USP19 deubiquitinase inactivation regulates α-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice.

The USP19 deubiquitinase is found in a locus associated with Parkinson's Disease (PD), interacts with chaperonins, and promotes secretion of α-synuclein (α-syn) through the misfolding-associated protein secretion (MAPS) pathway. Since these processes might modulate the processing of α-syn aggregates in PD, we inactivated USP19 (KO) in mice expressing the A53T mutation of α-syn and in whom α-syn preformed fibrils (PFF) had been injected in the striatum. Compared to WT, KO brains showed decreased accumulation of phospho-synuclein (pSyn) positive aggregates. This improvement was associated with less activation of microglia and improved performance in a tail-suspension test. Exposure of primary neurons from WT and KO mice to PFF in vitro also led to decreased accumulation of pSyn aggregates. KO did not affect uptake of PFF nor propagation of aggregates in the cultured neurons. We conclude that USP19 instead modulates intracellular dynamics of aggregates. At an early time following PFF injection when the number of pSyn-positive neurons were similar in WT and KO brains, the KO neurons contained less aggregates. KO brain aggregates stained more intensely with anti-ubiquitin antibodies. Immunoprecipitation of soluble proteins from WT and KO brains with antibodies to pSyn showed higher levels of ubiquitinated oligomeric species in the KO samples. We propose that the improved pathology in USP19 KO brains may arise from decreased formation or enhanced clearance of the more ubiquitinated aggregates and/or enhanced disassembly towards more soluble oligomeric species. USP19 inhibition may represent a novel therapeutic approach that targets the intracellular dynamics of α-syn complexes.

Fornix degeneration in risk factors of Alzheimer's disease, possible trigger of cognitive decline.

Risk factors of late-onset Alzheimer's disease (AD) such as aging, type 2 diabetes, obesity, heart failure, and traumatic brain injury can facilitate the appearance of cognitive decline and dementia by triggering cerebrovascular pathology and neuroinflammation. White matter (WM) microstructure and function are especially vulnerable to these conditions. Microstructural WM changes, assessed with diffusion weighted magnetic resonance imaging, can already be detected at preclinical stages of AD, and in the presence of the aforementioned risk factors. Particularly, the limbic system and cortico-cortical association WM tracts, which myelinate late during brain development, degenerate at the earliest stages. The fornix, a C-shaped WM tract that originates from the hippocampus, is one of the limbic tracts that shows early microstructural changes. Fornix integrity is necessary for ensuring an intact executive function and memory performance. Thus, a better understanding of the mechanisms that cause fornix degeneration is critical in the development of therapeutic strategies aiming to prevent cognitive decline in populations at risk. In this literature review, i) we deepen the idea that partial loss of forniceal integrity is an early event in AD, ii) we describe the role that common risk factors of AD can play in the degeneration of the fornix, and iii) we discuss some potential cellular and physiological mechanisms of WM degeneration in the scenario of cerebrovascular disease and inflammation.

Matisse and the Organoids: The Art of Science.

Over the past few decades, scientists have transformed the way they do and understand science. They are now exploring their more creative side. This approach has accelerated fascinating discoveries such as human induced pluripotent stem cells and brain organoids; however, they have not been able to jump over the communication barrier with society. La Danse des Astrocytes, a scene observed during a routine microscopy session working on midbrain organoids, has motivated this essay, which urges scientists to find new forms of science communication and to work as a community to achieve the consolidation of a scientific culture.

A functional cerebral endothelium is necessary to protect against cognitive decline.

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included NemoFl controls and three NemobeKO groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in NemobeKO mice and were not countered by treatments. Cerebrovascular function was compromised in NemobeKO groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. NemobeKO mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts.

Microfabricated disk technology: Rapid scale up in midbrain organoid generation.

By providing a three-dimensional in vitro culture system with key features of the substantia nigra region in the brain, 3D neuronal organoids derived from human induced pluripotent stem cells (iPSCs) provide living neuronal tissue resembling the midbrain region of the brain. However, a major limitation of conventional brain organoid culture is that it is often labor-intensive, requiring highly specialized personnel for moderate throughput. Additionally, the methods published for long-term cultures require time-consuming maintenance to generate brain organoids in large numbers. With the increasing need for human midbrain organoids (hMOs) to better understand and model Parkinson's disease (PD) in a dish, there is a need to implement new workflows and methods to both generate and maintain hMOs, while minimizing batch to batch variation. In this study, we developed a method with microfabricated disks to scale up the generation of hMOs. This opens up the possibility to generate larger numbers of hMOs, in a manner that minimizes the amount of labor required, while decreasing variability and maintaining the viability of these hMOs over time. Taken together, producing hMOs in this manner opens up the potential for these to be used to further PD studies.

Alzheimer's disease and cerebrovascular pathology alter inward rectifier potassium (KIR 2.1) channels in endothelium of mouse cerebral arteries.

BACKGROUND AND PURPOSE: Inward rectifier potassium (KIR ) channels are key effectors of vasodilatation in neurovascular coupling (NVC). KIR channels expressed in cerebral endothelial cells (ECs) have been confirmed as essential modulators of NVC. Alzheimer's disease (AD) and cerebrovascular disease (CVD) impact on EC-KIR channel function, but whether oxidative stress or inflammation explains this impairment remains elusive. EXPERIMENTAL APPROACH: We evaluated KIR channel function in intact and EC-denuded pial arteries of wild-type (WT) and transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APP mice, recapitulating amyloid ß-induced oxidative stress seen in AD) or a constitutively active form of TGF-ß1 (TGF mice, recapitulating inflammation seen in cerebrovascular pathology). The benefits of antioxidant (catalase) or anti-inflammatory (indomethacin) drugs also were investigated. Vascular and neuronal components of NVC were assessed in vivo. KEY RESULTS: Our findings show that (i) KIR channel-mediated maximal vasodilatation in APP and TGF mice reaches only 37% and 10%, respectively, of the response seen in WT mice; (ii) KIR channel dysfunction results from KIR 2.1 subunit impairment; (iii) about 50% of K+ -induced artery dilatation is mediated by EC-KIR channels; (iv) oxidative stress and inflammation impair KIR channel function, which can be restored by antioxidant and anti-inflammatory drugs; and (v) inflammation induces KIR 2.1 overexpression and impairs NVC in TGF mice. CONCLUSION AND IMPLICATIONS: Therapies targeting both oxidative stress and inflammation are necessary for full recovery of KIR 2.1 channel function in cerebrovascular pathology caused by AD and CVD.

Applying hiPSCs and Biomaterials Towards an Understanding and Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is the leading cause of disability and mortality in children and young adults and has a profound impact on the socio-economic wellbeing of patients and their families. Initially, brain damage is caused by mechanical stress-induced axonal injury and vascular dysfunction, which can include hemorrhage, blood-brain barrier disruption, and ischemia. Subsequent neuronal degeneration, chronic inflammation, demyelination, oxidative stress, and the spread of excitotoxicity can further aggravate disease pathology. Thus, TBI treatment requires prompt intervention to protect against neuronal and vascular degeneration. Rapid advances in the field of stem cells (SCs) have revolutionized the prospect of repairing brain function following TBI. However, more than that, SCs can contribute substantially to our knowledge of this multifaced pathology. Research, based on human induced pluripotent SCs (hiPSCs) can help decode the molecular pathways of degeneration and recovery of neuronal and glial function, which makes these cells valuable tools for drug screening. Additionally, experimental approaches that include hiPSC-derived engineered tissues (brain organoids and bio-printed constructs) and biomaterials represent a step forward for the field of regenerative medicine since they provide a more suitable microenvironment that enhances cell survival and grafting success. In this review, we highlight the important role of hiPSCs in better understanding the molecular pathways of TBI-related pathology and in developing novel therapeutic approaches, building on where we are at present. We summarize some of the most relevant findings for regenerative therapies using biomaterials and outline key challenges for TBI treatments that remain to be addressed.

Nanotherapeutic Modulation of Human Neural Cells and Glioblastoma in Organoids and Monocultures.

Inflammatory processes in the brain are orchestrated by microglia and astrocytes in response to activators such as pathogen-associated molecular patterns, danger-associated molecular patterns and some nanostructures. Microglia are the primary immune responders in the brain and initiate responses amplified by astrocytes through intercellular signaling. Intercellular communication between neural cells can be studied in cerebral organoids, co-cultures or in vivo. We used human cerebral organoids and glioblastoma co-cultures to study glia modulation by dendritic polyglycerol sulfate (dPGS). dPGS is an extensively studied nanostructure with inherent anti-inflammatory properties. Under inflammatory conditions, lipocalin-2 levels in astrocytes are markedly increased and indirectly enhanced by soluble factors released from hyperactive microglia. dPGS is an effective anti-inflammatory modulator of these markers. Our results show that dPGS can enter neural cells in cerebral organoids and glial cells in monocultures in a time-dependent manner. dPGS markedly reduces lipocalin-2 abundance in the neural cells. Glioblastoma tumoroids of astrocytic origin respond to activated microglia with enhanced invasiveness, whereas conditioned media from dPGS-treated microglia reduce tumoroid invasiveness. Considering that many nanostructures have only been tested in cancer cells and rodent models, experiments in human 3D cerebral organoids and co-cultures are complementary in vitro models to evaluate nanotherapeutics in the pre-clinical setting. Thoroughly characterized organoids and standardized procedures for their preparation are prerequisites to gain information of translational value in nanomedicine. This study provides data for a well-characterized dendrimer (dPGS) that modulates the activation state of human microglia implicated in brain tumor invasiveness.

Vascular contributions to 16p11.2 deletion autism syndrome modeled in mice.

While the neuronal underpinnings of autism spectrum disorder (ASD) are being unraveled, vascular contributions to ASD remain elusive. Here, we investigated postnatal cerebrovascular development in the 16p11.2df/+ mouse model of 16p11.2 deletion ASD syndrome. We discover that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction results in impaired cerebral angiogenesis at postnatal day 14, and in altered neurovascular coupling and cerebrovascular reactivity at postnatal day 50. Moreover, we show that there is defective angiogenesis in primary 16p11.2df/+ mouse brain endothelial cells and in induced-pluripotent-stem-cell-derived endothelial cells from human carriers of the 16p11.2 deletion. Finally, we find that mice with an endothelium-specific 16p11.2 deletion (16p11.2ΔEC) partially recapitulate some of the behavioral changes seen in 16p11.2 syndrome, specifically hyperactivity and impaired motor learning. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, our results point to a potential role for endothelial impairment in ASD.

AT2R's (Angiotensin II Type 2 Receptor's) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease.

Antihypertensive medications targeting the renin-angiotensin system have lowered the incidence and progression of Alzheimer disease. Understanding how these medications function could lead to novel therapeutic strategies. AT4Rs (angiotensin IV receptors) have been associated with angiotensin receptor blockers' cognitive, cerebrovascular, and neuroinflammatory rescue in Alzheimer disease models. Yet, whether AT4Rs act alone or with AT2Rs remains unknown. Here, we investigated whether AT2Rs contribute to losartan's benefits and whether chronic AT2R activation could mimic angiotensin receptor blocker benefits in transgenic mice overexpressing familial Alzheimer disease mutations of the human APP (amyloid precursor protein). Losartan-treated mice (10 mg/kg per day, drinking water, 7 months) received intracerebroventricular (1 month) administration of vehicle or AT2R antagonist PD123319 (1.6 nmol/day). PD123319 countered losartan's benefits on spatial learning and memory, neurovascular coupling, and hampered those on oxidative stress and nitric oxide bioavailability. PD123319 did not oppose losartan's benefits on short-term memory and vasodilatory function and had no benefit on neuroinflammation or Aß (amyloid ß) pathology. Mice receiving either vehicle or selective AT2R agonist compound 21 (intracerebroventricular: 1 nmol/day, 1 month or drinking water: 10 mg/kg per day, 7 months), showed no improvement in memory, vasodilatory function, or nitric oxide bioavailability. Compound 21 treatment normalized neurovascular coupling, reduced astrogliosis independent of persisting microgliosis, and exacerbated oxidative stress in APP mice. Compound 21 reduced dense core Aß plaques, but not diffuse plaques or Aß species. Our findings suggest that targeting AT2Rs is not an ideal strategy for restoring Aß-related cognitive and cerebrovascular deficits.

Benefits of physical exercise on cognition and glial white matter pathology in a mouse model of vascular cognitive impairment and dementia.

White matter (WM) pathology is a clinically predictive feature of vascular cognitive impairment and dementia (VCID). Mice overexpressing transforming growth factor-ß1 (TGF) with an underlying cerebrovascular pathology when fed a high cholesterol diet (HCD) develop cognitive deficits (VCID mice) that we recently found could be prevented by physical exercise (EX). Here, we further investigated cognitive and WM pathology in VCID mice and examined the cellular substrates of the protective effects of moderate aerobic EX focusing on WM alterations. Six groups were studied: Wild-type (WT) and TGF mice (n = 20-24/group) fed standard lab chow or a 2% HCD, with two HCD-fed groups given concurrent access to running wheels. HCD had a significant negative effect in TGF mice that was prevented by EX on working and object recognition memory, the latter also altered in WT HCD mice. Whisker-evoked increases in cerebral blood flow (CBF) were reduced in HCD-fed mice, deficits that were countered by EX, and baseline WM CBF was similarly affected. VCID mice displayed WM functional deficits characterized by lower compound action potential amplitude not found in EX groups. Moreover, there was an increased number of collapsing capillaries, galectin-3-expressing microglial cells, as well as a reduced number of oligodendrocytes in the WM of VCID mice; all of which were prevented by EX. Our findings indicate that a compromised cerebral circulation precedes reduced WM vascularization, enhanced WM inflammation and impaired oligodendrogenesis that all likely account for the increased susceptibility to memory impairments in VCID mice, which can be prevented by EX. MAIN POINTS: A compromised cerebral circulation increases susceptibility to anatomical and functional white matter changes that develop alongside cognitive deficits when challenged with a high cholesterol diet; preventable by a translational regimen of exercise.

Pleiotropic Benefits of the Angiotensin Receptor Blocker Candesartan in a Mouse Model of Alzheimer Disease.

The angiotensin receptor blocker losartan mitigated cerebrovascular and cognitive deficits in mouse models of Alzheimer disease, in line with some clinical evidence of reduced onset and progression to Alzheimer disease. We investigated whether these benefits apply to another angiotensin receptor blocker, namely candesartan. Adult transgenic mice overexpressing a mutated form of the human APP (amyloid precursor protein) and wild-type controls were treated with vehicle or candesartan (cohort 1: 2 months, 1 mg/kg per day, osmotic subcutaneous minipumps; cohort 2: 5 months, 10 mg/kg per day in drinking water). Candesartan largely restored endothelial and smooth muscle function and reduced neuroinflammation in both cohorts, without improving sensory evoked cerebral blood flow responses. Candesartan exerted restorative effects on the reduced number of Ki67-immunopositive proliferating cells in the granule cell layer of the hippocampus but not on that of DCX (doublecortin)-positive immature granule cells, despite normalizing the length of their dendritic projections in the molecular layer. Amyloid plaque load and impaired cognitive function were unaltered by candesartan, and blood pressure was decreased in treated APP and wild-type mice. Overall, findings show that candesartan shared several advantages reported previously for losartan, but it exhibited limited cognitive benefits and stronger blood pressure lowering effects. The choice of angiotensin receptor blocker may thus be critical for therapeutic efficacy in patients with vascular diseases at high risk of developing Alzheimer disease.

Structural neuroimaging as clinical predictor: A review of machine learning applications.

In this paper, we provide an extensive overview of machine learning techniques applied to structural magnetic resonance imaging (MRI) data to obtain clinical classifiers. We specifically address practical problems commonly encountered in the literature, with the aim of helping researchers improve the application of these techniques in future works. Additionally, we survey how these algorithms are applied to a wide range of diseases and disorders (e.g. Alzheimer's disease (AD), Parkinson's disease (PD), autism, multiple sclerosis, traumatic brain injury, etc.) in order to provide a comprehensive view of the state of the art in different fields.

Impact of Altered Cholinergic Tones on the Neurovascular Coupling Response to Whisker Stimulation.

Brain imaging techniques that use vascular signals to map changes in neuronal activity rely on the coupling between electrophysiology and hemodynamics, a phenomenon referred to as "neurovascular coupling" (NVC). It is unknown whether this relationship remains reliable under altered brain states associated with acetylcholine (ACh) levels, such as attention and arousal and in pathological conditions such as Alzheimer's disease. We therefore assessed the effects of varying ACh tone on whisker-evoked NVC responses in rat barrel cortex, measured by cerebral blood flow (CBF) and neurophysiological recordings (local field potentials, LFPs). We found that acutely enhanced ACh tone significantly potentiated whisker-evoked CBF responses through muscarinic ACh receptors and concurrently facilitated neuronal responses, as illustrated by increases in the amplitude and power in high frequencies of the evoked LFPs. However, the cellular identity of the activated neuronal network within the responsive barrel was unchanged, as characterized by c-Fos upregulation in pyramidal cells and GABA interneurons coexpressing vasoactive intestinal polypeptide. In contrast, chronic ACh deprivation hindered whisker-evoked CBF responses and the amplitude and power in most frequency bands of the evoked LFPs and reduced the rostrocaudal extent and area of the activated barrel without altering its identity. Correlations between LFP power and CBF, used to estimate NVC, were enhanced under high ACh tone and disturbed significantly by ACh depletion. We conclude that ACh is not only a facilitator but also a prerequisite for the full expression of sensory-evoked NVC responses, indicating that ACh may alter the fidelity of hemodynamic signals in assessing changes in evoked neuronal activity.SIGNIFICANCE STATEMENT Neurovascular coupling, defined as the tight relationship between activated neurons and hemodynamic responses, is a fundamental brain function that underlies hemodynamic-based functional brain imaging techniques. However, the impact of altered brain states on this relationship is largely unknown. We therefore investigated how acetylcholine (ACh), known to drive brain states of attention and arousal and to be deficient in pathologies such as Alzheimer's disease, would alter neurovascular coupling responses to sensory stimulation. Whereas acutely increased ACh enhanced neuronal responses and the resulting hemodynamic signals, chronic loss of cholinergic input resulted in dramatic impairments in both types of sensory-evoked signals. We conclude that ACh is not only a potent modulator but also a requirement for the full expression of sensory-evoked neurovascular coupling responses.

The Disconnection Hypothesis in Alzheimer's Disease Studied Through Multimodal Magnetic Resonance Imaging: Structural, Perfusion, and Diffusion Tensor Imaging.

According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer's disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r = 0.90, p <  0.0001; right: r = 0.597, p = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r = 0.551, p = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group.

Age at First Episode Modulates Diagnosis-Related Structural Brain Abnormalities in Psychosis.

Brain volume and thickness abnormalities have been reported in first-episode psychosis (FEP). However, it is unclear if and how they are modulated by brain developmental stage (and, therefore, by age at FEP as a proxy). This is a multicenter cross-sectional case-control brain magnetic resonance imaging (MRI) study. Patients with FEP (n = 196), 65.3% males, with a wide age at FEP span (12-35 y), and healthy controls (HC) (n = 157), matched for age, sex, and handedness, were scanned at 6 sites. Gray matter volume and thickness measurements were generated for several brain regions using FreeSurfer software. The nonlinear relationship between age at scan (a proxy for age at FEP in patients) and volume and thickness measurements was explored in patients with schizophrenia spectrum disorders (SSD), affective psychoses (AFP), and HC. Earlier SSD cases (ie, FEP before 15-20 y) showed significant volume and thickness deficits in frontal lobe, volume deficits in temporal lobe, and volume enlargements in ventricular system and basal ganglia. First-episode AFP patients had smaller cingulate cortex volume and thicker temporal cortex only at early age at FEP (before 18-20 y). The AFP group also had age-constant (12-35-y age span) volume enlargements in the frontal and parietal lobe. Our study suggests that age at first episode modulates the structural brain abnormalities found in FEP patients in a nonlinear and diagnosis-dependent manner. Future MRI studies should take these results into account when interpreting samples with different ages at onset and diagnosis.

Cerebral blood flow is an earlier indicator of perfusion abnormalities than cerebral blood volume in Alzheimer's disease.

The purpose of this study was to elucidate whether cerebral blood flow (CBF) can better characterize perfusion abnormalities in predementia stages of Alzheimer's disease (AD) than cerebral blood volume (CBV) and whether cortical atrophy is more associated with decreased CBV or with decreased CBF. We compared measurements of CBV, CBF, and mean cortical thickness obtained from magnetic resonance images in a group of healthy controls, patients with mild cognitive impairment (MCI) who converted to AD after 2 years of clinical follow-up (MCI-c), and patients with mild AD. A significant decrease in perfusion was detected in the parietal lobes of the MCI-c patients with CBF parametric maps but not with CBV maps. In the MCI-c group, a negative correlation between CBF values and cortical thickness in the right parahippocampal gyrus suggests an increase in CBF that depends on cortical atrophy in predementia stages of AD. Our study also suggests that CBF deficits appear before CBV deficits in the progression of AD, as CBV abnormalities were only detected at the AD stage, whereas CBF changes were already detected in the MCI stage. These results confirm the hypothesis that CBF is a more sensitive parameter than CBV for perfusion abnormalities in MCI-c patients.

Comparison of different methods of spatial normalization of FDG-PET brain images in the voxel-wise analysis of MCI patients and controls.

OBJECTIVE: One of the most interesting clinical applications of 18F-FDG PET imaging in neurodegenerative pathologies is that of establishing the prognosis of patients with mild cognitive impairment (MCI), some of whom have a high risk of progressing to Alzheimer's disease (AD). One method of analyzing these images is to perform statistical parametric mapping (SPM) analysis. Spatial normalization is a critical step in such an analysis. The purpose of this study was to assess the effect of using different methods of spatial normalization on the results of SPM analysis of 18F-FDG PET images by comparing patients with MCI and controls. METHODS: We evaluated the results of three spatial normalization methods in an SPM analysis by comparing patients diagnosed with MCI with a group of control subjects. We tested three methods of spatial normalization: MRI-DARTEL and MRI-SPM8, which combine structural and functional images, and FDG-SPM8, which is based on the functional images only. RESULTS: The results obtained with the three methods were consistent in terms of the main pattern of functional alterations detected; namely, a bilateral reduction in glucose metabolism in the frontal and parietal cortices in the patient group. However, MRI-SPM8 also revealed differences in the left temporal cortex, and MRI-DARTEL revealed further differences in the left temporal cortex, precuneus, and left posterior cingulate. CONCLUSIONS: The results obtained with MRI-DARTEL were the most consistent with the pattern of changes in AD. When we compared our observations with those of previous reports, MRI-SPM8 and FDG-SPM8 seemed to show an incomplete pattern. Our results suggest that basing the spatial normalization method on functional images only can considerably impair the results of SPM analysis of 18F-FDG PET studies.

Is the cerebellum the optimal reference region for intensity normalization of perfusion MR studies in early Alzheimer's disease?

The cerebellum is the region most commonly used as a reference when normalizing the intensity of perfusion images acquired using magnetic resonance imaging (MRI) in Alzheimer's disease (AD) studies. In addition, the cerebellum provides unbiased estimations with nuclear medicine techniques. However, no reports confirm the cerebellum as an optimal reference region in MRI studies or evaluate the consequences of using different normalization regions. In this study, we address the effect of using the cerebellum, whole-brain white matter, and whole-brain cortical gray matter in the normalization of cerebral blood flow (CBF) parametric maps by comparing patients with stable mild cognitive impairment (MCI), patients with AD and healthy controls. According to our results, normalization by whole-brain cortical gray matter enables more sensitive detection of perfusion abnormalities in AD patients and reveals a larger number of affected regions than data normalized by the cerebellum or whole-brain white matter. Therefore, the cerebellum is not the most valid reference region in MRI studies for early stages of AD. After normalization by whole-brain cortical gray matter, we found a significant decrease in CBF in both parietal lobes and an increase in CBF in the right medial temporal lobe. We found no differences in perfusion between patients with stable MCI and healthy controls either before or after normalization.