Longitudinal progression of grey matter atrophy in non-amnestic Alzheimer’s disease

Abstract

Recent models of Alzheimer's disease progression propose that disease may be transmitted between brain areas either via local diffusion or long-distance transport via white matter fibre pathways. However, it is unclear whether such models are applicable in non-amnestic Alzheimer's disease, which is associated with domain-specific cognitive deficits and relatively spared episodic memory. To date, the anatomical progression of disease in non-amnestic patients remains understudied. We used longitudinal imaging to differentiate earlier atrophy and later disease spread in three non-amnestic variants, including logopenic-variant primary progressive aphasia (n = 25), posterior cortical atrophy (n = 20), and frontal-variant Alzheimer's disease (n = 12), as well as 17 amnestic Alzheimer's disease patients. Patients were compared to 37 matched controls. All patients had autopsy (n = 7) or CSF (n = 67) evidence of Alzheimer's disease pathology. We first assessed atrophy in suspected sites of disease origin, adjusting for age, sex, and severity of cognitive impairment; we then performed exploratory whole-brain analysis to investigate longitudinal disease spread both within and outside these regions. Additionally, we asked whether each phenotype exhibited more rapid change in its associated disease foci than other phenotypes. Finally, we investigated whether atrophy was related to structural brain connectivity. Each non-amnestic phenotype displayed unique patterns of initial atrophy and subsequent neocortical change that correlated with cognitive decline. Longitudinal atrophy included areas both proximal to and distant from sites of initial atrophy, suggesting heterogeneous mechanisms of disease spread. Moreover, regional rates of neocortical change differed by phenotype. Logopenicvariant patients exhibited greater initial atrophy and more rapid longitudinal change in left lateral temporal areas than other groups. Frontal-variant patients had pronounced atrophy in left insula and middle frontal gyrus, combined with more rapid atrophy of left insula than other non-amnestic patients. In the medial temporal lobes, non-amnestic patients had less atrophy at their initial scan than amnestic patients, but longitudinal rate of change did not differ between patient groups. Medial temporal sparing in non-amnestic Alzheimer's disease may thus be due in part to later onset of medial temporal degeneration than in amnestic patients rather than different rates of atrophy over time. Finally, the magnitude of longitudinal atrophy was predicted by structural connectivity, measured in terms of node degree; this result provides indirect support for the role of long-distance fibre pathways in the spread of neurodegenerative disease.

Data-driven detection of latent atrophy factors related to phenotypical variants of posterior cortical atrophy

“…However, individuals with atrophy that predominantly affected the limbic regions also showed worse global cognition, indicating that disproportionate limbic atrophy indicates worse cognition overall. As this factor was also the only one associated with global atrophy, it seems that high limbic factor expression might be a feature of late-stage posterior cortical atrophy, which is in accordance with findings reported in previous studies Firth et al, 2019;Phillips et al, 2019).…”

Establishing two principal dimensions of cognitive variation in logopenic progressive aphasia

“…Disrupted functional connectivity of the middle frontal gyrus with prefrontal, lateral and medial parietal regions has been linked to working memory impairments in LPA ( Whitwell et al , 2015 b ), with cortical thickness of this region further associated with reduced verbal fluency (as measured by mean length of utterance during story telling) in patients with primary progressive aphasia ( Rogalski et al , 2011 a ). Although not typical of the early LPA atrophy pattern, middle frontal gyrus atrophy has been described previously in the syndrome ( Rohrer et al , 2010 ; Phillips et al , 2019 ) and tends to become more salient as atrophy progresses along the left sylvian fissure into fronto-insular regions ( Rohrer et al , 2013 ). It is possible, therefore, that this middle frontal region shows greater inter-participant variance and thus greater sensitivity to detect associations in the VBM correlation analyses.…”

Impairments of auditory scene analysis in posterior cortical atrophy

“…To our knowledge, audiometric deficits have not previously been identified as a feature of PCA but this corroborates emerging evidence that pure tone detection can be impaired even in canonical dementia syndromes (most notably, non-fluent/agrammatic variant primary progressive aphasia) that typically spare the peripheral auditory pathways ( Hardy et al , 2016 , 2019 ). The processing of pitch change (particularly in the context of a task requiring working memory) is likely to depend on temporo-parietal junctional cortices that are targeted in PCA ( Crutch et al , 2012 ; Plack et al , 2014 ; Golden et al , 2016 ; Firth et al , 2019 ; Phillips et al , 2019 ): impaired pitch processing here may also indicate a more general impairment of magnitude estimation, as patients with PCA also have difficulties with other aspects of numerical and spatial magnitude encoding ( Delazer et al , 2006 ; Spotorno et al , 2014 ; González et al , 2019 ) and these processes are likely to depend on neural mechanisms that are at least partly shared across modalities ( Kadosh et al , 2008 ; Bonn and Cantlon, 2012 ).…”