David Perry

Opiate antagonist receptor binding in vivo: evidence for a new receptor binding model.

The in vivo accumulation and retention of the opiate antagonist tracers [3H]diprenorphine and [3H]naloxone at cerebral opiate receptor sites in rats exceed that expected from their known in vitro receptor affinities. The [3H]diprenorphine serum and brain levels can be stimulated with a pharmacokinetic model that contains the receptors in a micro-compartment. The receptor micro-compartment consists of a population of binding sites next to a diffusion boundary which restricts ligand diffusion away from the receptor. Such an arrangement introduces a delay in the binding equilibrium of potent antagonists with the receptor sites and an increase in the apparent in vivo receptor affinity at subsaturating doses of the ligand; at saturating ligand concentrations these functions of the receptor micro-compartment are abolished. A physiological interpretation of the receptor micro-compartment could be the location of clustered opiate receptor sites on the exterior cell surface next to the synaptic cleft as the diffusion boundary. This kinetic approach involving a combination of pharmacokinetics and drug-receptor interactions permits the quantitative analysis of receptor site availability in the intact animal. Our results support the hypothesis that only one receptor population affects the in vivo disposition of the antagonist tracers, while they do not exclude the presence of low affinity binding sites that have been observed with the use of [3H]naloxone in vitro. Moreover, the binding site population observed in vivo may be responsible for mediating opiate agonist analgesia.

The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features

A frontal variant of Alzheimers disease has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimers disease pathology. The description of this rare Alzheimers disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimers disease with a behavioural-predominant presentation (behavioural Alzheimers disease) and a neuropathological diagnosis of high-likelihood Alzheimers disease (n = 17) and/or biomarker evidence of Alzheimers disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimers disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimers disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimers disease: 53%; dysexecutive Alzheimers disease: 83%) than behavioural (behavioural Alzheimers disease: 25%; dysexecutive Alzheimers disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimers disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimers disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimers disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimers disease (typical Alzheimers disease, n = 58), autopsy-confirmed/Alzheimers disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimers disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimers disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimers disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimers disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimers disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimers disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimers disease/dysexecutive Alzheimers disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimers disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimers disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimers disease and dysexecutive Alzheimers disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as the behavioural/dysexecutive variant of Alzheimers disease rather than frontal variant Alzheimers disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimers disease represent distinct phenotypes or a single continuum.

Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis

OBJECTIVEnMild traumatic brain injury (TBI) has been proposed as a risk factor for the development of Alzheimers disease, Parkinsons disease, depression, and other illnesses. This studys objective was to determine the association of prior mild TBI with the subsequent diagnosis (that is, at least 1 year postinjury) of neurological or psychiatric disease.nnnMETHODSnAll studies from January 1995 to February 2012 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, study references, and review articles. Reviewers abstracted the data and assessed study designs and characteristics.nnnRESULTSnFifty-seven studies met the inclusion criteria. A random effects meta-analysis revealed a significant association of prior TBI with subsequent neurological and psychiatric diagnoses. The pooled odds ratio (OR) for the development of any illness subsequent to prior TBI was 1.67 (95% CI 1.44-1.93, p < 0.0001). Prior TBI was independently associated with both neurological (OR 1.55, 95% CI 1.31-1.83, p < 0.0001) and psychiatric (OR 2.00, 95% CI 1.50-2.66, p < 0.0001) outcomes. Analyses of individual diagnoses revealed higher odds of Alzheimers disease, Parkinsons disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder in individuals with previous TBI as compared to those without TBI. This association was present when examining only studies of mild TBI and when considering the influence of study design and characteristics. Analysis of a subset of studies demonstrated no evidence that multiple TBIs were associated with higher odds of disease than a single TBI.nnnCONCLUSIONSnHistory of TBI, including mild TBI, is associated with the development of neurological and psychiatric illness. This finding indicates that either TBI is a risk factor for heterogeneous pathological processes or that TBI may contribute to a common pathological mechanism.

Progranulin Mutations as Risk Factors for Alzheimer Disease

IMPORTANCEnMutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review.nnnOBSERVATIONSnThis study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD.nnnCONCLUSIONS AND RELEVANCEnIn addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

[3H]diprenorphine receptor binding in vivo and in vitro

In order to investigate opiate receptor binding in vivo, [3H]diprenorphine was given s.c. to rats, and the tracer specifically bound to membraneous high affinity sites was determined with a rapid filtration technique after brain homogenization. Bound [3H]diprenorphine accounted for 70% of the total brain activity after tracer doses. The in vivo binding sites were saturable at 25-30 pmol/g brain. Fifty percent occupancy of the [3H]diprenorphine binding sites in vivo occurred at a dose (10-15 micrograms/kg) that is similar to the antagonistic ED50 of diprenorphine for reversing morphine analgesia. The in vitro binding capacity for [3H]diprenorphine was also approximately 30 pmol/g brain in fresh untreated Tris buffer brain homogenate; however, extensive homogenate dilution or standard membrane washing procedures resulted in a reduction of the [3H]diprenorphine binding site population to 13-22 pmol/g. These results indicate that the opiate receptor system is modified in vitro. Previous studies have shown that the [3H]diprenorphine tracer is retained at cerebral binding sites over several hours in vivo. A diffusion boundary model was proposed to account for the dose dependent tracer retention. In order to investigate the mechanism of the in vivo binding kinetics, [3H]diprenorphine dissociation was measured in brain homogenates after in vivo labeling, immediately following sacrifice of the animals to minimize in vitro artefacts. No differences were found in the dissociation curves at infinite homogenate dilution in the presence or absence of saturating diprenorphine concentrations under various ionic incubation conditions. This result argues against cooperative binding. It is consistent with the hypothesis that the [3H]diprenorphine tracer is retained in vivo because of a diffusion boundary next to the binding sites (receptor micro-compartment) that is destroyed during brain homogenization.

Anatomical correlates of reward-seeking behaviours in behavioural variant frontotemporal dementia

Behavioural variant frontotemporal dementia is characterized by abnormal responses to primary reward stimuli such as food, sex and intoxicants, suggesting abnormal functioning of brain circuitry mediating reward processing. The goal of this analysis was to determine whether abnormalities in reward-seeking behaviour in behavioural variant frontotemporal dementia are correlated with atrophy in regions known to mediate reward processing. Review of case histories in 103 patients with behavioural variant frontotemporal dementia identified overeating or increased sweet food preference in 80 (78%), new or increased alcohol or drug use in 27 (26%), and hypersexuality in 17 (17%). For each patient, a primary reward-seeking score of 0-3 was created with 1 point given for each target behaviour (increased seeking of food, drugs, or sex). Voxel-based morphometry performed in 91 patients with available imaging revealed that right ventral putamen and pallidum atrophy correlated with higher reward-seeking scores. Each of the reward-related behaviours involved partially overlapping right hemisphere reward circuit regions including putamen, globus pallidus, insula and thalamus. These findings indicate that in some patients with behavioural variant frontotemporal dementia, low volume of subcortical reward-related structures is associated with increased pursuit of primary rewards, which may be a product of increased thalamocortical feedback.

Presurgical mapping with magnetic source imaging: comparisons with intraoperative findings

We compare noninvasive preoperative mapping with magnetic source imaging to intraoperative cortical stimulation mapping. These techniques were directly compared in 17 patients who underwent preoperative and postoperative somatosensory mapping of a total of 22 comparable anatomic sites (digits, face). Our findings are presented in the context of previous studies that used magnetic source imaging and functional magnetic resonance imaging as noninvasive surrogates of intraoperative mapping for the identification of sensorimotor and language-specific brain functional centers in patients with brain tumors. We found that magnetic source imaging results were reasonably concordant with intraoperative mapping findings in over 90% of cases, and that concordance could be defined as “good” in 77% of cases. Magnetic source imaging therefore provides a viable, if coarse, identification of somatosensory areas and, consequently, can guide and reduce the time taken for intraoperative mapping procedures.

Criminal Behavior in Frontotemporal Dementia and Alzheimer Disease.

IMPORTANCEnNeurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life.nnnOBJECTIVEnTo investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder.nnnDESIGN, SETTING, AND PARTICIPANTSnWe conducted a retrospective medical record review of 2397 patients who were seen at the University of California, San Francisco, Memory and Aging Center between 1999 and 2012, including 545 patients with Alzheimer disease (AD), 171 patients with behavioral variant of frontotemporal dementia (bvFTD), 89 patients with semantic variant of primary progressive aphasia, and 30 patients with Huntington disease. Patient notes containing specific keywords denoting criminal behavior were reviewed. Data were stratified by criminal behavior type and diagnostic groups.nnnMAIN OUTCOMES AND MEASURESnFrequencies of criminal behavior and χ² statistics were calculated.nnnRESULTSnOf the 2397 patients studied, 204 (8.5%) had a history of criminal behavior that emerged during their illness. Of the major diagnostic groups, 42 of 545 patients (7.7%) with AD, 64 of 171 patients (37.4%) with bvFTD, 24 of 89 patients (27.0%) with semantic variant of primary progressive aphasia, and 6 of 30 patients (20%) with Huntington disease exhibited criminal behavior. A total of 14% of patients with bvFTD were statistically significantly more likely to present with criminal behavior compared with 2% of patients with AD (Pu2009<u2009.001) and 6.4% were statistically significantly more likely to exhibit violence compared with 2% of patients with AD (Pu2009=u2009.003). Common manifestations of criminal behavior in the bvFTD group included theft, traffic violations, sexual advances, trespassing, and public urination in contrast with those in the AD group, who commonly committed traffic violations, often related to cognitive impairment.nnnCONCLUSIONS AND RELEVANCEnCriminal behavior is more common in patients with bvFTD and semantic variant of primary progressive aphasia than in those with AD and is more likely to be an early manifestation of the disorder. Judicial evaluations of criminality in the demented individual might require different criteria than the classic insanity defense used in the American legal system; these individuals should be treated differently by the law. The appearance of new-onset criminal behavior in an adult should elicit a search for frontal and anterior temporal brain disease and for dementing disorders.

Distinct Subtypes of Behavioral Variant Frontotemporal Dementia Based on Patterns of Network Degeneration.

IMPORTANCEnClearer delineation of the phenotypic heterogeneity within behavioral variant frontotemporal dementia (bvFTD) will help uncover underlying biological mechanisms and improve clinicians ability to predict disease course and to design targeted management strategies.nnnOBJECTIVEnTo identify subtypes of bvFTD syndrome based on distinctive patterns of atrophy defined by selective vulnerability of specific functional networks targeted in bvFTD using statistical classification approaches.nnnDESIGN, SETTING AND PARTICIPANTSnIn this retrospective observational study, 90 patients meeting the Frontotemporal Dementia Consortium consensus criteria for bvFTD underwent evaluation at the Memory and Aging Center of the Department of Neurology at University of California, San Francisco. Patients underwent a multidisciplinary clinical evaluation, including clinical demographics, genetic testing, symptom evaluation, neurologic examination, neuropsychological bedside testing, and socioemotional assessments. All patients underwent structural magnetic resonance imaging at their earliest evaluation at the memory clinic. From each patients structural imaging scans, the mean volumes of 18 regions of interest (ROI) constituting the functional networks specifically vulnerable in bvFTD, including the salience network (SN), with key nodes in the frontoinsula and pregenual anterior cingulate, and the semantic appraisal network (SAN), anchored in the anterior temporal lobe and subgenual cingulate, were estimated. Principal component and cluster analyses of ROI volumes were used to identify patient clusters with anatomically distinct atrophy patterns. Data were collected from from June 19, 2002, to January 13, 2015.nnnMAIN OUTCOMES AND MEASURESnEvaluation of brain morphology and other clinical features, including presenting symptoms, neurologic examination signs, neuropsychological performance, rate of dementia progression, and socioemotional function, in each patient cluster.nnnRESULTSnNinety patients (54 men [60%]; 36 women [40%]; mean [SD] age at evaluation, 55.1 [9.7] years) were included in the analysis. Four subgroups of patients with bvFTD with distinct anatomic patterns of network degeneration were identified, including 2 salience network-predominant subgroups (frontal/temporal [SN-FT] and frontal [SN-F]), a semantic appraisal network-predominant group (SAN), and a subcortical-predominant group. Subgroups demonstrated distinct patterns of cognitive, socioemotional, and motor symptoms, as well as genetic compositions and estimated rates of disease progression.nnnCONCLUSIONS AND RELEVANCEnDivergent patterns of vulnerability in specific functional network components make an important contribution to the clinical heterogeneity of bvFTD. The data-driven anatomic classification identifies biologically meaningful anatomic phenotypes and provides a replicable approach to disambiguate the bvFTD syndrome.

Frontotemporal dementia with the V337M MAPT mutation: Tau-PET and pathology correlations

Objective: To assess the efficacy of [18F]AV1451 PET in visualizing tau pathology in vivo in a patient with frontotemporal dementia (FTD) associated with the V337M microtubule-associated protein tau (MAPT) mutation. Methods: MAPT mutations are associated with the deposition of hyperphosphorylated tau protein in neurons and glia. The PET tracer [18F]AV1451 binds with high affinity to paired helical filaments tau that comprises neurofibrillary tangles in Alzheimer disease (AD), while postmortem studies suggest lower or absent binding to the tau filaments of the majority of non-AD tauopathies. We describe clinical, structural MRI, and [18F]AV1451 PET findings in a V337M MAPT mutation carrier affected by FTD and pathologic findings in his affected mother and in an unrelated V337M MAPT carrier also affected with FTD. The biochemical similarity between paired helical filament tau in AD and MAPT V337M predicts that the tau pathology associated with this mutation constitutes a compelling target for [18F]AV1451 imaging. Results: We found a strong association between topography and degree of [18F]AV1451 tracer retention in the proband and distribution of tau pathology in the brain of the probands mother and the unrelated V337M mutation carrier. We also found a significant correlation between the degree of regional MRI brain atrophy and the extent of [18F]AV1451 binding in the proband and a strong association between the probands clinical presentation and the extent of regional brain atrophy and tau accumulation as assessed by structural brain MRI and [18F]AV1451PET. Conclusion: Our study supports the usefulness of [18F]AV1451 to characterize tau pathology in at least a subset of pathogenic MAPT mutations.