Angiotensin I converting enzyme polymorphism effects in patients with normal pressure hydrocephalus syndrome before and after surgery.

Previous reports have suggested an association between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE), cardiovascular disease, and cognitive performance. Normal pressure hydrocephalus (NPH) is considered to be an example of reversible dementia although the clinical improvement after shunting varies from subject to subject. An association has been suggested between vascular risk factors and the development of NPH. The ACE plays a major role in vascular pathology and physiology. In the present study we investigated the distribution of an ACE gene insertion/deletion polymorphism in 112 patients diagnosed with NPH and in 124 controls. We also evaluated the role of this genetic polymorphism in cognitive functioning before and following surgery in a subgroup of 72 patients. No differences in genetic or allele distributions were found between patients and healthy subjects, but among patients, carriers of D/D or D/I genotypes obtained less cognitive benefit following shunt surgery, especially on measures of memory and frontal function. Our data support previous findings in other conditions indicating that possession of at least one D allele is associated with poorer cognitive performance.

Neurochemical Modulation in Posteromedial Default-mode Network Cortex Induced by Transcranial Magnetic Stimulation.

BACKGROUND: The Default Mode Network (DMN) is severely compromised in several psychiatric and neurodegenerative disorders where plasticity alterations are observed. Glutamate and GABA are the major excitatory and inhibitory brain neurotransmitters respectively and are strongly related to plasticity responses and large-scale network expression. OBJECTIVE: To investigate whether regional Glx (Glutamate + Glutamine) and GABA could be modulated within the DMN after experimentally-controlled induction of plasticity and to study the effect of intrinsic connectivity over brain responses to stimulation. METHODS: We applied individually-guided neuronavigated Theta Burst Stimulation (TBS) to the left inferior parietal lobe (IPL) in-between two magnetic resonance spectroscopy (MRS) acquisitions to 36 young subjects. A resting-state fMRI sequence was also acquired before stimulation. RESULTS: After intermittent TBS, distal GABA increases in posteromedial DMN areas were observed. Instead, no significant changes were detected locally, in left IPL areas. Neurotransmitter modulation in posteromedial areas was related to baseline fMRI connectivity between this region and the TBS-targeted area. CONCLUSIONS: The prediction of neurotransmitter modulation by connectivity highlights the relevance of connectivity patterns to understand brain responses to plasticity-inducing protocols. The ability to modulate GABA in a key core of the DMN by means of TBS may open new avenues to evaluate plasticity mechanisms in a key area for major neurodegenerative and psychiatric conditions.

Dopamine DRD2 Taq I polymorphism associates with caudate nucleus volume and cognitive performance in memory impaired subjects.

We studied the relationship among dopamine receptor D2 (DRD2) Taq I genetic polymorphism, caudate nucleus volumetry as measured using MRI and neuropsychological functions in 49 memory impaired older people. Compared with DRD2 A1 carriers, subjects homozygous for the DRD2 A2 allele performed poorer in a measure of general cognitive functioning (MMSE) and in long term verbal memory, and presented reduced left caudate nucleus volumes. Caudate nucleus atrophy correlated with cognitive measures influenced by the genetic polymorphism and with visual memory performance. Our findings suggest that among the aged with cognitive impairments, the homozygous status for the A2 allele of the DRD2 Taq I polymorphism is associated with diminished cognitive performance and increased atrophy in the striatum.

Relationship among (1)H-magnetic resonance spectroscopy, brain volumetry and genetic polymorphisms in humans with memory impairment.

We investigated the relationship among neuroanatomical, neurochemical and genetic variables in 44 subjects with age-related memory impairment. Hydrogen magnetic resonance spectroscopy was used to determine N-acetyl/creatine (NAA/Cr) concentrations in basal ganglia and medial temporal regions. Volumetric measures were obtained for caudate nucleus and hippocampus. Genetic polymorphisms examined included apolipoproteins (APO) E and CI, angiotensin converting enzyme and dopamine D2 receptor TaqI genes. Age was found to be negatively correlated with hippocampal and basal ganglia volumes, but not with neurochemical values. Multiple regression analyses showed that the APOC1 polymorphism was the only variable which predicted NAA/Cr values in basal ganglia. NAA/Cr metabolites in the medial temporal lobe but not in the basal ganglia region were related with lower performance in verbal memory.

Task-dependent activity and connectivity predict episodic memory network-based responses to brain stimulation in healthy aging.

BACKGROUND: Transcranial magnetic stimulation (TMS) can affect episodic memory, one of the main cognitive hallmarks of aging, but the mechanisms of action remain unclear. OBJECTIVES: To evaluate the behavioral and functional impact of excitatory TMS in a group of healthy elders. METHODS: We applied a paradigm of repetitive TMS - intermittent theta-burst stimulation - over left inferior frontal gyrus in healthy elders (n = 24) and evaluated its impact on the performance of an episodic memory task with two levels of processing and the associated brain activity as captured by a pre and post fMRI scans. RESULTS: In the post-TMS fMRI we found TMS-related activity increases in left prefrontal and cerebellum-occipital areas specifically during deep encoding but not during shallow encoding or at rest. Furthermore, we found a task-dependent change in connectivity during the encoding task between cerebellum-occipital areas and the TMS-targeted left inferior frontal region. This connectivity change correlated with the TMS effects over brain networks. CONCLUSIONS: The results suggest that the aged brain responds to brain stimulation in a state-dependent manner as engaged by different tasks components and that TMS effect is related to inter-individual connectivity changes measures. These findings reveal fundamental insights into brain network dynamics in aging and the capacity to probe them with combined behavioral and stimulation approaches.

Thalamic diffusion differences related to cognitive function in white matter lesions.

Cerebral white matter lesions (WMLs) are related to cognitive deficits, probably due to a disruption of frontal-subcortical circuits. We explored thalamic diffusion differences related to white matter lesions (WMLs) and their association with cognitive function in middle-aged individuals. Ninety-six participants from the Barcelona-AsIA Neuropsychology Study were included. Participants were classified into groups based on low grade and high grade of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs). Tract-Based Spatial Statistics was used to study thalamic diffusion differences between groups. Mean fractional anisotropy (FA) values in significant areas were calculated for each subject and correlated with cognitive performance. Participants with high-grade PVHs and DWMHs showed lower FA thalamic values compared to those with low-grade PVHs and DWMHs, respectively. Decreased FA thalamic values in high-grade DWMHs, but not high-grade PVH, were related to lower levels of performance in psychomotor speed, verbal fluency, and visuospatial skills. Thalamic diffusion differences are related to lower cognitive function only in participants with high-grade DWMHs. These results support the hypothesis that fronto-subcortical disruption is associated with cognitive function only in DWMHs.

Remote thalamic microstructural abnormalities related to cognitive function in ischemic stroke patients.

OBJECTIVE: Ischemic stroke can lead to a continuum of cognitive sequelae, ranging from mild vascular cognitive impairment to vascular dementia. These cognitive deficits can be influenced by the disruption of cortico-subcortical circuits. We sought to explore remote thalamic microstructural abnormalities and their association with cognitive function after ischemic stroke. METHOD: Seventeen patients with right hemispheric ischemic stroke and 17 controls matched for age, sex, and years of education were included. All participants underwent neurological, neuropsychological, and diffusion tensor image examination. Patients were assessed 3 months poststroke. Voxel-wise analysis was used to study thalamic diffusion differences between groups. Mean fractional anisotropy (FA) and mean diffusivity (MD) values in significant thalamic areas were calculated for each subject and correlated with cognitive performance. RESULTS: Stroke patients showed lower FA values and higher MD values in specific areas of both the left and right thalamus compared with controls. In patients, decreased FA values were associated with lower verbal fluency performance in the right thalamus (R(2) = 0.45, ß = 0.74) and the left thalamus (R(2) = 0.57, ß = 0.77) after adjusting for diabetes mellitus. Moreover, increased MD values were associated with lower verbal fluency performance in the right thalamus (R(2) = 0.27, ß = -0.54) after adjusting for diabetes mellitus. In controls, thalamic FA and MD values were not related to any cognitive function. CONCLUSION: Our findings support the hypothesis that ischemic stroke lesions are associated with remote thalamic diffusion abnormalities, and that these abnormalities can contribute to cognitive dysfunction 3 months after a cerebrovascular event.

APOE status modulates the changes in network connectivity induced by brain stimulation in non-demented elders.

Behavioral consequences of a brain insult represent an interaction between the injury and the capacity of the rest of the brain to adapt to it. We provide experimental support for the notion that genetic factors play a critical role in such adaptation. We induced a controlled brain disruption using repetitive transcranial magnetic stimulation (rTMS) and show that APOE status determines its impact on distributed brain networks as assessed by functional MRI (fMRI).Twenty non-demented elders exhibiting mild memory dysfunction underwent two fMRI studies during face-name encoding tasks (before and after rTMS). Baseline task performance was associated with activation of a network of brain regions in prefrontal, parietal, medial temporal and visual associative areas. APOE ε4 bearers exhibited this pattern in two separate independent components, whereas ε4-non carriers presented a single partially overlapping network. Following rTMS all subjects showed slight ameliorations in memory performance, regardless of APOE status. However, after rTMS APOE ε4-carriers showed significant changes in brain network activation, expressing strikingly similar spatial configuration as the one observed in the non-carrier group prior to stimulation. Similarly, activity in areas of the default-mode network (DMN) was found in a single component among the ε4-non bearers, whereas among carriers it appeared disaggregated in three distinct spatiotemporal components that changed to an integrated single component after rTMS.Our findings demonstrate that genetic background play a fundamental role in the brain responses to focal insults, conditioning expression of distinct brain networks to sustain similar cognitive performance.

Brain structure and function related to cognitive reserve variables in normal aging, mild cognitive impairment and Alzheimer's disease.

Cognitive reserve (CR) is the brain's capacity to cope with cerebral damage to minimize clinical manifestations. The 'passive model' considers head or brain measures as anatomical substrates of CR, whereas the 'active model' emphasizes the use of brain networks effectively. Sixteen healthy subjects, 12 amnestic mild cognitive impairment (MCI) and 16 cases with mild Alzheimer's disease (AD) were included to investigate the relationships between proxies of CR and cerebral measures considered in the 'passive' and 'active' models. CR proxies were inferred premorbid IQ (WAIS Vocabulary test), 'education-occupation', a questionnaire of intellectual and social activities and a composite CR measure. MRI-derived whole-brain volumes and brain activity by functional MRI during a visual encoding task were obtained. Among healthy elders, higher CR was related to larger brains and reduced activity during cognitive processing, suggesting more effective use of cerebral networks. In contrast, higher CR was associated with reduced brain volumes in MCI and AD and increased brain function in the latter, indicating more advanced neuropathology but that active compensatory mechanisms are still at work in higher CR patients. The right superior temporal gyrus (BA 22) and the left superior parietal lobe (BA 7) showed greatest significant differences in direction of slope with CR and activation between controls and AD cases. Finally, a regression analysis revealed that fMRI patterns were more closely related to CR proxies than brain volumes. Overall, inverse relationships for healthy and pathological aging groups emerged between brain structure and function and CR variables.

Repetitive transcranial magnetic stimulation effects on brain function and cognition among elders with memory dysfunction. A randomized sham-controlled study.

In the present study, we aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on memory performance and brain activity in elders presenting with subjective memory complaints and a memory performance within the low normal range. Forty participants underwent 2 functional magnetic resonance imaging (fMRI) sessions, in which they were administered 2 equivalent face-name memory tasks. Following each fMRI, subjects were asked to pair faces with their corresponding proper name. In-between, high-frequency rTMS was applied randomly using real or sham stimulation in a double-blind design. Only subjects who received active rTMS improved in associative memory significantly. This was accompanied by additional recruitment of right prefrontal and bilaterial posterior cortical regions at the second fMRI session, relative to baseline scanning. Our findings reflect a potentiality of rTMS to recruit compensatory networks, which participate during the memory-encoding process. Present results represent the first evidence that rTMS is capable of transitorily and positively influencing brain function and cognition among elders with memory complaints.

Apolipoprotein E gender effects on cognitive performance in age-associated memory impairment.

Among 100 individuals with age-associated memory impairment (AAMI), APOE E4 carriers performed worse on memory. However, when subjects were considered by gender, this effect was only observed in females. APOE E4 may have a more robust cognitive influence on female than on male individuals with AAMI.

Marcadores genéticos relacionados con el déficit cognitivo en el envejecimiento / Genetic markers for cognitive decline in the elderly

En el presente trabajo se revisan estudios realizados en relación a los marcadores genéticos de vulnerabilidad al deterioro cognitivo en el envejecimiento. En concreto, se estudia el papel de varios polimorfismos genéticos en las entidades de Alteración de la Memoria Asociada a la Edad (AAMI, del inglés Age Associated Memory Impairment) y Alteración Cognitiva Leve (MCI, del inglés Mild Cognitive Impairment), por ser condiciones de alto riesgo para el desarrollo de demencia. Existen diversos genes candidatos cuyas variaciones parecen modular algún aspecto del funcionamiento cognitivo, estructura o actividad cerebral en el envejecimiento. Estas variaciones genéticas son, entre otras, las de los genes codificantes para: apolipoproteínas E y C1, enzima convertidor de angiotensina I (ACE), óxido nítrico sintetasa endotelial o tipo 3 (NOS3), receptores D2 de la dopamina (DRD2) y 2A de la serotonina (5HT2A). El campo de la genética de la conducta en el envejecimiento precisa beneficiarse de futuros avances metodológicos para investigar con mayor fiabilidad la asociación de variaciones genéticas con la función neuropsicológica (AU)