematically fused and used as a support for PET images for diagnostic and research purposes. We summarize here our current experience with the first integrated PET/MRI tomograph installed in Switzerland, concerning specifically three clinical applications: brain tumors characterization, the diagnosis of neurodegenerative dementias and the presurgical evaluation of pharmaco-resistant epilepsy. With this sequential tomograph, we could combine the full range of diagnostic MR sequences (including diffusion tensor imaging, tractography, spectroscopy, functional MR) with PET imaging of brain glucose metabolism (by 18F-Fluorodeoxyglucose–FDG) and of amino acid transport (by 18F-Fluoroethyltyrosine–FET). We also summarize the main results obtained in neuro-imaging by the different groups working with these new hybrid tomographs. These data show that PET/MRI, acquired in a single imaging session, may represent the modality of choice for neuro-imaging.

Florbetapir F 18 for brain imaging of beta-amyloid plaques

Recent trends in neurodegeneration research have been aimed at developing new amyloid ligands for the neuroimaging of dementia. Among the positron emission tomography (PET) radiotracers, fluorodeoxyglucose F 18 ((18)F-FDG) is the compound most widely used in the diagnosis of neurodegenerative dementias. However, this compound shows a level of specificity and sensitivity for early Alzheimer's disease detection that is lower than that provided by high-affinity ligands for β-amyloid (Aβ). Among the new widely available fluorine 18 ((18)F)-labeled Aβ ligands, florbetapir F 18 ((18))F-AV-45; Amyvid™) showed clear qualitative and quantitative correlations between in vivo PET imaging and postmortem histopathologic analysis of Aβ. Florbetapir F 18 stands out for its high Aβ affinity and its pharmacokinetic properties that allow 10-minute PET scan imaging within 90 minutes after administration (dose = 370 MBq). Importantly, no safety concerns for florbetapir F 18 were found in preclinical studies. In 2012, the U.S. Food and Drug Administration (FDA) approved Amyvid as a radiotracer helpful for excluding the presence of Aβ in the brain. It was then approved earlier this year by the European Medicines Agency (EMA).

Translational Research in Neurology

Dementia disorders are characterized by clinicopathological criteria. Molecular understandings of these disorders, based on immunohistochemical studies, biochemical investigations, genetic approaches, and animal models, have resulted in advances in diagnosis. Likewise, translational research has allowed us to apply our increasing basic scientific knowledge of neurodegeneration to the rational development of new investigational therapies based on our current understanding of disease pathogenesis. This review discusses the application of translational research to both diagnosis and treatment of dementia disorders. The development of biomarkers has yielded imaging and biochemical methods that assist the physician more than ever in the diagnosis of neurodegenerative dementias, especially Alzheimer disease. New diagnostic criteria for disease are based on these molecular-based techniques. And these biomarkers are of potential use in monitoring disease activity during therapeutic trials. Translational investigations likewise have led toward new avenues in targeted dementia research. This is particularly so in the development and testing of disease-modifying treatments that might slow or deter progressive deterioration. Recent clinical trials have not been based on empirical trials of established drugs but, rather, on trials of drugs shown, through experiments in biochemical, cell culture, and animal models, to interfere with known elements of the pathogenetic cascade of Alzheimer disease.

Huntington's Disease: Effect of Memantine on FDG-PET Brain Metabolism?

In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient choosing to continue treatment over the 18-month follow-up period). The treatment regimen was well tolerated. No significant differences on neuropsychological parameters before and after treatment were detected; but the patient who continued treatment did not deteriorate at 18 months' reevaluation, whereas the three patients who had stopped treatment after 3 to 4 months had minor progression in all cognitive domains on re-evaluation 12 months after the end of treatment.

Semantic Markers in the Diagnosis of Neurodegenerative Dementias

Background: The search for early cognitive markers of Alzheimer’s disease (AD) has focused on episodic memory and spatiotemporal orientation. However, recent research suggests that semantic memory is also impaired in the preclinical stages of AD. Methods: Age- and education-matched groups of participants with AD, mild cognitive impairment, and subjective memory complaints and healthy controls were assessed with 16 cognitive tests encompassing attention, orientation, episodic and semantic memory, and language tasks. Results: The battery correctly distinguished AD patients from healthy seniors in 92% of the cases. Three semantic memory-based tasks turned out to be particularly powerful for this purpose. Conclusion: Our results suggest that semantic memory tasks should be included in the battery of tests for the evaluation of cognitively impaired patients.

The contribution of brain perfusion SPECT and magnetic resonance imaging in early diagnosis of neurodegenerative dementia

Materials and methods 107 patients underwent MRI and SPECT using HMPAO at the Department of Radiology and Nuclear Medicine of AHEPA University Hospital. Our patients based on clinical diagnosis were categorized into 3 groups: a) Neurodegenerative dementia (ND) consisted of 61 patients (mean age71±9) with Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and mixed dementia, b) Vascular cognitive impairment VCI consisted 27 patients (mean age 70±7), and c) Normal group included 19 persons (mean age 64±7).

Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses?

Tau and beta-amyloid (Abeta) are proposed diagnostic biomarkers for Alzheimer disease (AD). Previous studies report their relationship to clinical diagnoses of AD and other dementias. To understand their value as predictors of disease-specific pathology, levels determined during life must be correlated with definitive diagnoses in mixed dementia groups and cognitively normal subjects. To correlate antemortem cerebrospinal fluid (CSF) tau and Abeta levels with definitive dementia diagnosis in a diverse group of patients; to calculate statistics for CSF tau and Abeta. Prospective study. Ten clinics experienced in the diagnosis of neurodegenerative dementias. Patients One hundred six patients with dementia and 4 cognitively normal subjects with a definitive diagnosis, and 69 clinically diagnosed cognitively normal subjects. Correlation of CSF tau and Abeta with final diagnosis. Mean tau level was 612 pg/mL for the 74 patients with AD, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for 3 patients with dementia with Lewy bodies, and 140 pg/mL for 73 cognitively normal control subjects. Tau was less than 334 pg/mL for 20 patients with AD. Abeta42 was reduced in patients with AD (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with dementia with Lewy bodies (14 fmol/mL) or prion disease (60 fmol/mL). Elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. However, some patients with AD have a level less than the mean +/- 2 SDs of the cognitively normal cohort.