ABSTRACT
BACKGROUND: The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer's disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. METHODS: VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. RESULTS: The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. DISCUSSION: VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.
Subject(s)
Alzheimer Disease , Frontotemporal Dementia , Frontotemporal Lobar Degeneration , Alzheimer Disease/pathology , Frontotemporal Dementia/pathology , Frontotemporal Lobar Degeneration/pathology , Gyrus Cinguli/pathology , Humans , Neurons/pathologyABSTRACT
OBJECTIVE: We aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration. METHODS: 337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures. RESULTS: DRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity. CONCLUSIONS: We conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD.
Subject(s)
Brain/pathology , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Receptors, Dopamine D4/genetics , Receptors, Dopamine D4/physiology , Aged , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Atrophy , Female , Frontotemporal Dementia/psychology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , Polymorphism, Genetic , SyndromeABSTRACT
AIMS: Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages. METHODS: We utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-µm-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases. RESULTS: In Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9× between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN. CONCLUSIONS: LC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.
Subject(s)
Alzheimer Disease/pathology , Dorsal Raphe Nucleus/pathology , Locus Coeruleus/pathology , tau Proteins/metabolism , Adult , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Disease Progression , Dorsal Raphe Nucleus/metabolism , Female , Humans , Inclusion Bodies/pathology , Locus Coeruleus/metabolism , Male , Middle AgedSubject(s)
Frontotemporal Lobar Degeneration , RNA-Binding Protein FUS/metabolism , Adult , Brain/metabolism , Brain/pathology , DNA-Binding Proteins/metabolism , Electroencephalography , Electromyography , Frontotemporal Lobar Degeneration/complications , Frontotemporal Lobar Degeneration/diagnosis , Frontotemporal Lobar Degeneration/metabolism , Humans , Magnetic Resonance Imaging , MaleABSTRACT
OBJECTIVE: We sought to determine whether the Val(158)Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions. METHODS: A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI. RESULTS: Whole-brain voxel-wise regression analyses revealed that COMT Val(158)Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits. CONCLUSIONS: The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.
Subject(s)
Catechol O-Methyltransferase/genetics , Cerebral Cortex/pathology , Dementia/pathology , Dopamine/physiology , Aged , Alleles , Alzheimer Disease/etiology , Alzheimer Disease/pathology , Cerebral Cortex/metabolism , Dementia/etiology , Dopamine/genetics , Female , Frontotemporal Dementia/etiology , Frontotemporal Dementia/pathology , Frontotemporal Lobar Degeneration/etiology , Frontotemporal Lobar Degeneration/pathology , Genotype , Humans , Magnetic Resonance Imaging/methods , Male , Methionine/genetics , Middle Aged , Polymorphism, Single Nucleotide/genetics , Prefrontal Cortex/metabolism , Prefrontal Cortex/pathology , Valine/geneticsABSTRACT
OBJECTIVE: To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). METHODS: Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls. RESULTS: PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88-0.92; FDG κ = 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10). CONCLUSIONS: PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.
Subject(s)
Alzheimer Disease/diagnosis , Amyloid/metabolism , Brain/diagnostic imaging , Brain/metabolism , Frontotemporal Lobar Degeneration/diagnosis , Positron-Emission Tomography , Aged , Aged, 80 and over , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Diagnosis, Differential , Female , Fluorodeoxyglucose F18 , Frontotemporal Lobar Degeneration/diagnostic imaging , Frontotemporal Lobar Degeneration/metabolism , Humans , Image Processing, Computer-Assisted , Male , Middle AgedABSTRACT
OBJECTIVES: To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression. METHODS: We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls. RESULTS: In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p(recessive) = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 × 10(-5)) and controls (r = -0.49, p = 2.2 × 10(-10)). CONCLUSIONS: In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.
Subject(s)
Frontotemporal Lobar Degeneration/genetics , Intercellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Penetrance , Polymorphism, Single Nucleotide/genetics , Protein Precursors/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Cohort Studies , Female , Frontotemporal Lobar Degeneration/blood , Frontotemporal Lobar Degeneration/diagnosis , Genetic Association Studies , Genetic Carrier Screening , Genetic Predisposition to Disease/genetics , Humans , Intercellular Signaling Peptides and Proteins/blood , Male , Membrane Proteins/blood , Middle Aged , Nerve Tissue Proteins/blood , Progranulins , Protein Precursors/bloodABSTRACT
BACKGROUND: We sought to describe the antemortem clinical and neuroimaging features among patients with frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). METHODS: Subjects were recruited from a consecutive series of patients with a primary neuropathologic diagnosis of FTLD-TDP and antemortem MRI. Twenty-eight patients met entry criteria: 9 with type 1, 5 with type 2, and 10 with type 3 FTLD-TDP. Four patients had too sparse FTLD-TDP pathology to be subtyped. Clinical, neuropsychological, and neuroimaging features of these cases were reviewed. Voxel-based morphometry was used to assess regional gray matter atrophy in relation to a group of 50 cognitively normal control subjects. RESULTS: Clinical diagnosis varied between the groups: semantic dementia was only associated with type 1 pathology, whereas progressive nonfluent aphasia and corticobasal syndrome were only associated with type 3. Behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease were seen in type 2 or type 3 pathology. The neuroimaging analysis revealed distinct patterns of atrophy between the pathologic subtypes: type 1 was associated with asymmetric anterior temporal lobe atrophy (either left- or right-predominant) with involvement also of the orbitofrontal lobes and insulae; type 2 with relatively symmetric atrophy of the medial temporal, medial prefrontal, and orbitofrontal-insular cortices; and type 3 with asymmetric atrophy (either left- or right-predominant) involving more dorsal areas including frontal, temporal, and inferior parietal cortices as well as striatum and thalamus. No significant atrophy was seen among patients with too sparse pathology to be subtyped. CONCLUSIONS: FTLD-TDP subtypes have distinct clinical and neuroimaging features, highlighting the relevance of FTLD-TDP subtyping to clinicopathologic correlation.
Subject(s)
Brain/metabolism , Brain/pathology , DNA-Binding Proteins/metabolism , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Magnetic Resonance Imaging , Aged , Aged, 80 and over , Aphasia/pathology , Atrophy , DNA-Binding Proteins/classification , Female , Frontal Lobe/metabolism , Frontal Lobe/pathology , Frontotemporal Lobar Degeneration/metabolism , Frontotemporal Lobar Degeneration/pathology , Humans , Inclusion Bodies/metabolism , Male , Middle Aged , Temporal Lobe/metabolism , Temporal Lobe/pathology , Thalamus/metabolism , Thalamus/pathologyABSTRACT
We performed a longitudinal anatomical study to map the progression of gray matter atrophy in anatomically defined predominantly left (LTLV) and right (RTLV) temporal lobe variants of semantic dementia (SD). T1-weighted MRI scans were obtained at presentation and one-year follow-up from 13 LTLV, 6 RTLV, and 25 control subjects. Tensor-based morphometry (TBM) in SPM2 was applied to derive a voxel-wise estimation of regional tissue loss over time from the deformation field required to warp the follow-up scan to the presentation scan in each subject. When compared to controls, both LTLV and RTLV showed significant progression of gray matter atrophy not only within the temporal lobe most affected at presentation, but also in the controlateral temporal regions (p<0.05 FWE corrected). In LTLV, significant progression of volume loss also involved the ventromedial frontal and the left anterior insular regions. These results identified the anatomic substrates of the previously reported clinical evolution of LTLV and RTLV into a unique 'merged' clinical syndrome characterized by semantic and behavioral deficits and bilateral temporal atrophy.
Subject(s)
Dementia/pathology , Magnetic Resonance Imaging/methods , Neurons/pathology , Temporal Lobe/pathology , Atrophy/pathology , Female , Functional Laterality , Humans , Longitudinal Studies , Male , Middle AgedABSTRACT
BACKGROUND: Neurophysiologic studies on human and nonhuman primates implicate an orbitofrontal-insular-striatal circuit in high-level regulation of feeding. However, the role of these areas in determining feeding disturbances in neurologic patients remains uncertain. OBJECTIVE AND METHODS: To determine brain structures critical for control of eating behavior, we performed a prospective, laboratory-based, free-feeding study of 18 healthy control subjects and 32 patients with neurodegenerative disease. MR voxel-based morphometry (VBM) was used to identify regions of significant atrophy in patients who overate compared with those who did not. RESULTS: Despite normal taste recognition, 6 of 32 patients compulsively binged, consuming large quantities of food after reporting appropriate satiety. All six patients who overate were clinically diagnosed with frontotemporal dementia (FTD), a disorder previously associated with disordered eating, while the nonovereaters were diagnosed with FTD, semantic dementia, progressive aphasia, progressive supranuclear palsy, and Alzheimer disease. VBM revealed that binge-eating patients had significantly greater atrophy in the right ventral insula, striatum, and orbitofrontal cortex. CONCLUSION: Binge eating can occur despite reported satiety and is associated with damage to a right-sided orbitofrontal-insular-striatal circuit in humans. These findings support a model in which ventral insular and orbitofrontal cortices serve as higher-order gustatory regions and cooperate with the striatum to guide appropriate feeding responses.
Subject(s)
Atrophy/pathology , Brain/pathology , Bulimia Nervosa/pathology , Dementia/pathology , Neural Pathways/pathology , Aged , Appetite/physiology , Atrophy/etiology , Atrophy/physiopathology , Brain/physiopathology , Bulimia Nervosa/etiology , Bulimia Nervosa/physiopathology , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Corpus Striatum/pathology , Corpus Striatum/physiopathology , Dementia/complications , Dementia/psychology , Feeding Behavior/physiology , Female , Functional Laterality/physiology , Humans , Magnetic Resonance Imaging , Male , Mental Disorders/etiology , Mental Disorders/pathology , Mental Disorders/physiopathology , Middle Aged , Neural Pathways/physiopathology , Neuropsychological Tests , Predictive Value of Tests , Prefrontal Cortex/pathology , Prefrontal Cortex/physiopathology , Reward , Satiety ResponseABSTRACT
We applied optimised voxel based morphometry (VBM) to brain MRIs from autopsy proven cases of tau positive frontotemporal lobar degeneration (FTLD-T, n = 6), ubiquitin and TDP-43 positive/tau negative FTLD (FTLD-U, n = 8) and cognitively normal controls (n = 61). The analysis revealed that FTLD-T and FTLD-U both show atrophy in the frontal cortex and striatum, but striatal atrophy is more severe in FTLD-T. Manual region of interest tracing of caudate and putamen volumes confirmed the VBM findings. These anatomical differences may help distinguish between FTLD spectrum pathological subtypes in vivo.
Subject(s)
Dementia/metabolism , Dementia/pathology , Magnetic Resonance Imaging , Ubiquitin/metabolism , tau Proteins/metabolism , Aged , Atrophy/pathology , Autopsy , Caudate Nucleus/anatomy & histology , Dementia/complications , Dementia/diagnosis , Dementia/etiology , Female , Humans , Male , Neuropsychological Tests , Putamen/anatomy & histology , Severity of Illness IndexABSTRACT
BACKGROUND: Acute limbic encephalitis has been reported in the setting of treatment-related immunosuppression and attributed to human herpesvirus-6 (HHV6) infection. Clinical and laboratory features of the syndrome, however, have not been well characterized. METHODS: We describe the clinical, EEG, MRI, and laboratory features of nine patients with acute limbic encephalitis after allogeneic hematopoietic stem cell transplantation (HSCT). To explore the relationship between HHV6 and this syndrome, we reviewed available CSF HHV6 PCR results from all HSCT patients seen at our center from March 17, 2003, through March 31, 2005. RESULTS: Patients displayed a consistent and distinctive clinical syndrome featuring anterograde amnesia, the syndrome of inappropriate antidiuretic hormone secretion, mild CSF pleocytosis, and temporal EEG abnormalities, often reflecting clinical or subclinical seizures. MRI showed hyperintensities within the uncus, amygdala, entorhinal area, and hippocampus on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) sequences. CSF PCR assays for HHV6 were positive in six of nine patients on initial lumbar puncture. All patients were treated with foscarnet or ganciclovir. Cognitive recovery varied among long-term survivors. The one brain autopsy showed limbic gliosis and profound neuronal loss in amygdala and hippocampus. Among 27 HSCT patients with CSF tested for HHV6 over a 2-year period, positive results occurred only in patients with clinical limbic encephalitis. CONCLUSIONS: Patients undergoing allogeneic hematopoietic stem cell transplantation are at risk for post-transplant acute limbic encephalitis (PALE), a distinct neurologic syndrome. Treatment considerations should include aggressive seizure control and, possibly, antiviral therapy. PALE can be associated with the CSF presence of human herpesvirus-6, but the pathogenic role of the virus requires further exploration.
Subject(s)
Encephalitis, Herpes Simplex/virology , Hematopoietic Stem Cell Transplantation/adverse effects , Herpesvirus 6, Human/immunology , Limbic Encephalitis/virology , Postoperative Complications/virology , Adult , Amnesia, Anterograde/immunology , Amnesia, Anterograde/physiopathology , Amnesia, Anterograde/virology , Amygdala/pathology , Amygdala/physiopathology , Antiviral Agents/therapeutic use , Diabetes Insipidus/immunology , Diabetes Insipidus/physiopathology , Diabetes Insipidus/virology , Encephalitis, Herpes Simplex/immunology , Encephalitis, Herpes Simplex/physiopathology , Epilepsy, Temporal Lobe/immunology , Epilepsy, Temporal Lobe/physiopathology , Epilepsy, Temporal Lobe/virology , Hippocampus/pathology , Hippocampus/physiopathology , Humans , Limbic Encephalitis/immunology , Limbic Encephalitis/physiopathology , Magnetic Resonance Imaging , Male , Middle Aged , Postoperative Complications/immunology , Postoperative Complications/physiopathology , Treatment OutcomeABSTRACT
To better define the anatomic distinctions between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), we retrospectively applied voxel-based morphometry to the earliest magnetic resonance imaging scans of autopsy-proven AD (N = 11), FTLD (N = 18), and controls (N = 40). Compared with controls, AD patients showed gray matter reductions in posterior temporoparietal and occipital cortex; FTLD patients showed atrophy in medial prefrontal and medial temporal cortex, insula, hippocampus, and amygdala; and patients with both disorders showed atrophy in dorsolateral and orbital prefrontal cortex and lateral temporal cortex (P(FWE-corr) < .05). Compared with FTLD, AD patients had decreased gray matter in posterior parietal and occipital cortex, whereas FTLD patients had selective atrophy in anterior cingulate, frontal insula, subcallosal gyrus, and striatum (P < .001, uncorrected). These findings suggest that AD and FTLD are anatomically distinct, with degeneration of a posterior parietal network in AD and degeneration of a paralimbic fronto-insular-striatal network in FTLD.
Subject(s)
Alzheimer Disease/pathology , Brain/pathology , Dementia/pathology , Image Processing, Computer-Assisted , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Amygdala/pathology , Atrophy , Cerebral Cortex/pathology , Corpus Striatum/pathology , Dementia/diagnosis , Diagnosis, Differential , Dominance, Cerebral/physiology , Female , Gyrus Cinguli/pathology , Hippocampus/pathology , Humans , Lewy Body Disease/diagnosis , Lewy Body Disease/pathology , Male , Middle AgedABSTRACT
BACKGROUND: The temporal variant of frontotemporal dementia (tvFTD) features asymmetric anterior temporal/amygdala degeneration as well as ventromedial frontal, insular, and inferoposterior temporal involvement. Left temporal atrophy has been linked to loss of semantic knowledge, whereas behavioral symptoms dominate the right temporal variant. OBJECTIVE: To investigate the first symptoms and the timing of subsequent symptoms in patients with left versus right tvFTD. METHODS: Twenty-six patients with tvFTD were identified. Six had right > left temporal atrophy (right temporal lobe variant [RTLV]) and were matched with six having comparable left > right temporal atrophy (left temporal lobe variant [LTLV]). Clinical records were reviewed to generate individualized symptom chronologies. RESULTS: In all patients, first symptoms involved semantics (4/6 LTLV, 1/6 RTLV), behavior (4/6 RTLV, 1/6 LTLV), or both (1 LTLV, 1 RTLV). Semantic loss began with anomia, word-finding difficulties, and repetitive speech, whereas the early behavioral syndrome was characterized by emotional distance, irritability, and disruption of physiologic drives (sleep, appetite, libido). After an average of 3 years, patients developed whichever of the two initial syndromes--semantic or behavioral--that they lacked at onset. A third stage, 5 to 7 years from onset, saw the emergence of disinhibition, compulsions, impaired face recognition, altered food preference, and weight gain. Compulsions in LTLV were directed toward visual, nonverbal stimuli, whereas patients with RTLV were drawn to games with words and symbols. CONCLUSIONS: The temporal variant of frontotemporal dementia follows a characteristic cognitive and behavioral progression that suggests early spread from one anterior temporal lobe to the other. Later symptoms implicate ventromedial frontal, insular, and inferoposterior temporal regions, but their precise anatomic correlates await confirmation.
Subject(s)
Atrophy/physiopathology , Dementia/physiopathology , Temporal Lobe/physiopathology , Affective Symptoms/etiology , Affective Symptoms/pathology , Affective Symptoms/physiopathology , Aged , Appetite/physiology , Atrophy/etiology , Atrophy/pathology , Cognition Disorders/etiology , Cognition Disorders/pathology , Cognition Disorders/physiopathology , Compulsive Behavior/etiology , Compulsive Behavior/pathology , Compulsive Behavior/physiopathology , Dementia/pathology , Dementia/psychology , Disease Progression , Female , Functional Laterality/physiology , Humans , Language Disorders/etiology , Language Disorders/pathology , Language Disorders/physiopathology , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , Predictive Value of Tests , Sleep Wake Disorders/etiology , Sleep Wake Disorders/pathology , Sleep Wake Disorders/physiopathology , Temporal Lobe/pathology , Time FactorsSubject(s)
Neurosyphilis/diagnosis , Oculomotor Nerve Diseases/diagnosis , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Brain/pathology , Diagnosis, Differential , Homosexuality, Male , Humans , Injections, Intravenous , Magnetic Resonance Imaging , Male , Middle Aged , Neurosyphilis/drug therapy , Neurosyphilis/pathology , Penicillin G/administration & dosage , Penicillin G/therapeutic use , Treatment OutcomeABSTRACT
OBJECTIVE: To evaluate the frequency and types of change in "self" seen in frontotemporal dementia (FTD) and to determine the relative involvement of the nondominant and dominant frontal and temporal brain regions in FTD patients with or without changes in a sense of self using neuropsychology tests and neuroimaging. BACKGROUND: The self has been defined as "the total, essential, or particular being of a person" involving "the essential qualities distinguishing one person from another." Some suggest that the frontal lobes play a dominant role in maintaining the self. FTD affects anterior frontal and temporal areas and can be associated with a loss of self. METHODS: Seventy-two consecutive FTD patients were evaluated with neuropsychiatric, neuropsychologic, and behavioral measures. Patients were imaged with MRI and SPECT. Charts were reviewed by a social psychologist to determine patients who exhibited a dramatic change in their self as defined by changes in political, social, or religious values. The brain areas with the most severe atrophy or hypoperfusion on neuroimaging were noted. RESULTS: Seven of 72 patients exhibited a dramatic change in self. In six of the seven, the selective dysfunction involved the nondominant frontal region. In contrast, only one of the other 65 patients without selective nondominant frontal dysfunction showed a change in self. CONCLUSIONS: FTD patients with asymmetric loss of function in the nondominant frontal lobe often exhibit a diminished maintenance of previously learned self-concepts despite intact memory and language. Normal nondominant frontal function is important for the maintenance of the self.
Subject(s)
Dementia/pathology , Dementia/psychology , Ego , Neuroanatomy , Aged , Chi-Square Distribution , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neuroanatomy/methods , Neuropsychological Tests , Tomography, Emission-Computed, Single-Photon/methodsABSTRACT
The epilepsies are a heterogeneous collection of seizure disorders with a lifetime expectancy risk rate of 2-4%. A convergence of evidence indicates that heritable factors contribute significantly to seizure susceptibility. Genetically epilepsy-prone rodent strains have been frequently used to examine the effect of genetic factors on seizure susceptibility. The most extensively studied of these have been strains that are susceptible to sound-induced convulsions (audiogenic seizures, or AGSs). Early observations of the AGS phenomenon were made in the laboratory of Dr. Ivan Pavlov; in the course of appetite-conditioning experiments in mice, the loud bell used to signal food presentation unexpectedly produced seizures in some animals. In 1947, DBA/2 (D2) mice were found to exhibit a genetic susceptibility to AGSs stimulated by a doorbell mounted in an iron tub. Since this discovery, AGSs have been among the most intensively studied phenotypes in behavioural genetics. Although several genetic loci confer susceptibility to AGSs, the corresponding genes have not been cloned. We report that null mutant mice lacking serotonin 5-HT2C receptors are extremely susceptible to AGSs. The onset of susceptibility is between two and three months of age, with complete penetrance in adult animals. AGS-induced immediate early gene expression indicates that AGSs are subcortical phenomena in auditory circuits. This AGS syndrome is the first produced by a known genetic defect; it provides a robust model for the examination of serotoninergic mechanisms in epilepsy.
Subject(s)
Mutation , Receptors, Serotonin/genetics , Seizures/genetics , Acoustic Stimulation , Animals , Brain/metabolism , Brain/pathology , Disease Models, Animal , Escape Reaction , Female , Male , Mice , Mice, Inbred C57BL , Receptor, Serotonin, 5-HT2C , Receptors, Serotonin/metabolism , Seizures/etiology , Seizures/metabolism , SoundABSTRACT
An opportunity sampling of 1,192 children regarding parameters of toilet training and elimination status was obtained by interview and questionnaire. Toilet training ages ranged from 0.75 to 5 years, with a mean of 2.4 +/- 0.6 years (standard deviation). Voiding frequency was inversely related to age; most children between 3 and 12 years old urinated 5 to 6 times per day. Influences of gender, urinary infections and parental recall were investigated. Nocturnal and diurnal enuresis was reported in 18% and 10% of our sample, respectively. Bowel movements per week ranged from 1 to 21, with a mean of 6.8 +/- 2.5.