Prospective memory impairments in Alzheimer's Disease and behavioral variant frontotemporal dementia: Clinical and neural correlates

BACKGROUND: Prospective memory (PM) refers to a future-oriented form of memory in which the individual must remember to execute an intended action either at a future point in time (Time-based) or in response to a specific event (Event-based). Lapses in PM are commonly exhibited in neurodegenerative disorders including Alzheimer's disease (AD) and frontotemporal dementia (FTD), however, the neurocognitive mechanisms driving these deficits remain unknown. OBJECTIVE: To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD). METHODS: Twelve AD, 12 bvFTD, and 12 healthy older Control participants completed a modified version of the Cambridge Prospective Memory test, which examines Time- and Event-based aspects of PM. All participants completed a standard neuropsychological assessment and underwent whole-brain structural MRI. RESULTS: AD and bvFTD patients displayed striking impairments across Time- and Event-based PM relative to Controls, however, Time-based PM was disproportionately affected in the AD group. Episodic memory dysfunction and hippocampal atrophy was found to correlate strongly with PM integrity in both patient groups, however, dissociable neural substrates were also evident for PM performance across dementia syndromes. CONCLUSION: Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient's daily life

Individualized Gaussian process-based prediction and detection of local and global gray matter abnormalities in elderly subjects.

Structural imaging based on MRI is an integral component of the clinical assessment of patients with potential dementia. We here propose an individualized Gaussian process-based inference scheme for clinical decision support in healthy and pathological aging elderly subjects using MRI. The approach aims at quantitative and transparent support for clinicians who aim to detect structural abnormalities in patients at risk of Alzheimer's disease or other types of dementia. Firstly, we introduce a generative model incorporating our knowledge about normative decline of local and global gray matter volume across the brain in elderly. By supposing smooth structural trajectories the models account for the general course of age-related structural decline as well as late-life accelerated loss. Considering healthy subjects' demography and global brain parameters as informative about normal brain aging variability affords individualized predictions in single cases. Using Gaussian process models as a normative reference, we predict new subjects' brain scans and quantify the local gray matter abnormalities in terms of Normative Probability Maps (NPM) and global z-scores. By integrating the observed expectation error and the predictive uncertainty, the local maps and global scores exploit the advantages of Bayesian inference for clinical decisions and provide a valuable extension of diagnostic information about pathological aging. We validate the approach in simulated data and real MRI data. We train the GP framework using 1238 healthy subjects with ages 18-94years, and predict in 415 independent test subjects diagnosed as healthy controls, Mild Cognitive Impairment and Alzheimer's disease

Improved Cardiorespiratory Fitness Is Associated with Increased Cortical Thickness in Mild Cognitive Impairment

Cortical atrophy is a biomarker of Alzheimer’s disease (AD) that correlates with clinical symptoms. This study examined changes in cortical thickness from before to after an exercise intervention in mild cognitive impairment (MCI) and healthy elders. Thirty physically inactive older adults (14 MCI, 16 healthy controls) underwent MRI before and after participating in a 12-week moderate intensity walking intervention. Participants were between the ages of 61 and 88. Change in cardiorespiratory fitness was assessed using residualized scores of the peak rate of oxygen consumption (V̇O2peak) from pre- to post-intervention. Structural magnetic resonance images were processed using FreeSurfer v5.1.0. V̇O2peak increased an average of 8.49%, which was comparable between MCI and healthy elders. Overall, cortical thickness was stable except for a significant decrease in the right fusiform gyrus in both groups. However, improvement in cardiorespiratory fitness due to the intervention (V̇O2peak) was positively correlated with cortical thickness change in the bilateral insula, precentral gyri, precuneus, posterior cingulate, and inferior and superior frontal cortices. Moreover, MCI participants exhibited stronger positive correlations compared to healthy elders in the left insula and superior temporal gyrus. A 12-week moderate intensity walking intervention led to significantly improved fitness in both MCI and healthy elders. Improved V̇O2peak was associated with widespread increased cortical thickness, which was similar between MCI and healthy elders. Thus, regular exercise may be an especially beneficial intervention to counteract cortical atrophy in all risk groups, and may provide protection against future cognitive decline in both healthy elders and MCI

Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer's disease

BACKGROUND Behavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer's disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI). METHODS Thirty-one a-MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1-weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients' behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD. RESULTS Apathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD. CONCLUSIONS This study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia

Comparison of prefrontal atrophy and episodic memory performance in dysexecutive Alzheimer’s disease and behavioural-variant frontotemporal dementia

Alzheimer’s disease (AD) sometimes presents with prominent executive dysfunction and associated prefrontal cortex atrophy. The impact of such executive deficits on episodic memory performance as well as their neural correlates in AD, however, remains unclear. The aim of the current study was to investigate episodic memory and brain atrophy in AD patients with relatively spared executive functioning (SEF-AD; n = 12) and AD patients with relatively impaired executive functioning (IEF-AD; n = 23). We also compared the AD subgroups with a group of behavioral-variant frontotemporal dementia patients (bvFTD; n = 22), who typically exhibit significant executive deficits, and age-matched healthy controls (n = 38). On cognitive testing, the three patient groups showed comparable memory profiles on standard episodic memory tests, with significant impairment relative to controls. Voxel-based morphometry analyses revealed extensive prefrontal and medial temporal lobe atrophy in IEF-AD and bvFTD, whereas this was limited to the middle frontal gyrus and hippocampus in SEF-AD. Moreover, the additional prefrontal atrophy in IEF-AD and bvFTD correlated with memory performance, whereas this was not the case for SEF-AD. These findings indicate that IEF-AD patients show prefrontal atrophy in regions similar to bvFTD, and suggest that this contributes to episodic memory performance. This has implications for the differential diagnosis of bvFTD and subtypes of AD

Diagnostic Utility of Cerebral White Matter Integrity in Early Alzheimer\u27s Disease

We compared white matter integrity with brain atrophy in healthy controls and participants with very mild dementia (Clinical Dementia Rating 0 vs. 0.5) from the Brain Aging Project, a longitudinal study of aging and memory at the University of Kansas Medical Center. Structural magnetic resonance imaging and diffusion tensor imaging (DTI) including fractional anisotropy and mean diffusivity were performed on 27 patients with very mild dementia (Clinical Dementia Rating = 0.5) of the Alzheimer\u27s type (DAT), and 32 cognitively normal subjects. Patient groups were compared across 6 volumetric measures and 14 DTI regions of interest. Very mildly demented patients showed expected disease-related patterns of brain atrophy with reductions in whole-brain and hippocampal volumes most prominent. DTI indices of white matter integrity were mixed. Right parahippocampus showed significant but small disease-related reductions in fractional anisotropy. Right parahippocampus and left internal capsule showed greater mean diffusivity in early DAT compared with controls. A series of discriminant analyses demonstrated that gray matter atrophy was a significantly better predictor of dementia status than were DTI indices. Brain atrophy was most strongly related to very mild DAT. Modest disease-related white matter anomalies were present in temporal cortex, and deep white matter had limited discriminatory diagnostic power, probably because of the very mild stage of disease in these participants

Diagnostic Utility of Cerebral White Matter Integrity in Early Alzheimer's Disease

This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Neuroscience on August 2010, available online: http://www.tandfonline.com/10.3109/00207454.2010.494788.We compared white matter integrity with brain atrophy in healthy controls and participants with very mild dementia (Clinical Dementia Rating 0 vs. 0.5) from the Brain Aging Project, a longitudinal study of aging and memory at the University of Kansas Medical Center. Structural magnetic resonance imaging and diffusion tensor imaging (DTI) including fractional anisotropy and mean diffusivity were performed on 27 patients with very mild dementia (Clinical Dementia Rating = 0.5) of the Alzheimer's type (DAT), and 32 cognitively normal subjects. Patient groups were compared across 6 volumetric measures and 14 DTI regions of interest. Very mildly demented patients showed expected disease-related patterns of brain atrophy with reductions in whole-brain and hippocampal volumes most prominent. DTI indices of white matter integrity were mixed. Right parahippocampus showed significant but small disease-related reductions in fractional anisotropy. Right parahippocampus and left internal capsule showed greater mean diffusivity in early DAT compared with controls. A series of discriminant analyses demonstrated that gray matter atrophy was a significantly better predictor of dementia status than were DTI indices. Brain atrophy was most strongly related to very mild DAT. Modest disease-related white matter anomalies were present in temporal cortex, and deep white matter had limited discriminatory diagnostic power, probably because of the very mild stage of disease in these participants

Magnetic resonance imaging In Alzheimer’s disease, mild cognitive impairment and normal aging : Multi-template tensor-based morphometry and visual rating

Alzheimer's disease (AD) is the most common neurodegenerative disease preceded by a stage of mild cognitive impairment (MCI). The structural brain changes in AD can be detected more than 20 years before symptoms appear. If we are to reveal early brain changes in AD process, it is important to develop new diagnostic methods. Magnetic resonance imaging (MRI) is an imaging technique used in the diagnosis and monitoring of neurodegenerative diseases. Magnetic resonance imaging can detect the typical signs of brain atrophy of degenerative diseases, but similar changes can also be seen in normal aging. Visual rating methods (VRM) have been developed for visual evaluation of atrophy in dementia. A computer-based tensor-based morphometry (TBM) analysis is capable of assessing the brain volume changes typically encountered in AD. This study compared the VRM and TBM analysis in MCI and AD subjects by cross-sectional and longitudinal examination. The working hypothesis was that TBM analysis would be better than the visual methods in detecting atrophy in the brain. TBM was also used to analyze volume changes in the deep gray matter (DGM). Possible associations between TBM changes and neuropsychological tests performances were examined. This working hypothesis was that the structural DGM changes would be associated with impairments in cognitive functions. In the cross-sectional study, TBM distinguished the MCI from controls more sensitively than VRM, but the methods were equally effective in differentiating AD from MCI and controls. In the longitudinal study, both methods were equally good in the evaluation of atrophy in MCI, if the groups were sufficiently large and the disease progressed to AD. Volume changes were found in DGM structures, and the atrophy of DGM structures was related to cognitive impairment in AD. Based on these results, a TBM analysis is more sensitive in detecting brain changes in early AD as compared to VRM. In addition, the study produced information about the involvement of the deep gray matter in cognitive impairment in AD.Magneettikuvaus Alzheimerin taudissa, lievässä muistihäiriössä ja normaalissa ikääntymisessä: Tensoripohjainen muotoanalyysi ja visuaalinen arviointimenetelmä Alzheimerin tauti (AT) on yleisin dementoiva sairaus, jota edeltää yleensä lievä muistitoimintojen heikentyminen. AT:n aivomuutoksia voidaan todeta yli 20 vuotta ennen sairastumista. Jotta vielä varhaisempia AT:n aivomuutoksia voidaan todeta, on tärkeää kehittää uusia diagnostisia menetelmiä. Magneettikuvausta (MK) käytetään rappeuttavien aivosairauksien diagnostiikassa ja seurannassa. MK:lla voidaan havaita aivorappeumasairauksille tyypillistä kutistumista, mutta samanlaisia muutoksia voi esiintyä myös normaalissa ikääntymisessä. Aivorappeuman arviointiin on kehitetty silmämääräisiä arviointimenetelmiä. Tietokoneperusteinen tensoripohjainen muotoanalyysi (TPM) laskee esimerkiksi AT:lle tyypillisiä aivojen tilavuusmuutoksia. Tämä tutkimus vertaili silmämääräisiä arvioitimenetelmiä ja TPM:ä lievässä muistitoimintojen heikentymisessä ja AT:ssa poikittais- ja pitkittäistutkimuksella. TPM:n oletettiin olevan silmämääräisiä menetelmiä parempi tunnistamaan aivojen kutistumismuutoksia. Lisäksi TPM:llä tutkittiin AT:iin liittyviä aivojen syvän harmaan aiheen muutoksia, joita verrattiin neuropsykologisten testien tuloksiin. Syvän harmaan aineen kutistumisen oletettiin olevan yhteydessä tietojenkäsittelyn heikentymiseen. Tulosten perustella TPM tunnisti AT:iin liittyviä aivomuutoksia silmämääräistä menetelmää paremmin jo lievän muistitoimintojen heikentymisen vaiheessa. AT:iin liittyviä aivomuutoksia löytyi myös aivojen syvästä harmaasta aineesta ja ne olivat osittain yhteydessä neuropsykologisten testien tuloksiin. Tutkimuksen perusteella TPM voi parantaa AT:n varhaisdiagnostiikkaa verrattuna silmämääräisiin arviointimenetelmiin. Tutkimus antoi myös tietoa aivojen syvän harmaan aineen osallisuudesta ihmisen tietojenkäsittelyyn