Stephen J. Bonasera

Clinical syndromes associated with posterior atrophy: Early age at onset AD spectrum

Objective: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes associated with posterior brain atrophy. We compared PCA and LPA to each other and to an age-matched group of patients with early age at onset of Alzheimer disease (EO-AD). We hypothesized that these 3 syndromes are part of a single clinical and biologic continuum. Methods: Voxel-based morphometry (VBM) was used to assess atrophy in 14 PCA, 10 LPA, and 16 EO-AD patients compared to 65 healthy controls. Genetic analysis for APOE was conducted in 30 patients and 44 controls. Four patients came to autopsy. An additional 14 were studied with the beta-amyloid specific PET with tracer 11C-labeled Pittsburgh Compound-B (PIB). Results: VBM results demonstrated that, compared to controls, each patient group showed a large area of overlapping atrophy in bilateral parietal, occipital, precuneus, posterior cingulate, posterior temporal, and hippocampal regions. Surrounding this common area, group-specific atrophy was found in small, symptom-specific regions for each group: the right ventral-occipital and superior parietal regions in PCA, the left middle and superior temporal gyri in LPA, and the prefrontal cortex in EO-AD. APOE ε4 frequency was higher in all patient groups compared to controls. Four PCA, 5 LPA, and 8 EO-AD patients showed evidence of cortical amyloid at pathology (n = 3) or on PIB-PET (n = 14). Conclusions: Logopenic progressive aphasia and posterior cortical atrophy showed largely overlapping anatomic and biologic features with early age at onset of Alzheimer disease, suggesting that these clinical syndromes represent the spectrum of clinical manifestation of the nontypical form of Alzheimer disease that presents at an early age. AD = Alzheimer disease; CBD = corticobasal degeneration; EO-AD = early age at onset of Alzheimer disease; LPA = logopenic progressive aphasia; MAC = Memory and Aging Center; PCA = posterior cortical atrophy; PIB = Pittsburgh Compound-B; PPA = primary progressive aphasia; UCSF = University of California San Francisco; VBM = voxel-based morphometry.

Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden

Patients with early age-of-onset Alzheimers disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimers disease are associated with differences in the distribution and burden of fibrillar amyloid-beta. Patients meeting criteria for probable Alzheimers disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 +/- 5.9 years) and late-onset (n = 18, 72.0 +/- 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-beta-ligand [(11)C]-labelled Pittsburgh compound-B and the glucose analogue [(18)F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 +/- 6.4) was studied for comparison. [(11)C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [(18)F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimers disease patient groups showed increased [(11)C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [(11)C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo-parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [(11)C]-labelled Pittsburgh compound-B and [(18)F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [(11)C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-beta was associated with greater posterior cortical hypometabolism in early-onset Alzheimers disease. Our data are consistent with a model in which both early amyloid-beta accumulation and increased vulnerability to amyloid-beta pathology play critical roles in the pathogenesis of Alzheimers disease in young patients.

Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer's disease and frontotemporal dementia

Apolipoprotein ε4 (apoE4) has been strongly linked with Alzheimers disease (AD) and contributes to several other neurological disorders. We investigated the influence of ε4 allele carrier status on the pattern of gray matter atrophy and disease severity in 51 patients with probable AD and 31 patients with behavioral variant frontotemporal dementia (bvFTD), compared with 56 healthy controls. Voxel-based morphometry was performed by using statistical parametric mapping. The ε4 allele frequency was higher in the AD group (P < 0.001) than the controls but not in the bvFTD group. No differences in demographic or cognitive profiles were observed between ε4 allele carriers and noncarriers within any of the diagnostic groups. However, ε4 carrier status was associated with more severe brain atrophy in disease-specific regions compared with noncarriers in both AD and bvFTD. AD ε4 carriers showed greater atrophy in the bilateral parietal cortex and right hippocampus, and bvFTD ε4 carriers demonstrated greater atrophy in the bilateral medial, dorsolateral, and orbital frontal cortex, anterior insula, and cingulate cortex with right predominance. This regional ε4 effect is consistent with the hypothesis that apoE may affect the morphologic expression uniquely in different neurodegenerative diseases. The atrophy patterns in ε4 carriers may indicate that they are at greater risk for clinical progression.

Essential function of HIPK2 in TGFβ-dependent survival of midbrain dopamine neurons

Transforming growth factor beta (TGFβ) is a potent trophic factor for midbrain dopamine (DA) neurons, but its in vivo function and signaling mechanisms are not entirely understood. We show that the transcriptional cofactor homeodomain interacting protein kinase 2 (HIPK2) is required for the TGFβ-mediated survival of mouse DA neurons. The targeted deletion of Hipk2 has no deleterious effect on the neurogenesis of DA neurons, but leads to a selective loss of these neurons that is due to increased apoptosis during programmed cell death. As a consequence, Hipk2−/− mutants show an array of psychomotor abnormalities. The function of HIPK2 depends on its interaction with receptor-regulated Smads to activate TGFβ target genes. In support of this notion, DA neurons from Hipk2−/− mutants fail to survive in the presence of TGFβ3 and Tgfβ3−/− mutants show DA neuron abnormalities similar to those seen in Hipk2−/− mutants. These data underscore the importance of the TGFβ-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration.

Mouse models of serotonin receptor function: toward a genetic dissection of serotonin systems

Central serotonin (5-hydroxytryptamine, 5-HT) systems regulate a wide variety of complex behaviors, and are targeted by drugs used in the treatment of diverse neuropsychiatric disorders. The actions of 5-HT are mediated by a large and heterogeneous family of 5-HT receptor subtypes. Studies of the functional significance of individual subtypes have been complicated by the limited availability of selective receptor agonist and antagonist drugs. Molecular genetic techniques offer complementary approaches for studying the behavioral roles of individual 5-HT receptor subtypes through the generation of gene-targeted and transgenic lines of mice with altered expression of 5-HT receptor genes. This review will examine insights into the serotonergic regulation of behavior that have been produced by the study of these lines, as well as discuss important caveats to the interpretation of these studies.

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

The anatomical distribution and pharmacology of serotonin 6 receptors (5-HT6Rs) implicate them as contributors to the serotonergic regulation of complex behavior. To complement the limited range of pharmacological tools available to examine 5-HT6R function, we have generated a mouse line bearing a constitutive null mutation of the 5-HT6R gene. No perturbations of baseline behavior were noted in a wide array of assays pertinent to multiple neurobehavioral processes. However, 5-HT6R mutant mice demonstrated reduced responses to the ataxic and sedative effects of ethanol. No differences in ethanol metabolism were evident between wild-type and 5-HT6R mutant mice. These findings implicate 5-HT6Rs in the serotonergic modulation of responses to ethanol.

Nuclear factor-κB-dependent reversal of aging-induced alterations in T cell cytokines

Immunosenescence is characterized by decreases in protective immune responses and increases in inflammation and autoimmunity. The T helper (Th)17 subset of cluster‐of‐differentiation (CD)4 T cells, which is identified by its generation of interleukin (IL) ‐17, is implicated in autoimmune pathogenesis. To elucidate immunosenescent changes in Th17 cell cytokines, splenic CD4 T cells from 22‐ to 24‐month‐old (old) mice and 6‐ to 10‐wk‐old (young) mice were incubated on anti‐CD3 plus anti‐CD28 (anti‐T cell antigen receptor) antibodies. After 96 h, T cells of old C57BL/6 and CBA mice generated up to 20‐fold more IL‐17 and up to 3‐fold more IL‐6 than those of young mice; T cells of young mice generated up to 5‐fold more IL‐21 than those of old mice;and no difference was found for IFN‐γ. At 24 h, cytokine mRNA levels paralleled 96 h cytokine concentrations. Naive CD4 T cells from old mice incubated on anti‐T cell antigen receptor antibodies with transforming growth factor‐β, IL‐1, IL‐6, and IL‐23 to induce de novo differentiation of Th17 cells had more IL‐17 mRNA and produced more IL‐17 than those of young mice. BAY11–7082 and the phytochemicals triptolide and butein suppressed nuclear concentrations of nuclear factor‐κB and secreted levels of IL‐17, IL‐21, and IFN‐γ in parallel, with greater potency in Th17 cells from young than old mice. Pharmacological correction of altered generation of Th17 cell cytokines in immunosenescence represents a novel therapeutic approach to aging‐induced inflammatory diseases.—Huang, M.‐C., Liao, J‐J., Bonasera, S., Longo, D. L., Goetzl, E. J. Nuclear factor‐κB‐dependent reversal of aging‐induced alterations in T cell cytokines. FASEB J. 22, 2142–2150 (2008)

Impact of Serotonin 2C Receptor Null Mutation on Physiology and Behavior Associated with Nigrostriatal Dopamine Pathway Function

The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT2CR) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT2CRs produces marked alterations in the activity and functional output of this pathway. 5-HT2CR mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of d-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D1 receptor agonist SKF 81297. Differences in DSt D1 or D2 receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT2CRs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.

Cellular Telephones Measure Activity and Lifespace in Community-Dwelling Adults: Proof of Principle

OBJECTIVES: To describe a system that uses off‐the‐shelf sensor and telecommunication technologies to continuously measure individual lifespace and activity levels in a novel way.

Treadmill gait speeds correlate with physical activity counts measured by cell phone accelerometers.

A number of important health-related outcomes are directly related to a persons ability to maintain normal gait speed. We hypothesize that cellular telephones may be repurposed to measure this important behavior in a noninvasive, continuous, precise, and inexpensive manner. The purpose of this study was to determine if physical activity (PA) counts collected by cell phone accelerometers could measure treadmill gait speeds. We also assessed how cell phone placement influenced treadmill gait speed measures. Participants included 55 young, middle-aged, and older community-dwelling men and women. We placed cell phones as a pendant around the neck, and on the left and right wrist, hip, and ankle. Subjects then completed an individualized treadmill protocol, alternating 1 min rest periods with 5 min of walking at different speeds (0.3-11.3 km/h; 0.2-7 mi/h). No persons were asked to walk at speeds faster than what they would achieve during day-to-day life. PA counts were calculated from all sensor locations. We built linear mixed statistical models of PA counts predicted by treadmill speeds ranging from 0.8 to 6.4 km/h (0.5-4 mi/h) while accounting for subject age, weight, and gender. We solved linear regression equations for treadmill gait speed, expressed as a function of PA counts, age, weight, and gender. At all locations, cell phone PA counts were strongly associated with treadmill gait speed. Cell phones worn at the hip yielded the best predictive model. We conclude that in both men and women, cell phone derived activity counts strongly correlate with treadmill gait speed over a wide range of subject ages and weights.