Brain atrophy in primary progressive aphasia involves the cholinergic basal forebrain and Ayala's nucleus

Abstract

Primary progressive aphasia (PPA) is characterized by left hemispheric frontotemporal cortical atrophy. Evidence from anatomical studies suggests that the nucleus subputaminalis (NSP), a subnucleus of the cholinergic basal forebrain, may be involved in the pathological process of PPA. Therefore, we studied the pattern of cortical and basal forebrain atrophy in 10 patients with a clinical diagnosis of PPA and 18 healthy age-matched controls using high-resolution magnetic resonance imaging (MRI). We determined the cholinergic basal forebrain nuclei according to Mesulam’s nomenclature and the NSP in MRI reference space based on histological sections and the MRI scan of a post-mortem brain in cranio. Using voxel-based analysis, we found left hemispheric cortical atrophy in PPA patients compared with controls, including prefrontal, lateral temporal and medial temporal lobe areas. We detected cholinergic basal forebrain atrophy in left predominant localizations of Ch4p, Ch4am, Ch4al, Ch3 and NSP. For the first time, we have described the pattern of basal forebrain atrophy in PPA and confirmed the involvement of NSP that had been predicted based on theoretical considerations. Our findings may enhance understanding of the role of cholinergic degeneration for the regional specificity of the cortical destruction leading to the syndrome of PPA.

Cholinergic depletion and basal forebrain volume in primary progressive aphasia

“…Secondary outcome analyses aimed to evaluate effects at the overall group and at the subgroup level, to examine the relationship between the AChE activity levels and structural changes, and to test the replicability of the BF atrophy in PPA reported previously (Teipel et al, 2016, Teipel et al, 2014).

Differences in AChE activity were assessed at the group level (PPA versus controls) using Kruskal-Wallis and with post hoc Mann-Witney U tests for differences between subgroups (uncorrected, two-tailed p values).

In order to evaluate the relationship between AChE activity levels and structural atrophy, AChE activity levels were calculated in each individual patient compared to controls in the regions that were characteristically atrophic for the subtype to which the case belonged (LV, NFV or SV) (VOI shown in Fig.

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“…The latter region was determined by subtracting the region of characteristic atrophy from the subjects normalized GM map (thresholded at > 0.25). For each individual patient, differences in AChE levels compared to controls were assessed using a modified t -test.In order to evaluate whether BF volume decreases that have previously been reported (Teipel et al, 2016, Teipel et al, 2014) could be replicated, a BF volume analysis was performed in the extended sample of 28 PPA and 111 control subjects. By means of an ANCOVA model, BF volumes were assessed at the group level in controls, LV, NFV and SV PPA with scanner type as nuisance variable, and post hoc Bonferroni correction for the number of comparisons at α = 0.05.…”

“…In order to evaluate whether BF volume decreases that have previously been reported (Teipel et al, 2016, Teipel et al, 2014) could be replicated, a BF volume analysis was performed in the extended sample of 28 PPA and 111 control subjects. By means of an ANCOVA model, BF volumes were assessed at the group level in controls, LV, NFV and SV PPA with scanner type as nuisance variable, and post hoc Bonferroni correction for the number of comparisons at α = 0.05.…”

“…According to MRI volumetric studies, the basal forebrain (BF) is atrophic in PPA SV and NFV (Teipel et al, 2016, Teipel et al, 2014), and mainly so the posterior part of the nucleus basalis (Ch4) and nucleus subputaminalis (NSP). The BF is the primary source of cholinergic transmission to the neo- and allocortex (Zaborszky et al, 2015), hence the hypothesis that a cholinergic deficit may also exist in non-AD cases of PPA.…”

Ein Geschwisterpaar mit einer seltenen Tau-Gen-Mutation (MAPT R5H)

“…For future trials, the detection of biomarkers for frontotemporal lobar degeneration in presymptomatic cohorts like the genetic frontotemporal dementia initiative (GENFI) is of help for stratifying subjects at risk. Jahre, 50 % Frauen) [10] mit einem Z-Score der linken Hemisphäre von -0,9 und der rechten Hemisphäre von + 0,4 im altersentsprechenden Normbereich liegende Volumina. Die regionale Verteilung der Atrophie (Abweichungen voxelbasierte Abnahme um mindestens z < -1,96) zeigte eine deutliche Seitenasymmetrie zuungunsten der linken Seite und Beteiligung präfrontaler und lateral temporaler Hirnregionen ( • " Abb.…”