Scott M. McGinnis

Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response

BACKGROUND Treatment of major depression with antidepressants is generally associated with a delay in onset of clinical response. Functional brain correlates of this phenomenon have not been previously characterized. METHODS Time course of changes in brain glucose metabolism were measured using positron emission tomography in hospitalized unipolar depressed patients treated with fluoxetine. Time-specific and response-specific effects were examined at 1 and 6 weeks of treatment. RESULTS Changes were seen over time, and characterized by three distinct patterns: 1) common changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6 weeks, and 3) unique changes seen only after chronic treatment. Fluoxetine responders and nonresponders, similar at 1 week, were differentiated by their 6-week pattern. Clinical improvement was uniquely associated with limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes. CONCLUSIONS Chronic treatment and clinical response to fluoxetine was associated with a reciprocal pattern of subcortical and limbic decreases and cortical increases. Reversal in the week-1 pattern at 6 weeks suggests a process of adaptation in specific brain regions over time in response to sustained serotonin reuptake inhibition. The inverse patterns in responders and nonresponders also suggests that failure to induce these adaptive changes may underlie treatment nonresponse.

Differential limbic–cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders

BACKGROUND Affective disorders are associated with comorbidity of depression and anxiety symptoms. Positron emission tomography resting-state studies in affective disorders have generally failed to isolate specific symptom effects. Emotion provocation studies in healthy volunteers have produced variable results, due to differences in experimental paradigm and instructions. METHODS To better delineate the neural correlates of sad mood and anxiety, this study used autobiographical memory scripts in eight healthy women to generate sadness, anxiety, or a neutral relaxed state in a within-subject design. RESULTS Sadness and anxiety, when contrasted to a neutral emotional state, engaged a set of distinct paralimbic-cortical regions, with a limited number of common effects. Sadness was accompanied by specific activations of the subgenual cingulate area (BA) 25 and dorsal insula, specific deactivation of the right prefrontal cortex BA 9, and more prominent deactivation of the posterior parietal cortex BAs 40/7. Anxiety was associated with specific activations of the ventral insula, the orbitofrontal and anterior temporal cortices, specific deactivation of parahippocampal gyri, and more prominent deactivation of the inferior temporal cortex BAs 20/37. CONCLUSIONS These findings are interpreted within a model in which sadness and anxiety are represented by segregated corticolimbic pathways, where a major role is played by selective dorsal cortical deactivations during sadness, and ventral cortical deactivations in anxiety.

Monoclonal IgM with unique specificity to gangliosides GM1 and GD1b and to lacto‐N ‐tetraose associated with human motor neuron disease

IgM lambda monoclonal antibodies in two patients with motor neuron disease showed the same unique antigenic specificity. They bound to gangliosides GM1 and GD1b and to lacto-N-tetraose-BSA. By immunofluorescence microscopy they bound to central and peripheral nerve tissue and to motor end-plates at the neuromuscular junction. Sera from control subjects did not contain antibodies of similar specificity. Monoclonal IgMs with the same unique specificity could be responsible for motor neuron disease in some patients with monoclonal gammopathies.

Mechanisms underlying age-and performance-related differences in working memory

This study took advantage of the subsecond temporal resolution of ERPs to investigate mechanisms underlying age- and performance-related differences in working memory. Young and old subjects participated in a verbal n-back task with three levels of difficulty. Each group was divided into high and low performers based on accuracy under the 2-back condition. Both old subjects and low-performing young subjects exhibited impairments in preliminary mismatch/match detection operations (indexed by the anterior N2 component). This may have undermined the quality of information available for the subsequent decision-making process (indexed by the P3 component), necessitating the appropriation of more resources. Additional anterior and right hemisphere activity was recruited by old subjects. Neural efficiency and the capacity to allocate more resources to decision-making differed between high and low performers in both age groups. Under low demand conditions, high performers executed the task utilizing fewer resources than low performers (indexed by the P3 amplitude). As task requirements increased, high-performing young and old subjects were able to appropriate additional resources to decision-making, whereas their low-performing counterparts allocated fewer resources. Higher task demands increased utilization of processing capacity for operations other than decision-making (e.g., sustained attention) that depend upon a shared pool of limited resources. As demands increased, all groups allocated additional resources to the process of sustaining attention (indexed by the posterior slow wave). Demands appeared to have exceeded capacity in low performers, leading to a reduction of resources available to the decision-making process, which likely contributed to a decline in performance.

Association of In Vivo [18F]AV-1451 Tau PET Imaging Results With Cortical Atrophy and Symptoms in Typical and Atypical Alzheimer Disease

Importance Previous postmortem studies have long demonstrated that neurofibrillary tangles made of hyperphosphorylated tau proteins are closely associated with Alzheimer disease clinical phenotype and neurodegeneration pattern. Validating these associations in vivo will lead to new diagnostic tools for Alzheimer disease and better understanding of its neurobiology. Objective To examine whether topographical distribution and severity of hyperphosphorylated tau pathologic findings measured by fluorine 18–labeled AV-1451 ([18F]AV-1451) positron emission tomographic (PET) imaging are linked with clinical phenotype and cortical atrophy in patients with Alzheimer disease. Design, Setting, and Participants This observational case series, conducted from July 1, 2012, to July 30, 2015, in an outpatient referral center for patients with neurodegenerative diseases, included 6 patients: 3 with typical amnesic Alzheimer disease and 3 with atypical variants (posterior cortical atrophy, logopenic variant primary progressive aphasia, and corticobasal syndrome). Patients underwent [18F]AV-1451 PET imaging to measure tau burden, carbon 11–labeled Pittsburgh Compound B ([11C]PiB) PET imaging to measure amyloid burden, and structural magnetic resonance imaging to measure cortical thickness. Seventy-seven age-matched controls with normal cognitive function also underwent structural magnetic resonance imaging but not tau or amyloid PET imaging. Main Outcomes and Measures Tau burden, amyloid burden, and cortical thickness. Results In all 6 patients (3 women and 3 men; mean age 61.8 years), the underlying clinical phenotype was associated with the regional distribution of the [18F]AV-1451 signal. Furthermore, within 68 cortical regions of interest measured from each patient, the magnitude of cortical atrophy was strongly correlated with the magnitude of [18F]AV-1451 binding (3 patients with amnesic Alzheimer disease, r = –0.82; P < .001; r = –0.70; P < .001; r = –0.58; P < .001; and 3 patients with nonamnesic Alzheimer disease, r = –0.51; P < .001; r = –0.63; P < .001; r = –0.70; P < .001), but not of [11C]PiB binding. Conclusions and Relevance These findings provide further in vivo evidence that distribution of the [18F]AV-1451 signal as seen on results of PET imaging is a valid marker of clinical symptoms and neurodegeneration. By localizing and quantifying hyperphosphorylated tau in vivo, results of tau PET imaging will likely serve as a key biomarker that links a specific type of molecular Alzheimer disease neuropathologic condition with clinically significant neurodegeneration, which will likely catalyze additional efforts to develop disease-modifying therapeutics.

ERP correlates of item recognition memory : Effects of age and performance

Decline in episodic memory is a common feature of healthy aging. Event-related potential (ERP) studies in young adults have consistently reported several modulations thought to index memory retrieval processes, but relatively limited work has explored the impact of aging on them. Further, work with functional imaging has demonstrated differential neural recruitment in elderly subjects depending on their level of cognitive performance which may reflect compensatory or, alternatively, inefficient processing. In the present study we examined the effect of aging and level of performance on both early (FN400, LPC) and later [late frontal effect (LFE)] ERP indices of recognition memory. We found that the FN400 and LPC were absent or attenuated in the older group relative to young adults, but that the LFE was actually increased, analogous to findings in the functional imaging literature. Additionally, the latter effect was most prominent in the poorer performing older participants. These findings suggest that weak memory retrieval supported by earlier ERP modulations, may lead to an enhanced LFE in the service of additional retrieval attempts.

Interrater reliability of the new criteria for behavioral variant frontotemporal dementia

Objective: To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD). Methods: Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings. Results: The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD (“almost perfect agreement”). Interrater reliability for 4 of the 6 core features had “substantial” agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61–0.80), whereas 2 had “moderate” agreement (apathy/inertia, neuropsychological; κ = 0.41–0.6). Clinician years of experience did not significantly influence rater accuracy. Conclusions: The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.

Treatment of Dementia With Lewy Bodies

Opinion statementDementia with Lewy bodies (DLB) is a multisystem disorder with diverse disease expression. A treatment regime restricted to the cognitive aspects of the disease does no favor to patients. Instead, patients should be educated to recognize the symptoms of this multisystem involvement. There are no treatments that slow the progression of disease, but symptomatic treatments can be effective. When thinking about treatment, we find it useful to divide the symptoms and signs into five categories: (a) cognitive features, (b) neuropsychiatric features, (c) motor dysfunction, (d) autonomic dysfunction, and (e) sleep dysfunction. Clinicians, funding bodies and industry are increasingly recognizing the importance of this common and debilitating disease.

Neuroimaging in Neurodegenerative Dementias

Neurodegenerative dementias are characterized by insidious onset and gradual progression of cognitive dysfunction, initially relatively focal with respect to cognitive domains and brain regions involved. Neuroimaging techniques have contributed enormously to both our understanding of large-scale network specificity in neurodegenerative syndromes and our ability to make clinical diagnoses of syndromes such as Alzheimers disease (AD), dementia with Lewy bodies (DLB), posterior cortical atrophy (PCA), logopenic primary progressive aphasia (PPA), agrammatic PPA, semantic dementia (SD), behavioral variant frontotemporal dementia (bvFTD), corticobasal syndrome (CBS), and progressive supranuclear palsy syndrome (PSPS). More importantly, rapid advances in imaging and computational techniques promise to improve our ability to make pathologic diagnoses of AD, DLB, and frontotemporal lobar degeneration (FTLD) pathologies in vivo at an early stage of illness. Neuroimaging is thus integral to the development and application of disease modifying therapies for neurodegenerative illnesses.

Flortaucipir tau PET imaging in semantic variant primary progressive aphasia

Objective The semantic variant of primary progressive aphasia (svPPA) is typically associated with frontotemporal lobar degeneration (FTLD) with longTAR DNA-binding protein (TDP)-43-positive neuropil threads and dystrophic neurites (type C), and is only rarely due to a primary tauopathy or Alzheimer’s disease. We undertook this study to investigate the localisation and magnitude of the presumed tau Positron Emission Tomography (PET) tracer [18F]Flortaucipir (FTP; also known as T807 or AV1451) in patients with svPPA, hypothesising that most patients would not show tracer uptake different from controls. Methods FTP and [11C]Pittsburgh compound B PET imaging as well as MRI were performed in seven patients with svPPA and in 20 controls. FTP signal was analysed by visual inspection and by quantitative comparison to controls, with and without partial volume correction. Results All seven patients showed elevated FTP uptake in the anterior temporal lobe with a leftward asymmetry that was not observed in healthy controls. This elevated FTP signal, largely co-localised with atrophy, was evident on both visual inspection and quantitative cortical surface-based analysis. Five patients were amyloid negative, one was amyloid positive and one has an unknown amyloid status. Conclusions In this series of patients with clinical profiles, structural MRI and amyloid PET imaging typical for svPPA, FTP signal was unexpectedly elevated with a spatial pattern localised to areas of atrophy. This raises questions about the possible off-target binding of this tracer to non-tau molecules associated with neurodegeneration. Further investigation with autopsy analysis will help illuminate the binding target(s) of FTP in cases of suspected FTLD-TDP neuropathology.