Cognitive Effects of White Matter Pathology in Normal and Pathological Aging

We examined whether cerebrovascular white matter pathology is related to cognition as measured by the compound score of CERAD neuropsychological battery in cognitively normal older adults, patients with mild cognitive impairment, and patients with Alzheimer's disease (total n = 149), controlling for age and education. Trend-level effects of white matter pathology on cognition were only observed in patients with Alzheimer's disease (p = 0.062, eta(2) = 0.052), patients with severe frontal white matter pathology performed notably worse than those with milder pathology. This indicates that frontal cerebrovascular pathology may have an additive negative effect on cognition in Alzheimer's disease

Comparison of high and low molar activity TSPO tracer [18F]F-DPA in a mouse model of Alzheimer’s disease

[18F]F-DPA, a novel translocator protein 18 kDa (TSPO)-specific radioligand for imaging neuroinflammation, has to date been synthesized with low to moderate molar activities (Am’s). In certain cases, low Am can skew the estimation of specific binding. The high proportion of the non-radioactive component can reduce the apparent-specific binding by competitively binding to receptors. We developed a nucleophilic synthesis of [18F]F-DPA resulting in high Am (990 ± 150 GBq/µmol) and performed in vivo comparison with low Am (9.0 ± 2.9 GBq/µmol) [18F]F-DPA in the same APP/PS1-21 and wild-type mice (injected masses: 0.34 ± 0.13 µg/kg and 38 ± 15 µg/kg, respectively). The high level of microgliosis in the APP/PS1-21 mouse model enables good differentiation between diseased and healthy animals and serves better to distinguish the effect of differing Am on specific binding. The differing injected masses affect the washout profile and shape of the time–activity curves. Ratios of standardized uptake values obtained with high and low Am [18F]F-DPA demonstrate that there is a 1.5-fold higher uptake of radioactivity in the brains of APP/PS1-21 animals when imaging is carried out with high Am [18F]F-DPA. The differences between APP/PS1-21 and wild-type animals showed higher significance when high Am was used.</p

Supplementary Material for: Parkinsonian Patients with Striatal Cribriform State Present Rapidly Progressive Axial Parkinsonism

<i>Objective:</i> To define the significance of striatal cribriform state (SCS) observed in patients with primary progressive parkinsonism. <i>Methods:</i> We reviewed medical records and brain magnetic resonance imaging studies of 1,260 patients with primary progressive parkinsonism. We identified 23 patients with SCS and analyzed their clinical features. <i>Results</i>: All 23 patients had rapidly progressive parkinsonism predominated by postural instability and gait disturbance. Clinical features of 18 of the 23 patients were compatible with progressive supranuclear palsy (PSP); 2 patients were compatible with parkinsonian type multiple system atrophy; 2 patients were compatible with mixed clinical features of both; and 1 patient had PSP-like clinical features. <i>Conclusions:</i> Most parkinsonian patients with SCS present rapidly progressive parkinsonism predominated by postural instability and gait disturbance. SCS observed in patients with parkinsonism does not seem to be a coincidental finding associated with the generalized cerebrovascular process

Neuroinflammation appears early and then plateaus in a mouse model of Alzheimer´s disease shown by PET imaging

Rationale: Neuroinflammation has been associated with different neurological diseases including Alzheimer’s disease. In Alzheimer’s disease the translocator protein 18kDa (TSPO) is overexpressed in the activated microglia that surround the β-amyloid plaques. In the current study we aimed to study the association between β-amyloid deposition and neuroinflammation in a longitudinal study in a mouse model of AD. Methods: To monitor the longitudinal changes in β-amyloid deposition and neuroinflammation we used in vivo PET imaging and ex vivo autoradiography with 11C-PIB and a TSPO tracer, 18F-GE-180, in APP23 mouse model of Alzheimer’s disease. Immunohistochemistry was also used to study the β-amyloid and activated microglia in the mouse brain tissue. Results: The longitudinal study from 17 to 26 months of age showed robust increased binding of 11C-PIB with aging in the frontal cortex, parietotemporal cortex, hippocampus and thalamus of APP23 mice while the increase in 18F-GE-180 binding with the aging was minimal in the areas of early amyloidosis such as frontal cortex and hippocampus. A clear positive correlation between β-amyloid deposition and neuroinflammation as detected with 11C-PIB and 18F-GE-180 was obtained only in the parietotemporal cortex, and thalamus. Conclusion: Neuroinflammation increase detected with 18F-GE-180 is less than the increase in amyloidosis detected with 11C-PIB. Furthermore, the binding of 18F-GE-180 plateaus at earlier stage of pathogenesis, while the amyloidosis continues to increase. We suggest that TSPO can be a good marker for early pathogenesis detection, but not for the long-term progression of the disease process

[(11)C]-MP4A PET cholinergic measurements in amnestic mild cognitive impairment, probable Alzheimer's disease, and dementia with Lewy bodies: a Bayesian method and voxel-based analysis

Non-invasive approaches for positron emission tomography (PET) parametric imaging of acetylcholinesterase (AChE) activity have been developed and applied to the investigation of dementia, mainly Alzheimer's disease (AD), but also dementia with Lewy bodies (DLB), not including, however, patients in the early disease stage. The few cholinergic PET studies on mild cognitive impairment (MCI) did not provide clinical follow-up. One limitation of the methods used so far is the relatively low sensitivity in measuring subcortical or deep cortical structures, which might represent specific disease markers. Here we assessed AChE activity with [11C]-MP4A and PET by a maximum a posteriori Bayesian method (MAPB) based on a 2-tissue compartment-3-rate-constant reference region model. 30 subjects were included: 10 multi-domain amnestic MCI (aMCI) with a follow up of 2 years, 7 probable AD (pAD), 4 DLB subjects, and 9 healthy controls. Regions of interest and voxel-based statistical parametric mapping analyses revealed significant and widespread AChE reductions in several cortical regions and in the hippocampus in all pAD subjects and aMCI subjects who progressed to AD (converters). Noteworthy, hippocampal AChE activity correlated significantly with long-term verbal and non-verbal memory in both aMCI converters and pAD. The pattern was more heterogeneous in early DLB patients, with only 2 out of 4 cases showing a severe or intermediate reduction of AChE activity. The comparable AChE reductions in pAD and aMCI converters indicate the presence of a widespread impairment of the cholinergic system already in the MCI phase. A more variable degree of cholinergic dysfunction is present in early DLB