Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease

Abstract

Amnestic Alzheimer's disease (AD) is characterized by early atrophy of the hippocampus and medial temporal lobes before spreading to the neocortex. In contrast, nonamnestic Alzheimer's patients have relative sparing of the hippocampus, but the pattern in which the disease spreads is unclear. We examined spreading disease in nonamnestic AD using a novel magnetic resonance imaging-based analysis adapted from pathologic staging studies, applied here to cross-sectional imaging data. We selected 240 T1-weighted scans from 129 patients with pathology confirmed by autopsy or cerebrospinal fluid, and atrophy maps were computed relative to 238 scans from 115 elderly controls. For each phenotype, the frequency of atrophy in 116 brain regions was used to infer the anatomical origin of disease and its progression across 4 phases of atrophy. Results from the amnestic cohort were used to determine appropriate parameter settings for the phase assignment algorithm, based on correspondence to Braak pathology staging. Phase 1 regions, which represent the origin of disease, included the hippocampus for the amnestic group (comprising 33 scans); left lateral temporal lobe for logopenic-variant primary progressive aphasia (88 scans); occipitoparietal cortex for posterior cortical atrophy (51 scans); temporoparietal cortex for corticobasal syndrome (31 scans); and frontotemporal cortex for behavioral/dysexecutive variant AD (37 scans). In nonamnestic patients, atrophy spread to other neocortical areas in later phases, but the hippocampus exhibited only late-phase atrophy in posterior cortical atrophy and corticobasal syndrome. Region-specific phase values were also associated with regional measures of tau, beta amyloid, neuronal loss, and gliosis for the subset of patients (n = 17) with neuropathology findings; this comparison represented a first validation of the phase assignment algorithm. We subsequently assigned a phase to each patient scan based on the similarity of regional atrophy patterns with atrophy predicted for the corresponding phenotype at each phase. Scan-specific phases were correlated with disease duration as well as global and domain-specific cognition, supporting these phase values as global estimates of patients' disease progression. Logistic regression models based on spatial overlap with model-predicted atrophy patterns reliably discriminated nonamnestic phenotypes from each other and from amnestic AD. The frequency-based phase assignment algorithm used in the present study thus represents a promising approach for studying the neocortical origin and spread of disease in nonamnestic AD.

Neuropathologic basis of in vivo cortical atrophy in the aphasic variant of Alzheimer's disease

“…There is emerging evidence that neocortical areas may be the earliest sites of neuropathology and neurodegeneration in non-amnestic variants of AD such as PPA-AD (62). The preponderance of AD neuropathology to left language regions in our PPA-AD cohort supports the possibility of a neocortical pathogenesis, and is consistent with longitudinal studies showing that the language network exhibits the earliest and most severe atrophy in PPA (63,64).…”

Clinical, Anatomical, and Pathological Features in the Three Variants of Primary Progressive Aphasia: A Review

“…Naming difficulties are correlated with the left posterior temporal cortex ( 108 ). Recently, a model of the progression of atrophy in lvPPA has been suggested, showing that atrophy progresses from the disease epicenter (left posterior superior and middle temporal gyri) to ipsilateral parietal and frontal lobes and contralateral temporal lobe ( 145 ).…”

Genome-wide RNA sequencing analysis reveals that IGF-2 attenuates memory decline, oxidative stress and amyloid plaques in an Alzheimer’s disease mouse model (AD) by activating the PI3K/AKT/CREB signaling pathway

“…The hippocampus that was known as the hippocampal region is part of the limbic system of the brain. In AD brain, it shows obvious atrophy of cerebral cortex, especially hippocampus and medial temporal lobe (Phillips et al, 2018). Hence, in our experiment, hippocampus was targeted.…”