Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program.

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.

Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect.

BACKGROUND: The APOE epsilon4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE epsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown. METHODS: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE epsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE epsilon4 allele, using a mixed model for longitudinal change with age. RESULTS: We analyzed 815 subjects: 317 APOE epsilon4 carriers (79 who were homozygous for the APOE epsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status. CONCLUSIONS: Age-related memory decline in APOE epsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

Neural correlates of heart rate variability during emotion.

The vagal (high frequency [HF]) component of heart rate variability (HRV) predicts survival in post-myocardial infarction patients and is considered to reflect vagal antagonism of sympathetic influences. Previous studies of the neural correlates of vagal tone involved mental stress tasks that included cognitive and emotional elements. To differentiate the neural substrates of vagal tone due to emotion, we correlated HF-HRV with measures of regional cerebral blood flow (rCBF) derived from positron emission tomography (PET) and (15)O-water in 12 healthy women during different emotional states. Happiness, sadness, disgust and three neutral conditions were each induced by film clips and recall of personal experiences (12 conditions). Inter-beat intervals derived from electrocardiographic recordings during the 60-second scans were spectrally-analyzed, generating 12 separate measures of HF-HRV in each subject. The six emotion and six neutral conditions were grouped together and contrasted. We observed substantial overlap between emotion-specific rCBF and the correlation between emotion-specific rCBF and HF-HRV, particularly in the medial prefrontal cortex. Emotion-specific rCBF also correlated with HF-HRV in the caudate nucleus, periacqueductal gray and left mid-insula. We also observed that the elements of cognitive control inherent in this experiment (that involved focusing on the target mental state) had definable neural substrates that correlated with HF-HRV and to a large extent differed from the emotion-specific correlates of HF-HRV. No statistically significant asymmetries were observed. Our findings are consistent with the view that the medial visceromotor network is a final common pathway by which emotional and cognitive functions recruit autonomic support.

The role of anterior and midcingulate cortex in emotional awareness: A domain-general processing perspective.

The cingulate cortex has been implicated in a wide range of overlapping cognitive, affective, skeletomotor, and visceromotor functions. In this chapter, we focus on the role of the anterior and midcingulate cortex (ACC and MCC) in facilitating a person's ability to recognize and understand his or her own emotions. Here, we illustrate how this ability-often referred to as "emotional awareness" (EA)-may require integration across each of the aforementioned functions. To appropriately situate the role of the cingulate in EA, we first summarize a number of studies that have highlighted ACC/MCC engagement in the context of emotion. We then describe prominent domain-general views of the ACC (in interaction with MCC), which together suggest that it may serve as a hub within a high-level visceromotor control system. This high-level system functions to predict and mobilize the required metabolic resources in a given situation via the integration of multimodal information available from both sensory cortices and memory. Based on this work, we show that EA can be seen as an important consequence of this integrative process and how it can help to explain the adaptive nature of such advanced emotional capacities. We close by briefly considering the potential clinical relevance of understanding ACC/MCC function and its specific role in emotion and awareness.

Faster cognitive decline in dementia due to Alzheimer disease with clinically undiagnosed Lewy body disease.

BACKGROUND: Neuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimer's disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimer's disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course. METHODS: Subjects with dementia included those with "pure" ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination. RESULTS: Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group (ß = -0.69, 95% CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not (ß = -0.30, 95% CI: -0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66% and 2.1%, respectively, had been diagnosed with LBD at any point during their clinical course. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013). CONCLUSIONS: The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success.

Time from ictal subdural EEG seizure onset to clinical seizure onset: an electrocorticographic time factor associated with temporal lobe epileptogenicity.

Long-term subdural video/electroencephalographic (EEG) monitoring was performed in a series of patients with medically intractable complex partial seizures, in a study of diagnostic accuracy, to test the hypothesis that the time from ictal subdural EEG seizure onset to clinical seizure onset (ECOT) is correlated with temporal lobe epileptogenicity and confirm measures of validity of ECOT for predicting seizure-free outcome following anterior temporal lobectomy and amygdalohippocampectomy (ATL/AH). In 34 patients with refractory temporal lobe epilepsy, subdural EEG monitoring localized the ictal epileptogenic focus to a single temporal lobe. In each patient, ECOT was analysed for correlation with temporal lobe epileptogenicity as measured by seizure interval in hours. Patients in whom ECOT was equal to or less than the mean (i.e. subdural EEG seizure onset preceding clinical seizure onset by at least 11.7 seconds) had a significantly greater likelihood of becoming seizure-free following ATL/AH compared to patients in whom ECOT was greater than the mean (i.e. subdural EEG seizure onset preceding clinical seizure onset by less than 11.7 seconds) (x(2) = 5.78, p<0.05). The validity of ECOT for predicting seizure-free outcome following ATL/AH is confirmed to have sensitivity of 55.0%, specificity of 85.7%, false positive rate of 15.4%, false negative rate of 42.9%, diagnostic value of 84.6% and diagnostic accuracy of 67.6%. In addition, a significant correlation, described by a second order polynomial relationship, was found between the natural exponential function of ECOT and seizure interval [f(x=0.415x(2) -25.554x + 267.036, r= 0.731, df= 32, t =6.05, p<0.001, where f(x)=e(ECOT) and x= seizure interval). This result provides the epileptologist with a quantitative tool capable of predicting seizure interval based on ECOT. The capability of ECOT to predict seizure interval may allow the patient and epileptologist to anticipate future seizure onset based on ECOT, potentially facilitating accurate timing of ictal seizure focus localization techniques and clinical intervention to abort seizure onset using various available central and peripheral nervous system stimulation therapeutic strategies. The results suggest a relationship between ECOT and seizure interval. Fundamental pathophysiologic processes involved in the transition from ictal EEG to clinical seizure onset may be responsible for temporal lobe epileptogenicity.

Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment.

Mitochondrial abnormalities are found in Alzheimer's disease (AD), but previous reports have not examined at-risk groups. In subjects with AD, mild cognitive impairment (MCI), and non-demented aged controls, platelet and lymphocyte mitochondria were isolated and analyzed for Complexes I, III, and IV of the electron transport chain. Western blots were used to control for differential enrichment of samples. Results demonstrated significant declines in Complexes III and IV in AD, and a significant decline in Complex IV in MCI. This report confirms mitochondrial deficiencies in AD, extends them to MCI, and suggests they are present at the earliest symptomatic stages of disease.

Correlation of electrocorticographic to clinical seizure onset and interhemispheric propagation times in temporal lobe epilepsy.

This study was performed to test the hypothesis that, in human temporal lobe epilepsy, electrocorticographic time factors involved in the ictal EEG to clinical ictal transition (electrocorticographic to clinical seizure onset time, ECOT) and the interhemispheric propagation of epileptic activity (interhemispheric propagation time, IHPT), which are independently correlated with temporal lobe epileptogenicity and predictive of seizure-free outcome following temporal lobectomy, are correlated with one another in a quantitative fashion. A series of 37 patients with medically intractable temporal lobe seizures was studied with long-term subdural videoelectroencephalographic monitoring. Temporal lobe seizure interhemispheric propagation time (IHPT) was found to be a negative, exponential function of electrocorticographic to clinical seizure onset time (ECOT) (f(x)=8.201x10(-0.016x), r=0.347, d.f.=35, t=2.19, p<0.05, where f(x)=IHPT and x=ECOT). A small increase in ECOT was associated with a substantial decrease in IHPT and vice versa. The results suggest the electrophysiological time factor, ECOT, involved in the transition from ictal EEG seizure onset to clinical seizure onset, may determine the speed of interhemispheric propagation of established epileptic activity. The results suggest the interesting hypothesis that, in human temporal lobe epilepsy and, perhaps, under non-pathological circumstances, the human temporal lobe might possess a "time-labeling" function amenable to quantitative analysis.

Gender Differences in Alzheimer Disease: Brain Atrophy, Histopathology Burden, and Cognition.

Multiple studies suggest that females are affected by Alzheimer disease (AD) more severely and more frequently than males. Other studies have failed to confirm this and the issue remains controversial. Difficulties include differences in study methods and male versus female life expectancy. Another element of uncertainty is that the majority of studies have lacked neuropathological confirmation of the AD diagnosis. We compared clinical and pathological AD severity in 1028 deceased subjects with full neuropathological examinations. The age of dementia onset did not differ by gender but females were more likely to proceed to very severe clinical and pathological disease, with significantly higher proportions having a Mini-Mental State Examination score of 5 or less and Braak stage VI neurofibrillary degeneration. Median neuritic plaque densities were similar in females and males with AD but females had significantly greater tangle density scores. In addition, we found that AD-control brain weight differences were significantly greater for females, even after adjustment for age, disease duration, and comorbid conditions. These findings suggest that when they are affected by AD, females progress more often to severe cognitive dysfunction, due to more severe neurofibrillary degeneration, and greater loss of brain parenchyma.

Prognostic value of concordant seizure focus localizing data in the selection of temporal lobectomy candidates.

This study was performed to test the hypotheses that (a) resection of the temporal lobe epileptic focus, amenable to noninvasive as opposed to invasive localization, is associated with superior seizure outcome and (b) that quadruple (versus lesser degrees of) concordance of seizure focus localizing data predicts superior seizure-free outcome. Eighty-three patients underwent invasive (subdural-EEG) and/or noninvasive (video/scalp-EEG, SPECT, PET, MRI, neuropsychological testing) evaluation. All patients underwent anterior temporal lobectomy and amygdalohippocampectomy (ATL/AH) and seizure outcome was assessed at minimum one-year follow-up. At 34.8 +/- 2.5 months following ATL/AH, outcome was superior for patients in whom the seizure focus was amenable to noninvasive compared to invasive localization (80% versus 40% seizure-free, X2 = 14.03, p < 0.05). Seizure outcome was superior for patients with quadruple, compared to all lesser degrees of, concordance of seizure focus localizing data (85% versus 51% seizure-free, X2 = 7.34, p < 0.05). Post-ATL/AH, seizure outcome is superior in patients (1) harboring an epileptic focus amenable to noninvasive localization and (2) with quadruple concordance of seizure focus localizing data. These findings support the development of temporal lobectomy selection criteria including up to four invasive and/or noninvasive concordant seizure focus localizing techniques.

Integration of Perceptual and Mnemonic Dysfunction: Sensory Auras Are Associated with Left Hemispheric Memory Impairment.

Memory function during the intracarotid amobarbital test was studied to test the hypothesis that left hemisphere memory impairment is associated with sensory auras. In a series of 37 patients undergoing preoperative evaluation for epilepsy surgery, the quantitative memory scores during amobarbital inactivation of right and left hemisphere were analyzed for correlation with habitual epileptic auras classified as either (a) experiential, forced emotion, or whole-body dysphoria or (b) sensory hallucinations and/or illusions or localized dysesthesias. The left hemispheric memory score impairment was significantly worse in association with auras classified as sensory hallucinations and/or illusions or localized dysesthesias compared with auras classified as experiential, forced emotion, or whole-body dysphoria (P < 0.05). This finding may assist in predicting left-sided hemispheric memory dysfunction in patients with seizures beginning as auras involving sensory material. The results suggest an integration of perceptual and mnemonic dysfunction in which sensory auras are associated with left hemispheric memory impairment.

Normalization of periictal bihemispheric cerebral perfusion in temporal lobe epilepsy.

Under normal circumstances, cerebral blood flow (CBF), between the two hemispheres is coupled in a direct (i.e. positive slope), linear fashion. However, in temporal lobe epilepsy, the relationship between the two temporal cortices, during the interictal and postictal periods, is the inverse of normal (i.e. correlation is with negative slope and linear). Long-term combined temporal lobe thermal diffusion flowmetry (TDF) subdural regional cerebral blood flow and electroencephalographic (EEG) recording was performed to test the hypothesis that, during the 10min periictal period (i.e. 5min before and 5min following clinical seizure onset), the cerebral perfusion relationship between epileptic and nonepileptic cortex returns to normal (i.e. becomes direct, with positive slope, and linear). A consecutive series of 13 patients with complex partial epilepsy was studied. During continuous monitoring of clinical phenomenology in time sequence with subdural CBF/EEG, the 10min periictal period was characterized by a direct, linear correlation between epileptic and nonepileptic temporal cortical blood flow ( [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] ). The fact that this pertubation in the CBF relationship between the bilateral temporal cortices begins prior to and continues for 5min following clinical and subdural EEG seizure onset raises the interesting possibility that normalization of periictal bilateral cerebral perfusion may be associated with temporal lobe epileptogenesis.

Neurologic consultation for seizures. When, why, and how to pursue.

Primary care physicians can successfully manage seizure in many patients who respond well to initial antiepileptic drug therapy. However, management of recurrent seizures is often complex and best accomplished by consultation with a neurologist or epilepsy specialist. In this article, Drs Labiner and Ahern discuss the issues involved in evaluation and treatment of seizure and offer a model for working with general neurologists and specialized epilepsy centers.

Age-related differences in prefrontal control of heart rate in humans: a pharmacological blockade study.

The Neurovisceral Integration Model is based on the premise of significant central nervous system-peripheral nervous system interactions. In support of this model we have previously shown that the prefrontal cortex tonically inhibits cardioacceleratory circuits as evidenced by increased heart rate (HR) when the prefrontal cortex is inactivated by injections of sodium amobarbitol (ISA) into the internal carotid artery. In this report we re-examine these data to investigate possible age-related differences in the prefrontal control of HR in humans. Seventy-three patients were divided into three groups based on a tertile split with mean ages of 20, 34, and 47, respectively. There were significant age-related differences in cortical control of HR as evidenced by a significant three way interaction of age (young, middle, old) by side (left versus right) by time (baseline and epochs 1-10 of inactivation) [Roy's Root (10,59)=0.378, p=0.028]. Results showed significant HR increases that did not differ between hemispheres in the youngest age group, significant increases in the middle age group that were larger in the right hemisphere than in the left, and significant HR increases in the oldest group in the right hemisphere only. The findings suggest important age-related differences in cortical inhibitory control of HR that appear less lateralized in the youngest group and significantly attenuated in the oldest age group. These results have important implications for the understanding of age-related differences in cognitive, affective, behavioral, and physiological functioning. In addition they support the importance of investigating central nervous system-peripheral nervous system relationships.

Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings.

Vagus nerve stimulation (VNS) therapy is an effective adjunctive treatment for chronic or recurrent treatment-resistant depression in adults, and for pharmacoresistant epilepsy in adults and adolescents. VNS therapy is administered through an implanted pulse generator that delivers programmed electrical pulses through an implanted lead to the left vagus nerve. Programmable pulse parameters include output current, frequency, pulse width, and ON/OFF times. Within a range of typical values, individual patients respond best to different combinations of parameter settings. The physician must identify the optimum settings for each patient while balancing the goals of maximizing efficacy, minimizing side effects, and preserving battery life. Output current is gradually increased from 0.25 mA to the maximum tolerable level (maximum, 3.5 mA); typical therapeutic settings range from 1.0 to 1.5 mA. Greater output current is associated with increased side effects, including voice alteration, cough, a feeling of throat tightening, and dyspnea. Frequency is typically programmed at 20 Hz in depression and 30 Hz in epilepsy. Pulse width is typically 250 or 500 micros. The recommended initial ON time is 30 s, followed by 5 min OFF; OFF time > ON time is recommended. As with pharmacotherapy, VNS therapy must be adjusted in a gradual, systematic fashion to individualize therapy for each patient.