Neuropsychiatric symptoms in Alzheimer's disease are related to functional connectivity alterations in the salience network

Neuropsychiatric syndromes are highly prevalent in Alzheimer's disease (AD), but their neurobiology is not completely understood. New methods in functional magnetic resonance imaging, such as intrinsic functional connectivity or “resting‐state” analysis, may help to clarify this issue. Using such approaches, alterations in the default‐mode and salience networks (SNs) have been described in Alzheimer's, although their relationship with specific symptoms remains unclear. We therefore carried out resting‐state functional connectivity analysis with 20 patients with mild to moderate AD, and correlated their scores on neuropsychiatric inventory syndromes (apathy, hyperactivity, affective syndrome, and psychosis) with maps of connectivity in the default mode network and SN. In addition, we compared network connectivity in these patients with that in 17 healthy elderly control subjects. All analyses were controlled for gray matter density and other potential confounds. Alzheimer's patients showed increased functional connectivity within the SN compared with controls (right anterior cingulate cortex and left medial frontal gyrus), along with reduced functional connectivity in the default‐mode network (bilateral precuneus). A correlation between increased connectivity in anterior cingulate cortex and right insula areas of the SN and hyperactivity syndrome (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) was found. These findings demonstrate an association between specific network changes in AD and particular neuropsychiatric symptom types. This underlines the potential clinical significance of resting state alterations in future diagnosis and therapy. Hum Brain Mapp 35:1237–1246, 2014. © 2013 Wiley Periodicals, Inc.     

Regional analysis of striatal and cortical amyloid deposition in patients with Alzheimer's disease

We aimed to analyse the detailed distribution pattern of amyloid‐β (Aβ) in the striatum, and to examine whether there is any correlation between Aβ deposition levels in the striatum and cortical regions. Twenty patients with Alzheimer's disease underwent positron emission tomography using ¹¹C‐Pittsburgh Compound B (¹¹C‐PiB) to quantify the Aβ deposition. Volumes‐of‐interest analyses were performed on the ventral striatum (VST), pre‐commissural dorsal caudate (pre‐DCA), post‐commissural caudate (post‐CA), pre‐commissural dorsal putamen (pre‐DPU), and post‐commissural putamen (post‐PU), followed by exploratory voxel‐wise analyses. Volumes‐of‐interest analyses of ¹¹C‐PiB binding showed: VST > pre‐DPU (P = 0.004), VST > pre‐DCA (P < 0.0001), pre‐DPU > post‐PU (P < 0.0001), and pre‐DCA > post‐CA (P < 0.0001), consistent with visual inspection of the ¹¹C‐PiB images. Exploratory voxel‐wise analyses of ¹¹C‐PiB binding showed a positive correlation between the VST and the medial part of the orbitofrontal area (P < 0.01 family‐wise error corrected). This study confirmed that there were ventral > dorsal, and anterior > posterior gradients of Aβ deposition in patients with Alzheimer's disease, and provided the first evidence of a robust correlation between Aβ deposition levels in the VST and the medial part of the orbitofrontal area. There are well‐known anatomical and functional links between these areas. These findings indicated that brain Aβ deposition was not randomly distributed, but had characteristic patterns related to anatomical connectivity and/or functional networks.     

Death‐associated protein kinase (DAPK1) in cerebral cortex of late‐onset Alzheimer's disease patients and aged controls

A. H. Hainsworth, R. C. Allsopp, A. Jim, J. F. Potter, J. Lowe, C. J. Talbot and R. J. Prettyman (2010) Neuropathology and Applied Neurobiology 36, 17–24
Death‐associated protein kinase (DAPK1) in cerebral cortex of late‐onset Alzheimer's disease patients and aged controls Aims: Here our objective was to detect the pro‐apoptotic serine/threonine kinase death‐associated protein kinase (DAPK1) in aged human cerebral cortex and to test the hypothesis that DAPK1 abundance is associated with late‐onset Alzheimer's disease (AD). Methods: Using Western analysis and immunohistochemistry we evaluated post mortem frontal cerebral cortex from patients with severe AD (mean age 76 years, range 66–91, n = 11, all male), and from control cases without serious central nervous system illness (mean age 77 years, range 61–95, n = 12, all male). We also examined brains of Tg2576 transgenic mice (males, aged 16–21 months), a model for chronic amyloid‐induced brain injury. Results: Immunohistochemical labelling showed DAPK1 expression in cortical neurones of human cortex and axonal tracts within subcortical white matter, both in AD and in control brains. Western analysis confirmed DAPK1 expression in all samples, although expression was very low in some control cases. DAPK1 abundance in the AD group was not significantly different from that in controls (P = 0.07, Mann–Whitney test). In brains of Tg2576 mice DAPK1 abundance was very similar to that in wild‐type littermates (P = 0.96, Mann–Whitney test). Conclusion: We found that DAPK1 was expressed in neurones of aged human frontal cortex, both in AD and in control cases.     

Hippocampal shape alterations are associated with regional Aβ load in cognitively normal elderly individuals

Aβ deposition is a driving force of Alzheimer's disease pathology and can be detected early by amyloid positron emission tomography. Identifying presymptomatic structural brain changes associated with Aβ deposition might lead to a better understanding of its consequences and provide early diagnostic information. In this respect we analyzed measures of cortical thickness and subcortical volumes along with hippocampal, thalamic and striatal shape and surface area by applying novel analysis strategies for structural magnetic resonance imaging. We included 69 cognitively normal elderly subjects after careful clinical and neuropsychological workup. Standardized uptake value ratios (cerebellar reference) for uptake of 11‐C‐Pittsburgh Compound B (PiB) were calculated from positron emission tomographic data for a cortical measurement and for bilateral hippocampus, thalamus and striatum. Associations to shape, surface area, volume and cortical thickness were tested using regression models that included significant predictors as covariates. Left anterior hippocampal shape was associated with regional PiB uptake (P < 0.05, FDR corrected), whereas volumes of the hippocampi and their subregions were not associated with cortical or regional PiB uptake (all P > 0.05, FDR corrected). Within the entorhinal cortical region of both hemispheres, thickness was negatively associated with cortical PiB uptake (P < 0.05, FDR corrected). Hence, localized shape measures and cortical thickness may be potential biomarkers of presymptomatic Alzheimer's disease.     

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease

Neuropsychiatric symptoms (NPSs) often occur in early‐age‐of‐onset Alzheimer's disease (EOAD) and cluster into sub‐syndromes (SSy). The aim of this study was to investigate the association between ¹⁸F‐FDG‐PET regional and connectivity‐based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective, and psychotic SSy). Eighty‐five percent of EOAD showed at least one NPS. Voxel‐wise correlations between SSy scores and brain glucose metabolism (assessed with ¹⁸F‐FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N = 51) and Healthy Controls (N = 57). The apathetic, hyperactivity, and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision‐making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. Hum Brain Mapp 37:4234–4247, 2016. © 2016 Wiley Periodicals, Inc.     

A patient with Alzheimer's disease complicated by elderly‐onset Cushing's syndrome who had undergone surgical treatment for adrenocorticotropic hormone‐independent macronodular adrenal hyperplasia

Cushing's syndrome (CS) is a rare disorder, especially in older people. Loss of brain volume and neurocognitive impairment of varying degrees has been demonstrated in patients with CS. However, there is a large difference between the median age of presentation of CS and that of Alzheimer's disease. We herein report a case of a patient with Alzheimer's disease complicated by elderly‐onset CS who had undergone surgical treatment for adrenal hyperplasia. Surgical correction of hypercortisolism seems to have slowed the progression of brain volume loss and cognitive dysfunction and improved psychiatric symptoms such as visual hallucination, restlessness, and psychomotor excitement. These improvements have remarkably reduced the burden on the patient's caregivers. The present case suggests that subclinical CS may be present, particularly in rapidly progressive dementia, and that surgical treatment of CS for neuropsychiatric symptoms is useful.     

Ventral striatal network connectivity reflects reward learning and behavior in patients with Parkinson's disease

A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward‐driven behaviors, which can result in life‐altering morbidity. The mesocorticolimbic dopamine network guides reward‐motivated behavior; however, its role in this treatment‐related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward‐learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD‐fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex‐matched PD patients with (n = 19) or without (n = 18) ICB. An incentive‐based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole‐brain voxelwise analyses and region‐of‐interest‐based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala‐to‐midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum‐to‐subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment‐avoidance learning. These data indicate that PD‐ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward‐based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509–521, 2018. © 2017 Wiley Periodicals, Inc.     

Neural correlates of attention‐executive dysfunction in lewy body dementia and Alzheimer's disease

Attentional and executive dysfunction contribute to cognitive impairment in both Lewy body dementia and Alzheimer's disease. Using functional MRI, we examined the neural correlates of three components of attention (alerting, orienting, and executive/conflict function) in 23 patients with Alzheimer's disease, 32 patients with Lewy body dementia (19 with dementia with Lewy bodies and 13 with Parkinson's disease with dementia), and 23 healthy controls using a modified Attention Network Test. Although the functional MRI demonstrated a similar fronto‐parieto‐occipital network activation in all groups, Alzheimer's disease and Lewy body dementia patients had greater activation of this network for incongruent and more difficult trials, which were also accompanied by slower reaction times. There was no recruitment of additional brain regions or, conversely, regional deficits in brain activation. The default mode network, however, displayed diverging activity patterns in the dementia groups. The Alzheimer's disease group had limited task related deactivations of the default mode network, whereas patients with Lewy body dementia showed heightened deactivation to all trials, which might be an attempt to allocate neural resources to impaired attentional networks. We posit that, despite a common endpoint of attention‐executive disturbances in both dementias, the pathophysiological basis of these is very different between these diseases. Hum Brain Mapp 37:1254–1270, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc .     

Gender differences in healthy aging and Alzheimer's Dementia: A 18F‐FDG‐PET study of brain and cognitive reserve

Cognitive reserve (CR) and brain reserve (BR) are protective factors against age‐associated cognitive decline and neurodegenerative disorders. Very limited evidence exists about gender effects on brain aging and on the effect of CR on brain modulation in healthy aging and Alzheimer's Dementia (AD). We investigated gender differences in brain metabolic activity and resting‐state network connectivity, as measured by ¹⁸F‐FDG‐PET, in healthy aging and AD, also considering the effects of education and occupation. The clinical and imaging data were retrieved from large datasets of healthy elderly subjects (HE) (225) and AD patients (282). In HE, males showed more extended age‐related reduction of brain metabolism than females in frontal medial cortex. We also found differences in brain modulation as metabolic increases induced by education and occupation, namely in posterior associative cortices in HE males and in the anterior limbic‐affective and executive networks in HE females. In AD patients, the correlations between education and occupation levels and brain hypometabolism showed gender differences, namely a posterior temporo‐parietal association in males and a frontal and limbic association in females, indicating the involvement of different networks. Finally, the metabolic connectivity in both HE and AD aligned with these results, suggesting greater efficiency in the posterior default mode network for males, and in the anterior frontal executive network for females. The basis of these brain gender differences in both aging and AD, obtained exploring cerebral metabolism, metabolic connectivity and the effects of education and occupation, is likely at the intersection between biological and sociodemographic factors. Hum Brain Mapp 38:4212–4227, 2017. © 2017 Wiley Periodicals, Inc.     

Parental age as a risk factor in Alzheimer's disease

Because of the associations between Alzheimer's disease and Down's syndrome, advanced maternal and paternal age, which are risk factors for Down's syndrome, have been proposed as risk factors for Alzheimer's disease. Parental age data were obtained from a group of patients with Alzheimer's disease and compared with comparable data for a group of nondemented subjects matched for age and socioeconomic level. As a way of detecting a familial causative factor in Alzheimer's disease, life-span data were also collected for parents of patients and control subjects. The results indicated that patients with Alzheimer's disease and nondemented control subjects did not differ in the mean ages of their parents at the time of the patients' or subjects' births, nor did parental age correlate significantly with age at onset of disease. Moreover, the parents of patients with Alzheimer's disease did not differ in mean age at death from the parents of nondemented control subjects.     

Precuneus degeneration in nondemented elderly individuals with APOE ɛ4: Evidence from structural and functional MRI analyses

Neurodegenerative diseases such as Alzheimer's disease (AD) have been recognized to exhibit disease‐specific brain vulnerability patterns. Apolipoprotein E (APOE ) ?4 allele imparts a high genetic risk of developing AD. Whether the APOE ?4 allele damages the brain when cognitive functions are still intact is important to understand, especially for possible early detection and intervention. This study aimed to examine the selective degeneration pattern associated with the APOE ?4 allele in the brains of cognitively normal elderly subjects. We enrolled 35 cognitively healthy ?4 carriers and 40 non‐carriers (53 to 81 years old) to evaluate group differences in cortical thickness and brain activation during a memory‐encoding task. We also assessed the functional connectivity of the brain regions with both structural and functional damages. The results from the neuropsychological tests showed that the performances of ?4 carriers and non‐carriers were comparable. Primarily, we found that the precuneus exhibited thinner cortical thickness and decreased deactivation during memory encoding. Furthermore, the connectivity analyses show that carriers exhibited damaged connectivity of the precuneus to several regions in the default mode network and the attention/executive control network. Our study reveals the degeneration pattern of the ?4 allele, which could be used as a potential biomarker for early detection for possible interventions and treatments. Hum Brain Mapp 38:271–282, 2017 . © 2016 Wiley Periodicals, Inc.     

Rich club analysis in the Alzheimer's disease connectome reveals a relatively undisturbed structural core network

Diffusion imaging can assess the white matter connections within the brain, revealing how neural pathways break down in Alzheimer's disease (AD). We analyzed 3‐Tesla whole‐brain diffusion‐weighted images from 202 participants scanned by the Alzheimer's Disease Neuroimaging Initiative–50 healthy controls, 110 with mild cognitive impairment (MCI) and 42 AD patients. From whole‐brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We tested whether AD disrupts the “rich club” – a network property where high‐degree network nodes are more interconnected than expected by chance. We calculated the rich club properties at a range of degree thresholds, as well as other network topology measures including global degree, clustering coefficient, path length, and efficiency. Network disruptions predominated in the low‐degree regions of the connectome in patients, relative to controls. The other metrics also showed alterations, suggesting a distinctive pattern of disruption in AD, less pronounced in MCI, targeting global brain connectivity, and focusing on more remotely connected nodes rather than the central core of the network. AD involves severely reduced structural connectivity; our step‐wise rich club coefficients analyze points to disruptions predominantly in the peripheral network components; other modalities of data are needed to know if this indicates impaired communication among non rich club regions. The highly connected core was relatively preserved, offering new evidence on the neural basis of progressive risk for cognitive decline. Hum Brain Mapp 36:3087–3103, 2015. © 2015 Wiley Periodicals, Inc.     

Higher body mass index is associated with reduced posterior default mode connectivity in older adults

Obesity is a complex neurobehavioral disorder that has been linked to changes in brain structure and function. However, the impact of obesity on functional connectivity and cognition in aging humans is largely unknown. Therefore, the association of body mass index (BMI), resting‐state network connectivity, and cognitive performance in 712 healthy, well‐characterized older adults of the Leipzig Research Center for Civilization Diseases (LIFE) cohort (60–80 years old, mean BMI 27.6 kg/m² ± 4.2 SD, main sample: n = 521, replication sample: n = 191) was determined. Statistical analyses included a multivariate model selection approach followed by univariate analyses to adjust for possible confounders. Results showed that a higher BMI was significantly associated with lower default mode functional connectivity in the posterior cingulate cortex and precuneus. The effect remained stable after controlling for age, sex, head motion, registration quality, cardiovascular, and genetic factors as well as in replication analyses. Lower functional connectivity in BMI‐associated areas correlated with worse executive function. In addition, higher BMI correlated with stronger head motion. Using 3T neuroimaging in a large cohort of healthy older adults, independent negative associations of obesity and functional connectivity in the posterior default mode network were observed. In addition, a subtle link between lower resting‐state connectivity in BMI‐associated regions and cognitive function was found. The findings might indicate that obesity is associated with patterns of decreased default mode connectivity similar to those seen in populations at risk for Alzheimer's disease. Hum Brain Mapp 38:3502–3515, 2017. © 2017 Wiley Periodicals, Inc.     

Olfactory performance and resting state functional connectivity in non‐demented drug naïve patients with Parkinson's disease

Olfactory performance in Parkinson's disease (PD) is closely associated with subsequent cognitive decline. In the present study, we analyzed the olfaction‐dependent functional connectivity with a hypothesis that olfactory performance would influence functional connectivity within key brain areas of PD. A total of 110 nondemented drug‐naïve patients with PD were subdivided into three groups of high score (PD‐H, n = 23), middle score (PD‐M, n = 64), and low score (PD‐L, n = 23) based on olfactory performance. We performed the resting‐state functional connectivity with seed region of interest in the posterior cingulate cortex (PCC) and caudate. An analysis of functional connectivity revealed that PD‐L patients exhibited a significant attenuation of cortical functional connectivity with the PCC in the bilateral primary sensory areas, right frontal areas, and right parietal areas compared to PD‐H or PD‐M patients. Meanwhile, PD‐L patients exhibited a significant enhancement of striatocortical functional connectivity in the bilateral occipital areas and right frontal areas compared to PD‐H or PD‐M patients. In the voxel‐wise correlation analysis, olfactory performance was positively associated with cortical functional connectivity with the PCC in similar areas of attenuated cortical connectivity in PD‐L patients relative to PD‐H patients. On the other hand, the cortical functional connectivity with the caudate was negatively correlated with olfactory performance in similar areas of increased connectivity in PD‐L patients relative to PD‐H patients. The present study demonstrated that resting state functional connectivity exhibits a distinctive pattern depending on olfactory performance, which might shed light on a meaningful relationship between olfactory impairment and cognitive dysfunction in PD. Hum Brain Mapp 36:1716–1727, 2015. © 2014 Wiley Periodicals, Inc.     

Grab‐AD: Generalizability and reproducibility of altered brain activity and diagnostic classification in Alzheimer's Disease

Alzheimer's disease (AD) is associated with disruptions in brain activity and networks. However, there is substantial inconsistency among studies that have investigated functional brain alterations in AD; such contradictions have hindered efforts to elucidate the core disease mechanisms. In this study, we aim to comprehensively characterize AD‐associated functional brain alterations using one of the world's largest resting‐state functional MRI (fMRI) biobank for the disorder. The biobank includes fMRI data from six neuroimaging centers, with a total of 252 AD patients, 221 mild cognitive impairment (MCI) patients and 215 healthy comparison individuals. Meta‐analytic techniques were used to unveil reliable differences in brain function among the three groups. Relative to the healthy comparison group, AD was associated with significantly reduced functional connectivity and local activity in the default‐mode network, basal ganglia and cingulate gyrus, along with increased connectivity or local activity in the prefrontal lobe and hippocampus (p < .05, Bonferroni corrected). Moreover, these functional alterations were significantly correlated with the degree of cognitive impairment (AD and MCI groups) and amyloid‐β burden. Machine learning models were trained to recognize key fMRI features to predict individual diagnostic status and clinical score. Leave‐one‐site‐out cross‐validation established that diagnostic status (mean area under the receiver operating characteristic curve: 0.85) and clinical score (mean correlation coefficient between predicted and actual Mini‐Mental State Examination scores: 0.56, p < .0001) could be predicted with high accuracy. Collectively, our findings highlight the potential for a reproducible and generalizable functional brain imaging biomarker to aid the early diagnosis of AD and track its progression.     

Limbic grey matter changes in early Parkinson's disease

The purpose of this study was to investigate local and network‐related changes of limbic grey matter in early Parkinson's disease (PD) and their inter‐relation with non‐motor symptom severity. We applied voxel‐based morphometric methods in 538 T1 MRI images retrieved from the Parkinson's Progression Markers Initiative website. Grey matter densities and cross‐sectional estimates of age‐related grey matter change were compared between subjects with early PD (n = 366) and age‐matched healthy controls (n = 172) within a regression model, and associations of grey matter density with symptoms were investigated. Structural brain networks were obtained using covariance analysis seeded in regions showing grey matter abnormalities in PD subject group. Patients displayed focally reduced grey matter density in the right amygdala, which was present from the earliest stages of the disease without further advance in mild‐moderate disease stages. Right amygdala grey matter density showed negative correlation with autonomic dysfunction and positive with cognitive performance in patients, but no significant interrelations were found with anxiety scores. Patients with PD also demonstrated right amygdala structural disconnection with less structural connectivity of the right amygdala with the cerebellum and thalamus but increased covariance with bilateral temporal cortices compared with controls. Age‐related grey matter change was also increased in PD preferentially in the limbic system. In conclusion, detailed brain morphometry in a large group of early PD highlights predominant limbic grey matter deficits with stronger age associations compared with controls and associated altered structural connectivity pattern. This provides in vivo evidence for early limbic grey matter pathology and structural network changes that may reflect extranigral disease spread in PD. Hum Brain Mapp 38:3566–3578, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease

Alzheimer's disease (AD) can present with distinct clinical variants. Identifying the earliest neurodegenerative changes associated with each variant has implications for early diagnosis, and for understanding the mechanisms that underlie regional vulnerability and disease progression in AD. We performed voxel‐based morphometry to detect atrophy patterns in early clinical stages of four AD phenotypes: Posterior cortical atrophy (PCA, “visual variant,” n = 93), logopenic variant primary progressive aphasia (lvPPA, “language variant,” n = 74), and memory‐predominant AD categorized as early age‐of‐onset (EOAD, <65 years, n = 114) and late age‐of‐onset (LOAD, >65 years, n = 114). Patients with each syndrome were stratified based on: (1) degree of functional impairment, as measured by the clinical dementia rating (CDR) scale, and (2) overall extent of brain atrophy, as measured by a neuroimaging approach that sums the number of brain voxels showing significantly lower gray matter volume than cognitively normal controls (n = 80). Even at the earliest clinical stage (CDR = 0.5 or bottom quartile of overall atrophy), patients with each syndrome showed both common and variant‐specific atrophy. Common atrophy across variants was found in temporoparietal regions that comprise the posterior default mode network (DMN). Early syndrome‐specific atrophy mirrored functional brain networks underlying functions that are uniquely affected in each variant: Language network in lvPPA, posterior cingulate cortex‐hippocampal circuit in amnestic EOAD and LOAD, and visual networks in PCA. At more advanced stages, atrophy patterns largely converged across AD variants. These findings support a model in which neurodegeneration selectively targets both the DMN and syndrome‐specific vulnerable networks at the earliest clinical stages of AD. Hum Brain Mapp 36:4421–4437, 2015. © 2015 Wiley Periodicals, Inc .     

Vorzeitiges Gehirnaltern bei Down-Syndrom

Clinical and neuropathological findings of a 63-year-old male and a 25-year-old female with Down's syndrome are presented. Neuropathological examination of the older patient revealed intense features of Alzheimer's disease or senile dementia, including congophilic angiopathy and extensive mineral deposits in the globus pallidus and in the white matter of the cerebellum. In the hippocampus of the younger patient, plaque-like bodies and a few neurofibrillary tangles were found. From a survey of the cases hitherto reported in the literature it appears that among patients over 50 years of age it is common to encounter pathological features typical of Alzheimer's disease or senile dementia, that plaque-like bodies may occur in the second decade, neurofibrillary tangles in the third decade and a congophilic angiopathy in the fourth decade. The congophilic angiopathy is a frequent finding. Due to their high frequency, calcium or calciumlike deposits are regarded as important histopathological substrates of Down's syndrome. The clinical symptomatology of the long-surviving patients with Down's syndrome is that of a non-characteristic brain aging process and differs from that of the typical Alzheimer's disease. Organic dementia is not regularly found. Altogether, the anatomical findings in adult patients with Down's syndrome indicate a premature aging of the brain, which becomes more significant and widespread with increasing age.     

Pittsburgh compound B retention and progression of cognitive status – a meta‐analysis

Our aim was to conduct a meta‐analysis of longitudinal studies assessing the association between Pittsburgh compound B (PiB) retention and the progression of cognitive status in healthy elderly, in patients with mild cognitive impairment (MCI) and in patients with Alzheimer's disease (AD). PubMed, MEDLINE, Embase and the Cochrane Library up to April 2013 were searched for studies reporting PiB retention at baseline and conversion of clinical status at follow‐up, with manual searches of bibliographies of key retrieved articles and relevant reviews. Two independent reviewers extracted data on individual numbers with PiB positive or negative status at baseline and corresponding numbers of patients with cognitive decline at follow‐up (conversion from healthy elderly to MCI or AD, or from MCI to AD, or a Mini‐Mental State Examination decline >3 for AD patients). Relative risks were pooled using fixed‐effects or random‐effects models as appropriate. Associations were tested in subgroups representing three different phases of AD. Publication bias was evaluated with funnel plots. Twelve cohort studies including 1275 participants were included with a follow‐up period ranging from 1 to 3.8 years. The pooled adjusted relative risks were 3.75 (95% confidence interval 2.76–5.09; P for heterogeneity 0.16; fixed‐effects model) for disease progression, 1.73 (0.63–4.75; P for heterogeneity 0.27; fixed‐effects model) for AD patients (four studies), 4.03 (2.68–6.07; P for heterogeneity 0.49; fixed‐effects model) for MCI patients (eight studies) and 3.67 (2.25–5.99; P for heterogeneity 0.26; fixed‐effects model) for disease progression in healthy elderly (six studies). Baseline PiB positive status is associated with a significantly increased risk of cognitive progression in healthy elderly and MCI patients.     

Striato‐cortical connections in Parkinson's and Alzheimer's diseases: Relation to cognition

Background : Functional connectivity is abnormal in PD and in early Alzheimer's disease. Objectives : The objective of this study was to evaluate resting‐state striato‐cortical connectivity in PD and Alzheimer's disease and assess their relation to cognitive outcomes. Groups with mild cognitive impairment as a result of different pathologies (PD vs. Alzheimer's disease) were also compared. Methods : Seed‐based connectivity of the dorsal, middle, and ventral striatum was analyzed in 111 patients using functional MRI. The correlation between connectivity at regions of between‐group differences and clinical outcomes was assessed. Results : Patients showed lower striatal connectivity than controls. Connectivity between the middle (associative) striatum and precuneus negatively correlated with executive functions in PD and with memory performance in Alzheimer's disease. PD with cognitive impairment showed decreased connectivity of the dorsal (motor) striatum when compared with early Alzheimer's disease. Conclusions : Striatal connectivity was reduced in patients when compared with controls. Similar compensatory mechanisms were employed to overcome various cognitive deficits in PD and Alzheimer's disease. © 2017 International Parkinson and Movement Disorder Society