Cholinergic depletion and basal forebrain volume in primary progressive aphasia

Schaeverbeke, Jolien; Evenepoel, Charlotte; Bruffaerts, Rose; Laere, Koen Van; Bormans, Guy; Dries, Eva; Tousseyn, Thomas; Nelissen, Natalie; Peeters, Ronald; Vandenbulcke, Mathieu; Dupont, Patrick; Vandenberghe, Rik

doi:10.1016/j.nicl.2016.11.027

Cited by 21 publications

(21 citation statements)

References 57 publications

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“…We found that pathological increases in delta power uniquely contributed to classification into the PPA group, independent of volumetric and sex differences. One of the potential mechanisms of delta increases may be related to the depletion of cholinergic projections from the basal forebrain to the cortex (Schaeverbeke et al, ), although this mechanism is more pertinent to AD pathology and therefore to lvPPA than nfvPPA (Rohrer, Rossor, & Warren, ). Pathologic slowing of spectral activity has been reported in other clinical populations as well, for example, Stoffers et al () found slowing in both demented and non‐demented Parkinson's disease patients.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous oscillatory markers of cognitive status in two forms of dementia

Shah-Basak

Kielar

Deschamps

et al. 2018

Human Brain Mapping

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Abnormal oscillatory brain activity in dementia may indicate incipient neuronal/synaptic dysfunction, rather than frank structural atrophy. Leveraging a potential link between the degree of abnormal oscillatory activity and cognitive symptom severity, one could localize brain regions in a diseased but pre-atrophic state, which may be more amenable to interventions. In the current study, we evaluated the relationships among cognitive deficits, regional volumetric changes, and resting-state magnetoencephalography abnormalities in patients with mild cognitive impairment (MCI; N = 10; age: 75.9 AE 7.3) or primary progressive aphasia (PPA; N = 12; 69.7 AE 8.0), and compared them to normal aging [young (N = 18; 24.6 AE 3.5), older controls (N = 24; 67.2 AE 9.7]. Whole-brain source-level resting-state estimates of relative oscillatory power in the delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz), and beta (15-30 Hz) bands were combined with gray matter volumes and cognitive scores to examine between-group differences and brain-behavior correlations. Language and executive function (EF) abilities were impaired in patients with PPA, while episodic memory was impaired in MCI. Widespread oscillatory speeding and volumetric shrinkage was associated with normal aging, whereas the trajectory in PPA indicated widespread oscillatory slowing with additional volumetric reductions. Increases in delta and decreases in alpha power uniquely predicted group membership to PPA. Beyond volumetric reductions, more delta predicted poorer memory. In patients with MCI, no consistent group difference among oscillatory measures was found. The contributions of delta/alpha power on memory abilities were larger than volumetric differences. Spontaneous oscillatory abnormalities in association with cognitive symptom severity can serve as a marker of neuronal dysfunction in dementia, providing targets for promising treatments. K E Y W O R D S dementia, magnetoencephalography, mild cognitive impairment, normal aging, primary progressive aphasia, resting-state

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Section: Discussionmentioning

confidence: 99%

Spontaneous oscillatory markers of cognitive status in two forms of dementia

Shah-Basak

Kielar

Deschamps

et al. 2018

Human Brain Mapping

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“…; Schaeverbeke et al . ). The resulting modulated gray matter volumes have been adjusted for overall brain size (total intracranial volume) by using the ‘nonlinear only’ component in the spatial normalization process for modulation of gray matter voxel intensities (Barnes et al .…”

Section: Methodsmentioning

confidence: 97%

“…Structural magnetic resonance imaging A structural T 1 -weighted MRI was acquired on a 3T Philips Achieva scanner (Philips, Best, The Netherlands) (3-D turbo field echo sequence, 32-channel Philips sensitivity encoding head coil: coronal inversion recovery prepared 3-D gradient-echo images, inversion time 900 ms, echo time/repetition time 4.6/9.6, flip angle 8°, voxel size 0.98 9 0.98 9 1.2 mm 3 ). Pre-processing of the T 1 -weighted MRI scans was performed with voxel-based morphometry (VBM8, http://dbm.neuro.uni-jena.de/vbmrunning) (Ashburner and Friston 2000) running on Statistical Parametric Mapping (SPM8, Wellcome Trust Centre for Neuroimaging, London, UK, http://www.fil.ion.uc l.ac.uk/spm) implemented in Matlab R2012b (Mathworks, Natick, MA, USA) as described in previous studies (Gillebert et al 2015;Schaeverbeke et al 2017). The resulting modulated gray matter volumes have been adjusted for overall brain size (total intracranial volume) by using the 'nonlinear only' component in the spatial normalization process for modulation of gray matter voxel intensities (Barnes et al 2010).…”

Section: Imaging Proceduresmentioning

confidence: 99%

Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults

Schaeverbeke

Gille

Adamczuk

et al. 2019

Journal of Neurochemistry

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The main pathophysiological alterations of Alzheimer's disease (AD) include loss of neuronal and synaptic integrity, amyloidogenic processing, and neuroinflammation. Similar alterations can, however, also be observed in cognitively intact older subjects and may prelude the clinical manifestation of AD. The objectives of this prospective cross‐sectional study in a cohort of 38 cognitively intact older adults were twofold: (i) to investigate the latent relationship among cerebrospinal fluid (CSF) biomarkers reflecting the main pathophysiological processes of AD, and (ii) to assess the correlation between these biomarkers and gray matter volume as well as amyloid load. All subjects underwent extensive neuropsychological examinations, CSF sampling, [18F]‐flutemetamol amyloid positron emission tomography, and T1‐weighted magnetic resonance imaging. A factor analysis revealed one factor that explained most of the variance in the CSF biomarker dataset clustering t‐tau, α‐synuclein, p‐tau181, neurogranin, BACE1, visinin‐like protein 1, chitinase‐3‐like protein 1 (YKL‐40), Aβ1–40 and Aβ1–38. Higher scores on this factor correlated with lower gray matter volume and with higher amyloid load in the precuneus. At the level of individual CSF biomarkers, levels of visinin‐like protein 1, neurogranin, BACE1, Aβ1–40, Aβ1–38, and YKL‐40 all correlated inversely with gray matter volume of the precuneus. These findings demonstrate that in cognitively intact older subjects, CSF levels of synaptic and neuronal integrity biomarkers, amyloidogenic processing and measures of innate immunity (YKL‐40) display a latent structure of common variance, which is associated with loss of structural integrity of brain regions implicated in the earliest stages of AD. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript, and for *Preregistration* because the study was pre‐registered at https://osf.io/7qm9t/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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“…All T 1 -weighted images underwent preprocessing with voxel-based morphometry (VBM8) [ 59 ] as previously described [ 60 , 61 ]. This included corrections for gradient nonlinearity and intensity inhomogeneity in the MRI.…”

Section: Methodsmentioning

confidence: 99%

Single-word comprehension deficits in the nonfluent variant of primary progressive aphasia

et al. 2018

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BackgroundA subset of patients with the nonfluent variant of primary progressive aphasia (PPA) exhibit concomitant single-word comprehension problems, constituting a ‘mixed variant’ phenotype. This phenotype is rare and currently not fully characterized. The aim of this study was twofold: to assess the prevalence and nature of single-word comprehension problems in the nonfluent variant and to study multimodal imaging characteristics of atrophy, tau, and amyloid burden associated with this mixed phenotype.MethodsA consecutive memory-clinic recruited series of 20 PPA patients (12 nonfluent, five semantic, and three logopenic variants) were studied on neurolinguistic and neuropsychological domains relative to 64 cognitively intact healthy older control subjects. The neuroimaging battery included high-resolution volumetric magnetic resonance imaging processed with voxel-based morphometry, and positron emission tomography with the tau-tracer [18F]-THK5351 and amyloid-tracer [11C]-Pittsburgh Compound B.ResultsSeven out of 12 subjects who had been classified a priori with nonfluent variant PPA showed deficits on conventional single-word comprehension tasks along with speech apraxia and agrammatism, corresponding to a mixed variant phenotype. These mixed variant cases included three females and four males, with a mean age at onset of 65 years (range 44–77 years). Object knowledge and object recognition were additionally affected, although less severely compared with the semantic variant. The mixed variant was characterized by a distributed atrophy pattern in frontal and temporoparietal regions. A more focal pattern of elevated [18F]-THK5351 binding was present in the supplementary motor area, the left premotor cortex, midbrain, and basal ganglia. This pattern was closely similar to that seen in pure nonfluent variant PPA. At the individual patient level, elevated [18F]-THK5351 binding in the supplementary motor area and premotor cortex was present in six out of seven mixed variant cases and in five and four of these cases, respectively, in the thalamus and midbrain. Amyloid biomarker positivity was present in two out of seven mixed variant cases, compared with none of the five pure nonfluent cases.ConclusionsA substantial proportion of PPA patients with speech apraxia and agrammatism also have single-word comprehension deficits. At the neurobiological level, the mixed variant shows a high degree of similarity with the pure nonfluent variant of PPA.Trial registrationEudraCT, 2014–002976-10. Registered on 13-01-2015.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0393-8) contains supplementary material, which is available to authorized users.

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Cholinergic depletion and basal forebrain volume in primary progressive aphasia

Cited by 21 publications

References 57 publications

Spontaneous oscillatory markers of cognitive status in two forms of dementia

Spontaneous oscillatory markers of cognitive status in two forms of dementia

Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults

Single-word comprehension deficits in the nonfluent variant of primary progressive aphasia

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