The ability to encode and retrieve our daily personal experiences, called episodic memory, is supported by the circuitry of the medial temporal lobe (MTL), including the hippocampus, which interacts ...extensively with a number of specific distributed cortical and subcortical structures. In both animals and humans, evidence from anatomical, neuropsychological, and physiological studies indicates that cortical components of this system have key functions in several aspects of perception and cognition, whereas the MTL structures mediate the organization and persistence of the network of memories whose details are stored in those cortical areas. Structures within the MTL, and particularly the hippocampus, have distinct functions in combining information from multiple cortical streams, supporting our ability to encode and retrieve details of events that compose episodic memories. Conversely, selective damage in the hippocampus, MTL, and other structures of the large-scale memory system, or deterioration of these areas in several diseases and disorders, compromises episodic memory. A growing body of evidence is converging on a functional organization of the cortical, subcortical, and MTL structures that support the fundamental features of episodic memory in humans and animals.
New preclinical Alzheimer disease (AD) diagnostic criteria have been developed using biomarkers in cognitively normal (CN) adults. We implemented these criteria using an MRI biomarker previously ...associated with AD dementia, testing the hypothesis that individuals at high risk for preclinical AD would be at elevated risk for cognitive decline.
The Alzheimer's Disease Neuroimaging Initiative database was interrogated for CN individuals. MRI data were processed using a published set of a priori regions of interest to derive a single measure known as the AD signature (ADsig). Each individual was classified as ADsig-low (≥ 1 SD below the mean: high risk for preclinical AD), ADsig-average (within 1 SD of mean), or ADsig-high (≥ 1 SD above mean). A 3-year cognitive decline outcome was defined a priori using change in Clinical Dementia Rating sum of boxes and selected neuropsychological measures.
Individuals at high risk for preclinical AD were more likely to experience cognitive decline, which developed in 21% compared with 7% of ADsig-average and 0% of ADsig-high groups (p = 0.03). Logistic regression demonstrated that every 1 SD of cortical thinning was associated with a nearly tripled risk of cognitive decline (p = 0.02). Of those for whom baseline CSF data were available, 60% of the high risk for preclinical AD group had CSF characteristics consistent with AD while 36% of the ADsig-average and 19% of the ADsig-high groups had such CSF characteristics (p = 0.1).
This approach to the detection of individuals at high risk for preclinical AD-identified in single CN individuals using this quantitative ADsig MRI biomarker-may provide investigators with a population enriched for AD pathobiology and with a relatively high likelihood of imminent cognitive decline consistent with prodromal AD.
Hereditary frontotemporal dementia associated with mutations in the microtubule‐associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on ...the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms.
Using resting-state functional magnetic resonance imaging data from two independent samples of healthy adults, we parsed the amygdala's intrinsic connectivity into three partially distinct ...large-scale networks that strongly resemble the known anatomical organization of amygdala connectivity in rodents and monkeys. Moreover, in a third independent sample, we discovered that people who fostered and maintained larger and more complex social networks not only had larger amygdala volumes, but also amygdalae with stronger intrinsic connectivity within two of these networks: one putatively subserving perceptual abilities and one subserving affiliative behaviors. Our findings were anatomically specific to amygdalar circuitry in that individual differences in social network size and complexity could not be explained by the strength of intrinsic connectivity between nodes within two networks that do not typically involve the amygdala (i.e., the mentalizing and mirror networks), and were behaviorally specific in that amygdala connectivity did not correlate with other self-report measures of sociality.
Although both normal aging and Alzheimer's disease (AD) are associated with regional cortical atrophy, few studies have directly compared the spatial patterns and magnitude of effects of these two ...processes. The extant literature has not addressed two important questions: 1) Is the pattern of age-related cortical atrophy different if cognitively intact elderly individuals with silent AD pathology are excluded? and 2) Does the age- or AD-related atrophy relate to cognitive function? Here we studied 142 young controls, 87 older controls, and 28 mild AD patients. In addition, we studied 35 older controls with neuroimaging data indicating the absence of brain amyloid. Whole-cortex analyses identified regions of interest (ROIs) of cortical atrophy in aging and in AD. Results showed that some regions are predominantly affected by age with relatively little additional atrophy in patients with AD, e.g., calcarine cortex; other regions are predominantly affected by AD with much less of an effect of age, e.g., medial temporal cortex. Finally, other regions are affected by both aging and AD, e.g., dorsolateral prefrontal cortex and inferior parietal lobule. Thus, the processes of aging and AD have both differential and partially overlapping effects on specific regions of the cerebral cortex. In particular, some frontoparietal regions are affected by both processes, most temporal lobe regions are affected much more prominently by AD than aging, while sensorimotor and some prefrontal regions are affected specifically by aging and minimally more by AD. Within normal older adults, atrophy in aging-specific cortical regions relates to cognitive performance, while in AD patients atrophy in AD-specific regions relates to cognitive performance. Further work is warranted to investigate the behavioral and clinical relevance of these findings in additional detail, as well as their histological basis; ROIs generated from the present study could be used strategically in such investigations.
•Some cortical regions atrophy in normal aging, while others atrophy in Alzheimer's.•Some cortical—especially frontoparietal—regions are affected by both processes.•In normal older adults, thinning in aging-specific regions relates to cognition.•In AD patients, thinning in AD-specific regions relates to cognitive performance.
Apathy is a symptom shared among many neurological and psychiatric disorders. However, the underlying neurocircuitry remains incompletely understood. Apathy is one of the core features of behavioural ...variant frontotemporal dementia (bvFTD), a neurodegenerative disease presenting with heterogeneous combinations of socioaffective symptoms and executive dysfunction. We reviewed all neuroimaging studies of apathy in frontotemporal dementia (FTD) attempting to refine a neurocircuitry model and inform clinical definitions. Levels of apathy have been consistently shown to correlate with the severity of executive dysfunctions across a wide range of diseases, including FTD. Some authors view 'energisation'-the loss of which is central in apathy-as a core executive function. Apathy in FTD is most robustly associated with atrophy, hypometabolism and/or hypoperfusion in the dorsolateral prefrontal cortex, the anterior and middle cingulate cortex, the orbitofrontal cortex and the medial and ventromedial superior frontal gyri. Data also suggest that abnormalities in connecting white matter pathways and functionally connected more posterior cortical areas could contribute to apathy. There is a lack of consistency across studies due to small samples, lenient statistical thresholds, variable measurement scales and the focus on apathy as a unitary concept. Integrating findings across studies, we revise a neurocircuitry model of apathy divided along three subcomponents (cognition/planning, initiation, emotional-affective/motivation) with specific neuroanatomical and cognitive substrates. To increase consistency in clinical practice, a recommendation is made to modify the bvFTD diagnostic criteria of apathy/inertia. More generally, we argue that bvFTD constitutes a disease model to study the neurocircuitry of complex behaviours as a 'lesion-based' approach to neuropsychiatric symptoms observed across diagnostic categories.
The causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB ...and PD dementia, but their contribution to these diseases during life is unknown.
To contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function.
This cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center's memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11-labeled Pittsburgh Compound B (11CPiB) positron emission tomography (PET).
Imaging with fluorine 18-labeled AV-1451 (18FAV-1451) (formerly known as 18FT807), 11CPiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale.
Main outcomes were differentiation of diagnostic groups on the basis of 18FAV-1451 binding, the association of 18FAV-1451 binding with 11CPiB binding, and the association of 18FAV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with 11CPiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function.
In patients with DLB, cortical 18FAV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased 18FAV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical 18FAV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical 11CPiB retention. For DLB and PD-impaired patients, greater 18FAV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score.
Patients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau copathology in the Lewy body diseases.
Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. ...Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.
Objective
To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer F‐18‐AV‐1451 (previously known as T807), tailored to allow in ...vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.
Methods
We applied F‐18‐AV‐1451 phosphor screen autoradiography, F‐18‐AV‐1451 nuclear emulsion autoradiography, and H‐3‐AV‐1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration–tau, frontotemporal lobar degeneration–transactive response DNA binding protein 43 (TDP‐43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology.
Results
Our data suggest that F‐18‐AV‐1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non‐Alzheimer tauopathy brains or to lesions containing β‐amyloid, α‐synuclein, or TDP‐43. F‐18‐AV‐1451 off‐target binding to neuromelanin‐ and melanin‐containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified.
Interpretation
Our data suggest that F‐18‐AV‐1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament‐tau–containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non‐Alzheimer tauopathy cases and to the existence of some F‐18‐AV‐1451 off‐target binding. These findings provide important insights for interpreting in vivo patterns of F‐18‐AV‐1451 retention. Ann Neurol 2015 Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo ...that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies.
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