SUMMARY The parietal lobe has long been viewed as a collection of architectonic and functional subdivisions. Though much parietal research has focused on mechanisms of visuospatial attention and control-related processes, more recent functional neuroimaging studies of memory retrieval have reported greater activity in left lateral parietal cortex (LLPC) when items are correctly identified as previously studied (“old”) vs. unstudied (“new”). These studies have suggested functional divisions within LLPC that may provide distinct contributions towards recognition memory judgments. Here, we define regions within LLPC by developing a novel parcellation scheme that integrates data from resting state functional connectivity MRI (rsfcMRI) and functional MRI (fMRI). This combined approach results in a six-fold parcellation of LLPC based on the presence (or absence) of memory retrieval-related activity, dissociations in the profile of task-evoked timecourses, and membership in large-scale brain networks. This parcellation should serve as a roadmap for future investigations aimed at understanding LLPC function.

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.

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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.