A clinicopathological approach to the diagnosis of dementia

Elahi, Fanny M.; Miller, Bruce L.

doi:10.1038/nrneurol.2017.96

Cited by 261 publications

(217 citation statements)

References 262 publications

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“…The genes described here can be crudely divided to 1 of the following 3 groups: genes that are associated with alpha‐synuclein, but not with a PD syndrome (eg, PLA2G6, C19orf12 [MPAN]); genes that are clinically associated with PD, but not always with LB pathology (eg, LRRK2 and Parkin ); and genes that are associated with both a PD clinical syndrome and LB pathology (eg, SNCA and GBA ). These genes have also been associated clinically with DLB . Pathologically PD dementia and DLB may seem similar, and both have been reported with SNCA and GBA mutations.…”

Section: Discussionmentioning

confidence: 87%

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Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

2017

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Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson’s disease (PD). However mounting data from genetic-PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. Here we review the literature of genetic-PD autopsies from cases with molecularly-confirmed PD or parkinsonism and summarize main findings on SNCA (n=25), Parkin (n=20, 17 bi-allelic and 3 heterozygotes), PINK1 (n=5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n=1), LRRK2 (n=55), GBA (n=10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n= 8 patients, two with PD), MPAN (n=2), FBXO7, RAB39B and ATXN2 (SCA2), as well as on 22q deletion syndrome (n=3). Findings from autopsies of heterozygous mutation carriers of genes which are traditionally considered recessively-inherited are also discussed. Lewy bodies may be present in syndromes clinically distinctive from PD (e.g., MPAN-related neurodegeneration) and absent in patients with clinical PD syndrome (e.g., LRRK2-PD or Parkin-PD). Therefore, we may conclude that the presence of Lewy bodies are not specific to the diagnosis of PD and that PD can be diagnosed even in the absence of Lewy body pathology. Interventions that reduce alpha-synuclein load may be more justified in SNCA-PD or GBA-PD than in other genetic forms of PD. The number of reported genetic-PD autopsies remains small and there are limited genotype-clinical-pathological-phenotype studies. Therefore, larger series of autopsies from genetic-PD patients are required.

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Section: Discussionmentioning

confidence: 87%

“…These genes have also been associated clinically with DLB. 117 Pathologically PD dementia and DLB may seem similar, 1 and both have been reported with SNCA and GBA mutations. Whether the Braak staging that was proposed for idiopathic PD 118 applies to neuropathology in these cases remains to be investigated.…”

Section: S C H N E I D E R a N D A L C A L A Ymentioning

confidence: 94%

Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

2017

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“…Since 1955, dementias related to aging have been classified into two types: VD, caused by focal atrophic ischemic lesions, and AD, caused by cortical neurodegenerative process 19 . Differentiation between the two types of dementias is often difficult and involves a number of clinical tests and imaging exams.…”

Section: Discussionmentioning

confidence: 99%

“…Differentiation between the two types of dementias is often difficult and involves a number of clinical tests and imaging exams. Identifying the type of dementia is extremely important as treatment depends on the correct diagnosis 7,19 .…”

Section: Discussionmentioning

confidence: 99%

Assessment of hemodynamic and vascular parameters in Alzheimer's disease, vascular dementia and mild cognitive abnormalities: a pilot study

Santos

Rodrigues

Zogheib

et al. 2017

Rev. bras. geriatr. gerontol.

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Objectives: this pilot study correlated cardiovascular parameters such as atherosclerosis and arterial stiffness in patients with aged-related dementia and sought to identify hemodynamic differences that can help in differential diagnosis. Method: a longitudinal prospective study was performed of 46 patients aged 60 to 80 years in the city of Belo Horizonte, Minas Gerais, Brazil. The patients were classified into three groups: those with Alzheimer's disease (AD), vascular dementia (VD) or mild cognitive impairment (MCI). The groups were classified by clinical examination and CT or magnetic resonance imaging tests of the encephalon. The arterial stiffness and other hemodynamic parameters of the patients were measured using the Mobil-O-Graph device and carotid artery ultrasound scanning. Data analysis was performed by descriptive statistics, multinomial logistic regression and analysis of variance. Results: 18 patients (39.1%) had MCI, 18 (39.1%) AD and 10 (21.8%) VD. Image exams revealed greater obstructive microangiopathy in the AD group than the MCI group ( p<0.05), which in turn exhibited greater normality in such tests than the AD group ( p<0.05). There were no significant differences among the groups for the hemodynamic variables. The carotid artery ultrasound examinations identified a greater degree of normality in the MCI group than the AD group ( p<0.05). Conclusion: the results do not support the idea of using noninvasive hemodynamic evaluation methods as additional exams in the differential diagnosis of these pathologies.

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“…Patients with FTLD harbour either deposits of tau, TDP-43 or fused in sarcoma (FUS),1–3 but in most cases the specific underlying proteinopathy cannot be ascertained in vivo. Thus, patients with different clinical syndromes may show identical neuropathological findings, and in turn a specific clinical syndrome can be the expression of more than one proteinopathy 2. The challenges in predicting the underlying proteinopathy are an important limitation for achieving an accurate diagnosis and for the development of protein-specific therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD

Alcolea

Irwin

Illán-Gala

et al. 2018

J Neurol Neurosurg Psychiatry

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ObjectivesThe combination of high YKL-40 (a glial inflammatory marker) and low sAPPβ (a soluble β fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar degeneration (FTLD) in clinical series. We investigate these biomarkers in a neuropathologically confirmed cohort of patients with FTLD.MethodsCSF samples were selected from the Penn FTD Center (University of Pennsylvania). Participants were followed to autopsy and had a neuropathological diagnosis of FTLD-Tau (n=24), transactive response DNA-binding protein with 43 kDa (FTLD-TDP) (n=25) or Alzheimer’s disease (AD, n=97). We compared levels of YKL-40 and sAPPβ between groups and with cognitively normal controls (n=77), and assessed their diagnostic utility using receiver operating characteristic curves. We also investigated the effect of AD copathology and the correlation between these CSF markers and tau burden at autopsy.ResultsBoth FTLD groups had lower levels of sAPPβ, higher levels of YKL-40 and lower sAPPβ:YKL-40 ratio in CSF compared with controls. The group of pure FTLD-Tau (without AD copathology) showed higher levels of YKL-40 than AD and than pure FTLD-TDP. YKL-40 levels correlated with pathological tau burden. The sAPPβ:YKL-40 ratio had an area under the curve (AUC) of 0.91 (95% CI 0.86 to 0.96) to distinguish subjects with FTLD from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95% CI 0.61 to 0.79) and to discriminate FTLD-Tau from FTLD-TDP (AUC 0.67; 95% CI 0.51 to 0.82).ConclusionsOur study provides pathological confirmation that the combination of low sAPPβ and high YKL-40 in CSF is associated with FTLD. These biomarkers could be useful in particular clinical settings when FTLD is suspected.

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A clinicopathological approach to the diagnosis of dementia

Cited by 261 publications

References 262 publications

Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

Assessment of hemodynamic and vascular parameters in Alzheimer's disease, vascular dementia and mild cognitive abnormalities: a pilot study

Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD

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