PET imaging of amyloid deposition in patients with mild cognitive impairment

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3 ± 7.8 (S.D.) years) underwent PET studies with ¹¹C-PIB, and ¹⁸F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1 ± 6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps < 0.01). The PIB retention in MCI converters was comparable to AD patients (p > 0.01). Correlations were observed in the MCI patients between PIB retention and CSF Aβ_1-42, total Tau and episodic memory, respectively.     

Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation

Six young related pre-symptomatic carriers of a His163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucose metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an ¹¹C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.     

Changes in cerebral glucose metabolism in patients with mild-to-moderate Alzheimer's disease: a pilot study with the Chinese herbal medicine fuzhisan

The aim of this study was to investigate the effects of fuzhisan (FZS, 10 mg/day), a Chinese herbal medicine, on cerebral glucose metabolism and neuropsychological metrics in patients with mild-to-moderate Alzheimer's disease (AD). This was a 12-week, randomized, double-blind, placebo-controlled pilot study. Twenty-two subjects were randomly assigned to groups that received FZS (n = 12) or placebo (n = 10). Positron emission tomography (PET) was used to study the regional cerebral metabolic rate of glucose consumption (rCMRglc) at baseline and week 12. We evaluated the clinical efficacy of FZS on cognition and behavioral functions using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Neuropsychiatric Index (NPI), respectively. Compared with placebo, FZS significantly improved ADAS-Cog scores and NPI scores at week 12. Moreover, FZS treatment favorably improved rCMRglc in the bilateral temporal and parietal cortices, hippocampus, and posterior cingulate gyrus. These results suggest that FZS treatment may have a positive effect on cognition, behavioral functions, and rCMRglc in mild-to-moderate AD patients.     

Neural correlates of delayed episodic memory in patients with mild cognitive impairment—A FDG PET study

Mild cognitive impairment (MCI) is characterized by cognitive deficits which do not yet reach the threshold of dementia but represent a putative preclinical state of Alzheimer's disease (AD). Little is known about the neural correlates of delayed episodic memory which is among the earliest signs of cognitive decline in patients at risk of developing AD. We performed resting state positron emission tomography (PET) with ¹⁸Fluorodeoxyglucose (FDG) in patients with MCI, and hypothesized a correlation between delayed episodic memory performance and frontal glucose metabolism since the latter is relatively spared in the preclinical phase of the disease. 43 patients (age: 69.7 ± 7.9 years; 24 male, 19 female) with MCI were investigated by FDG PET. Significant positive correlations with delayed episodic memory performance were calculated by statistical parametric mapping. To our knowledge the present study is the first to demonstrate by FDG PET the neural correlates of delayed episodic memory in patients with MCI. Our study revealed a pattern of cerebral glucose metabolism including bifrontal regions which may contribute to the delayed episodic memory performance of patients with MCI. Since not all patients with MCI will further deteriorate, AD specific mechanism may not be concluded from the present study but warrant longitudinal investigations.     

PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD

The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients’ cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16–24 mg/day) and 6 patients the placebo, and this was followed by 9 months’ galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity (¹¹C-PMP) and ¹¹C-nicotine binding. Neuropsychological tests were performed throughout the study. Inhibition (30–40%) of cortical AChE activity was observed after 3 weeks to 12 months of galantamine treatment. No significant change in mean cortical ¹¹C-nicotine binding was observed during the study. ¹¹C-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and ¹¹C-nicotine binding correlated positively with the results of a cognitive test of attention. In conclusion, galantamine caused sustained AChE inhibition for up to 12 months. At the individual level, the in vivo cortical AChE inhibition and ¹¹C-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.     

In vivo evaluation of amyloid deposition and brain glucose metabolism of 5XFAD mice using positron emission tomography

Positron emission tomography (PET) has been used extensively to evaluate the neuropathology of Alzheimer's disease (AD) in vivo. Radiotracers directed toward the amyloid deposition such as [¹⁸F]-FDDNP (2-(1-{6-[(2-[F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile) and [¹¹C]-PIB (Pittsburg compound B) have shown exceptional value in animal models and AD patients. Previously, the glucose analogue [¹⁸F]-FDG (2-[(18)F]fluorodeoxyglucose) allowed researchers and clinicians to evaluate the brain glucose consumption and proved its utility for the early diagnosis and the monitoring of the progression of AD. Animal models of AD are based on the transgenic expression of different human mutant genes linked to familial AD. The novel transgenic 5XFAD mouse containing 5 mutated genes in its genome has been proposed as an AD model with rapid and massive cerebral amyloid deposition. PET studies performed with animal-dedicated scanners indicate that PET with amyloid-targeted radiotracers can detect the pathological amyloid deposition in transgenic mice and rats. However, in other studies no differences were found between transgenic mice and their wild type littermates. We sought to investigate in 5XFAD mice if the radiotracers [¹¹C]-PIB, and [¹⁸F]-Florbetapir could quantify the amyloid deposition in vivo and if [¹⁸F]-FDG could do so with regard to glucose consumption. We found that 5XFAD animals presented higher cerebral binding of [¹⁸F]-Florbetapir, [¹¹C]-PIB, and [¹⁸F]-FDG. These results support the use of amyloid PET radiotracers for the evaluation of AD animal models. Probably, the increased uptake observed with [¹⁸F]-FDG is a consequence of glial activation that occurs in 5XFAD mice.     

High Activities of BACE1 in Brains with Mild Cognitive Impairment

We recently discovered elevated β-secretase 1 (BACE1) activity in brains with sporadic Alzheimer disease (AD). Moreover, we also found high levels of BACE1 enzymatic activity in the cerebrospinal fluid from patients with both mild cognitive impairment (MCI) and AD. These results suggest that elevation of BACE1 enzymatic activity may occur early or may contribute to AD. We therefore examined whether BACE1 enzymatic activity was changed in MCI brains. BACE1 activity and tumor necrosis factor (TNF)-α levels were measured by enzymatic assay and ELISA in the temporal cortex from 18 patients with clinically well-characterized AD, 18 patients with MCI, and 18 healthy controls. We found a significant increase in BACE1 activity and protein level in brains of MCI and AD patients. Moreover, increased BACE1 activity correlated with plaque numbers and cognition status. We also found an increase in TNF-α in MCI brains. In vitro study revealed that TNF-α rather than other cytokines can up-regulate BACE1 protein expression. These findings suggest that BACE1 increase occurs early in MCI and is possibly induced by TNF-α and that BACE1 enzymatic activity may be important for conversion of MCI to AD.Searching the early events of Alzheimer disease (AD) is becoming critical for effective diagnosis and treatment. Neuritic plaques and neurofibrillary tangles are two major pathologic characteristics of AD and major targets for AD diagnosis. Amyloid β (Aβ) peptide is a major component of neuritic plaques. β-Secretase 1 (BACE1), also known as β-site amyloid precursor protein (APP) cleaving enzyme, is an aspartic protease, a critical enzyme to promote Aβ generation.^1–4 We originally discovered that BACE1 activity and protein expression are significantly increased in AD brains.^5,6 Because the signals from cerebrospinal fluid (CSF) reflect most of neuropathologic changes in AD, we have studied BACE1 activity in the CSF from patients with mild cognitive impairment (MCI) and AD and found elevated BACE1 activity in the CSF of both MCI and AD patients.^7,8 These results indicate that activation of BACE1 may play an important role in the early stage of AD when cognitive deficits are first observed and in progressive dementia associated with AD. However, whether BACE1 enzymatic activity and protein expression were altered in the brain as early as at the MCI stage was not known, possibly because of limits of sources of autopsied brain tissues. To examine whether BACE1 was activated in the brain during the early stages of AD (ie, MCI), we took advantage of the brain bank⁹ of rapidly autopsied MCI and AD brain tissues and biochemically measured BACE1 activity in brains of nondemented (ND) controls, MCI patients, and AD patients. We found that BACE1 enzymatic activity was significantly increased in both MCI and AD brains in the present study. Moreover, we also found that BACE1 activity was positively correlated with numbers of plaques and negatively correlated with Mini-Mental State Examination (MMSE) scores in MCI patients. Interestingly however, we also observed that there was no significant difference in BACE1 activity between MCI and AD patients. Because recent studies demonstrated that BACE1 may affect neuronal activity and brain metabolism,^10–13 we conclude that BACE1 activity precedes the clinical diagnosis of AD and could be an early indicator of neuronal dysfunction or disease in AD.     

Cognition, glucose metabolism and amyloid burden in Alzheimer's disease

The authors investigated relationships between glucose metabolism, amyloid load, and measures of cognitive and functional impairment in Alzheimer's disease (AD). Patients meeting criteria for probable AD underwent ¹¹C-labeled Pittsburgh Compound-B ([¹¹C]PIB) and 18F-fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) imaging and were assessed on a set of clinical measures. The Pittsburgh Compound-B (PIB) Distribution volume ratios and fluorodeoxyglucose (FDG) scans were spatially normalized and average PIB counts from regions-of-interest (ROI) were used to compute a measure of global PIB uptake. Separate voxel-wise regressions explored local and global relationships between metabolism, amyloid burden, and clinical measures. Regressions reflected cognitive domains assessed by individual measures, with visuospatial tests associated with more posterior metabolism, and language tests associated with metabolism in the left hemisphere. Correlating regional FDG uptake with these measures confirmed these findings. In contrast, no correlations were found between either voxel-wise or regional PIB uptake and any of the clinical measures. Finally, there were no associations between regional PIB and FDG uptake. We conclude that regional and global amyloid burden does not correlate with clinical status or glucose metabolism in AD.     

C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment

C9orf72 G₄C₂ repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer's disease (AD) is less clear. We assessed the prevalence of G₄C₂ pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G₄C₂ repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G₄C₂ repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor.     

Reduced 5-HT2A receptor binding in patients with mild cognitive impairment

Previous studies of patients with Alzheimer's disease (AD) have described reduced brain serotonin 2A (5-HT_2A) receptor density. It is unclear whether this abnormality sets in early in the course of the disease and whether it is related to early cognitive and neuropsychiatric symptoms.We assessed cerebral 5-HT_2A receptor binding in patients with mild cognitive impairment (MCI) and related 5-HT_2A receptor binding to clinical symptoms. Sixteen patients with MCI of the amnestic type (mean age 73, mean MMSE 26.1) and 17 age and sex matched control subjects were studied with MRI and [¹⁸F]altanserin PET in a bolus–infusion approach. A significant global reduction of 20–30% in 5-HT_2A binding (atrophy corrected) was found in most neocortical areas. Reduced 5-HT_2A binding in the striatum correlated significantly with Neuropsychiatric Inventory depression and anxiety scores. We conclude that widespread reductions in 5-HT_2A receptor binding were found in amnestic MCI, pointing at the presence of serotonergic dysfunction in prodromal AD. This may provide some of the pathophysiological background for the neuropsychiatric symptoms found in early AD.     

Comparative efficacy of lithium and aducanumab for cognitive decline in patients with mild cognitive impairment or Alzheimer’s disease: A systematic review and network meta-analysis

BackgroundIn 2021, the US Food and Drug Administration granted an accelerated approval to aducanumab for patients with mild cognitive impairment (MCI) and mild dementia caused by Alzheimer’s disease (AD); however, the cost of aducanumab is high, at approximately $28,000 for one year per person. On the other hand, lithium is much cheaper at $40 a year, and has been reported to be effective for the cognitive decline observed in both patients with MCI and AD. In contrast to acetylcholinesterase inhibitors and N-methyl D-aspartate receptor antagonists, aducanumab and lithium may be disease-modifying drugs. Therefore, we focused on aducanumab and lithium and compared the effects of these drugs on the cognitive decline in MCI and AD patients using a network meta-analysis.MethodsPubMed, the Cochrane Library, CINHAL, and ClinicalTrials.gov were searched for randomized controlled trials testing lithium or aducanumab for the treatment of cognitive decline in patients with MCI or AD, up to January 31, 2022. A frequentist fixed-effect network meta-analysis was performed to estimate direct and indirect effects. The primary outcome was change scores in cognitive decline measured by Mini-Mental State Examination. This study has been registered with PROSPERO (number CRD42022304807).ResultsNetwork meta-analysis demonstrated that lithium was significantly more effective than aducanumab in the primary outcome.ConclusionAlthough there were various limitations in this study, lithium may be a more cost-effective treatment than aducanumab for MCI and AD.     

+10 T/C polymorphisms in the gene of transforming growth factor-beta1 are associated with neurodegeneration and its clinical evolution

Transforming growth factor-beta1 (TGF-beta1) acts as an immunosuppressant by inhibiting the expression of several pro-inflammatory cytokines. Its gene contains single nucleotide polymorphisms (SNPs) at codon +10 (T-->C) and +25 (G-->C) that appear to influence the level of expression of TGF-beta1. We investigated these SNPs in 198 healthy controls (HC), 193 patients with Alzheimer's disease (AD) and 48 patients with mild cognitive impairment (MCI). Among the latter, after a 4-year follow-up, 21 were diagnosed as AD (MCI-->AD) while 18 did not progress (stable MCI). We observed that both the +10 C allele and the CC genotype were over-represented in AD when compared to HC. These variants significantly raised the risk of disease independently of the status of apolipoprotein E4. The CC genotype was also over-expressed in MCI, especially in MCI-->AD. These results suggest that TGF-beta1 may be one of the early markers involved in the inflammatory mechanisms underlying the pathogenesis of AD.     

Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo

Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) ε4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE ε4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (β-amyloid [Aβ] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Aβ, tau, phosphorylated tau (P-tau) and interleukin-1β (IL-1β) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1β and Aβ₄₂ peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was “turned on” by excess Aβ peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.     

Efficacy of non-invasive brain stimulation on global cognition and neuropsychiatric symptoms in Alzheimer’s disease and mild cognitive impairment: A meta-analysis and systematic review

BackgroundNon-invasive brain stimulation (NIBS) techniques have shown some promise in improving cognitive and neuropsychiatric symptoms (NPS) in people with Alzheimer’s disease (AD) and its prodromal stage, mild cognitive impairment (MCI). However, data from clinical trials involving NIBS have shown inconsistent results. This meta-analysis investigated the efficacy of NIBS, specifically repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) compared to sham stimulation on global cognition and NPS in people with AD and MCI.MethodMulti-session randomized sham-controlled clinical trials were identified through MEDLINE, PsycINFO, and Embase until June 2021. Standardized mean difference (SMD) and 95% confidence interval (CI) between the active and sham treatments were calculated using random-effects meta-analyses. Included studies reported outcome measures for global cognition and/or NPS. Heterogeneity, from different NIBS techniques, disease populations, or tests used to assess global cognition or NPS, was measured using chi-square and I², and investigated using subgroup analyses. Possible effects of covariates were also investigated using meta-regressions.ResultThe pooled meta-analyses included 19 studies measuring global cognition (N_active=288, N_sham=264), and 9 studies investigating NPS (N_active=165, N_sham=140). NIBS significantly improved global cognition (SMD=1.14; 95% CI=0.49,1.78; p = 0.001; I² = 90.2%) and NPS (SMD=0.82; 95% CI=0.13, 1.50; p = 0.019; I² = 86.1%) relative to sham stimulation in patients with AD and MCI. Subgroup analyses found these effects were restricted to rTMS but not tDCS, and to patients with AD but not MCI. Meta-regression showed that age was significantly associated with global cognition response (N_studies=16, p = 0.020, I² = 89.51%, R² = 28.96%), with larger effects sizes in younger populations. All significant meta-analyses had large effect sizes (SMD ≥0.8), suggesting clinical utility of NIBS in the short term. There remained substantial heterogeneity across all subgroup analyses and meta-regressions (all I² > 50%). Egger’s tests showed no evidence of publication biases.ConclusionrTMS improved global cognition and NPS in those with AD. Further studies in MCI and using tDCS will help to fully evaluate the specific NIBS techniques and populations most likely to benefit on global cognition and NPS measures. Additional research should investigate the long term clinical utility of NIBS in these populations.     

Amyloid‐Aβ Peptide in Olfactory Mucosa and Mesenchymal Stromal Cells of Mild Cognitive Impairment and Alzheimer's Disease Patients

Patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) might develop olfactory dysfunction that correlates with progression of disease. Alteration of olfactory neuroepithelium associated with MCI may be useful as predictor of cognitive decline. Biomarkers with higher sensitivity and specificity would allow to understand the biological progression of the pathology in association with the clinical course of the disease. In this study, magnetic resonance images, apolipoprotein E (ApoE) load, Olfactory Connecticut test and Montreal Cognitive Assessment (MoCA) indices were obtained from noncognitive impaired (NCI), MCI and AD patients. We established a culture of patient‐derived olfactory stromal cells from biopsies of olfactory mucosa (OM) to test whether biological properties of mesenchymal stromal cells (MSC) are concurrent with MCI and AD psychophysical pathology. We determined the expression of amyloid Aβ peptides in the neuroepithelium of tissue sections from MCI and AD, as well as in cultured cells of OM. Reduced migration and proliferation of stromal (CD90⁺) cells in MCI and AD with respect to NCI patients was determined. A higher proportion of anosmic MCI and AD cases were concurrent with the ApoE ε4 allele. In summary, dysmetabolism of amyloid was concurrent with migration and proliferation impairment of patient‐derived stem cells.     

Cholinergic activity correlates with reserve proxies in Alzheimer's disease

The clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain “reserve capacity.” A possible association between the cholinergic system and reserve is suggested by preclinical observations that the cholinergic system allows cortical plasticity and by clinical observations of variable responses to cholinergic treatments depending on the patient’s educational level. The aim of this study was to investigate the association of reserve proxies, that is, education and occupation, with acetylcholinesterase (AChE) activity, measured voxelwise by [¹¹C]-MP4A and positron emission tomography (PET), in 9 healthy controls (HC), 7 patients with early probable AD, and 9 subjects with mild cognitive impairment (MCI) at the time of PET imaging, who progressed to AD at follow-up (prodromal AD). The analysis of prodromal and early AD showed positive correlations between education and AChE activity in the hippocampus, bilaterally, and between occupation and AChE activity in the right posterior cingulate gyrus. The significant correlation between AChE activity in structures belonging to the memory network and reserve proxies suggests that the brain reserve in AD is associated with a preserved/stimulated cholinergic neurotransmission.     

Subjective cognitive decline predicts future deterioration in cognitively normal patients with Parkinson's disease

Increasing evidence suggests that subjective cognitive decline (SCD) is a potential predictor of future cognitive decline or dementia. We investigated whether SCD in patients with Parkinson's disease (PD) is a predictor of future cognitive decline. Forty-six cognitively normal patients with PD were selected using comprehensive neuropsychological tests, and classified depending on the presence (PD-SCD⁺, n = 25) or absence of SCD (PD-SCD⁻, n = 21). After a mean follow-up of 2.4 years, we repeated the cognitive assessments with the same subjects. The clinical characteristics and cognitive performance of the 2 groups did not differ at baseline. At the follow-up assessment, 11 patients in the PD-SCD⁺ group (44.0%) and 2 in the PD-SCD⁻ group (9.5%) were diagnosed with mild cognitive impairment (MCI), and the PD-SCD⁺ patients showed more rapid decline in semantic fluency and visuospatial memory tasks than those in the PD-SCD⁻ group. A multivariate logistic regression analysis showed that presence of SCD (odds ratio, 8.378; 95% confidential interval, 1.472–47.683, p = 0.017) and higher Unified PD Rating Scale motor score of 20 or more (odds ratio, 4.539; 95% confidential interval, 1.004–20.528; p = 0.049) were risk factors for incident MCI. Present results demonstrate that SCD in cognitively normal patients with PD is an independent risk factor for incident MCI and acts as a predictor for future cognitive decline.     

Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease: a combined [C]DASB and [F]altanserin-PET study

In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT_2A) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT_2A receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [¹⁸F]altanserin and [¹¹C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([¹¹C]DASB). Overall [¹⁸F]altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [¹¹C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [¹¹C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT_2A receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.     

Effects of age and β-amyloid on cognitive changes in normal elderly people

Age-related decline is common in multiple cognitive domains. β-amyloid (Aβ) deposition, a pathological hallmark of Alzheimer's disease, is also associated with cognitive changes in many older people. In this study, we examined a wide range of cognitive function in order to differentiate the effect of age and Aβ on cognition during aging. Using positron emission tomography (PET) imaging with the radiotracer Pittsburgh Compound B (PIB), we classified normal older subjects as High PIB-Old and Low PIB-Old and applied sequential multivariate analyses (i.e., principal components analysis [PCA] and discriminant analysis) to obtain summary measures of cognitive tests encompassing multiple cognitive domains. Among 5 cognitive components, a significant age effect was observed in component scores of visual memory and executive functions, regardless of the level of Aβ. Discriminant scores (weighted scores of the 5 cognitive components) revealed a significant effect of both age and Aβ and were further associated with quantitative PIB counts. The results of the current study highlight both effects of age and Aβ on cognitive changes in normal elderly.     

Upregulation of select rab GTPases in cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease

Endocytic system dysfunction is one of the earliest disturbances that occur in Alzheimer's disease (AD), and may underlie the selective vulnerability of cholinergic basal forebrain (CBF) neurons during the progression of dementia. Herein we report that genes regulating early and late endosomes are selectively upregulated within CBF neurons in mild cognitive impairment (MCI) and AD. Specifically, upregulation of rab4, rab5, rab7, and rab27 was observed in CBF neurons microdissected from postmortem brains of individuals with MCI and AD compared to age-matched control subjects with no cognitive impairment (NCI). Upregulated expression of rab4, rab5, rab7, and rab27 correlated with antemortem measures of cognitive decline in individuals with MCI and AD. qPCR validated upregulation of these select rab GTPases within microdissected samples of the basal forebrain. Moreover, quantitative immunoblot analysis demonstrated upregulation of rab5 protein expression in the basal forebrain of subjects with MCI and AD. The elevation of rab4, rab5, and rab7 expression is consistent with our recent observations in CA1 pyramidal neurons in MCI and AD. These findings provide further support that endosomal pathology accelerates endocytosis and endosome recycling, which may promote aberrant endosomal signaling and neurodegeneration throughout the progression of AD.