Graeme Schwindt

Functional imaging studies of episodic memory in Alzheimer's disease: a quantitative meta-analysis

Alzheimers Disease (AD) is a progressive neurodegenerative disorder, rapidly increasing in prevalence as the population ages. As the potential for disease-modifying therapy grows, a large body of literature has aimed at finding reliable, noninvasive biomarkers of AD, to allow for early intervention and sensitive tracking of therapeutic response. Task-related functional brain imaging techniques have been increasingly used to examine episodic memory function in AD. In the present study we completed a quantitative meta-analysis of this growing literature, to establish consensus and elucidate consistent patterns across this important research area. Results from encoding and retrieval paradigms were analyzed using the activation likelihood estimation (ALE) technique for patient and control groups. Second-level ALE analyses directly compared activation between these two groups. Results indicated a number of consistent findings across the included studies. Controls showed consistently greater activity than patients in a number of regions including the MTL and frontal pole across encoding and retrieval paradigms. Patients demonstrated increased activation likelihood in areas of the ventral lateral prefrontal cortex and other regions. Our findings quantitatively confirm the widely-cited deficits in MTL activity among AD patients, and also bring to light a pattern of differential prefrontal involvement, which may be implicated in compensatory changes occurring in AD. On the whole, this study quantitatively demonstrates that functional imaging studies show consistent, if complex, patterns of brain activation differences between patients and controls. These findings support the continued evaluation of functional neuroimaging for clinical use.

Chronic vagus nerve stimulation for treatment-resistant depression decreases resting ventromedial prefrontal glucose metabolism

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treatment-resistant depression (TRD). Its mechanism of action is not fully understood. Longitudinal measurement of changes in brain metabolism associated with VNS can provide insights into this new treatment modality. Eight severely depressed outpatients who were highly treatment-resistant underwent electrical stimulation of the left vagus nerve for approximately one year. The main outcome measures were resting regional brain glucose uptake measured with positron emission tomography (PET) and the 24-item Hamilton Depression Scale. The most significant and extensive change over one year of chronic VNS localized to the ventromedial prefrontal cortex extending from the subgenual cingulate to the frontal pole. This region continued to decline in metabolism even toward the end of the study. Clinically, this cohort showed a trend for improvement. No correlations surfaced between change in glucose uptake and depression scores. However, the sample size was small; none remitted; and the range of depression scores was limited. Chronic VNS as adjunctive therapy in patients with severe TRD produces protracted and robust declines in resting brain activity within the ventromedial prefrontal cortex, a network with dense connectivity to the amygdala and structures monitoring the internal milieu.

Whole-brain white matter disruption in semantic and nonfluent variants of primary progressive aphasia

Semantic (svPPA) and nonfluent (nfPPA) variants of primary progressive aphasia are associated with distinct patterns of cortical atrophy and underlying pathology. Little is known, however, about their contrasting spread of white matter disruption and how this relates to grey matter (GM) loss. We undertook a structural MRI study to investigate this relationship. We used diffusion tensor imaging, tract‐based spatial statistics, and voxel‐based morphometry to examine fractional anisotropy (FA) and directional diffusivities in nine patients with svPPA and nine patients with nfPPA, and compared them to 16 matched controls after accounting for global GM atrophy. Significant differences in topography of white matter changes were found, with more ventral involvement in svPPA patients and more widespread frontal involvement in nfPPA individuals. However, each group had both ventral and dorsal tract changes, and both showed spread of diffusion abnormalities beyond sites of local atrophy. There was a clear dissociation in sensitivity of diffusion tensor imaging measures between groups. SvPPA patients showed widespread changes in FA and radial diffusivity, whereas changes in axial diffusivity were more restricted and proximal to sites of GM atrophy. NfPPA patients showed isolated changes in FA, but widespread axial and radial diffusivity changes. These findings reveal the extent of white matter disruption in these variants of PPA after accounting for GM loss. Further, they suggest that differences in the relative sensitivity of diffusion metrics may reflect differences in the nature of underlying white matter pathology in these two subtypes. Hum Brain Mapp, 2013.

Hemodynamic effects of cholinesterase inhibition in mild Alzheimer's disease

To evaluate the spatiotemporal progression of perfusion changes in early stages of Alzheimers disease (AD), we imaged the perfusion response to pharmacological treatment in a group of mild AD patients and contrasted it to the perfusion of age‐, sex‐, and education‐matched healthy volunteers over the same time interval.

Enhancement of automated blood flow estimates (ENABLE) from arterial spin-labeled MRI

To validate a multiparametric automated algorithm—ENhancement of Automated Blood fLow Estimates (ENABLE)—that identifies useful and poor arterial spin‐labeled (ASL) difference images in multiple postlabeling delay (PLD) acquisitions and thereby improve clinical ASL.

Characterizing abnormal white matter structure in primary progressive aphasia

prion protein gene (PRNP). The phenotypes associated with these genetic forms are Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker (GSS) and fatal familial insomnia (FFI). P102L mutation is usually associated with GSS phenotype. Objective: To describe the phenotypic heterogeneity in a Brazilian family with P102L mutation. Methods: Patient 1 was seen in the Cognitive and Behavioral Neurology Unit of the Hospital das Clinicas of the University of Sao Paulo School of Medicine in 2002 with an atypical and probably genetic dementia. We tracked all clinical, laboratory, neuroimaging and pathological data from the other affected members of the family. Results: Patient 1: woman, age at onset: 27 yo; memory and attention deficits, gate disturbance, progression to severe dementia in 2 years. MRI: brain atrophy. CSF 14.3.3: negative. EEG: excess of lower frequencies. PRNP: P102L, M129V. Patient 2 (uncle of #1): age at onset: 53 yo, rapidly progressive dementia; death in 8 months. Frontal and extrapyramidal syndromes and myoclonias. MRI: frontal atrophy. EEG: non specific changes. Clinical diagnosis of possible CJD; brain biopsy: spongiform encephalopathy. PRNP: not available. Patient 3 (sister of #2): age of onset: 54 yo; dizziness, cognitive decline, gate disturbance and blindness; death after 4 years. MRI: brain atrophy; hyperintensities in frontal and parietal cortex on DWI. PRNP: P102L, M129M. Patient 4 (daughter of #3): age of onset: 36 yo; progressive ataxia, spasticity, back pain, and feet numbness. Mild executive function deficit after 2 years. Severe dementia 7 years after onset. MRI: cerebellar atrophy. PRNP: P102L, M129V. Conclusions: Prion disease associated with P102L mutation presented with high phenotypic heterogeneity in this Brazilian family.