Purpose We report the first clinicopathological series of longitudinal FDG-PET scans in post-mortem (PM) verified cognitively normal elderly (NL) followed to the onset of Alzheimer's-type dementia (DAT), and in patients with mild DAT with progressive cognitive deterioration. Methods Four NL subjects and three patients with mild DAT received longitudinal clinical, neuropsychological and dynamic FDG-PET examinations with arterial input functions.NL subjects were followed for 13±5 years, received FDG-PET examinations over 7±2 years, and autopsy 6±3 years after the last FDG-PET. Two NL declined to mild cognitive impairment (MCI), and two developed probable DAT before death. DAT patients were followed for 9±3 years, received FDG-PET examinations over 3±2 years, and autopsy 7±1 years after the last FDG-PET. Two DAT patients progressed to moderate-to-severe dementia and one developed vascular dementia. Results The two NL subjects who declined to DAT received a PM diagnosis of definite AD. Their FDG-PET scans indicated a progression of deficits in the cerebral metabolic rate for glucose (CMRglc) from the hippocampus to the parietotemporal and posterior cingulate cortices. One DAT patient showed AD with diffuse Lewy body disease (LBD) at PM, and her last in vivo PET was indicative of possible LBD for the presence of occipital as well as parietotemporal hypometabolism. Conclusion Progressive CMRglc reductions on FDG-PET occur years in advance of clinical DAT symptoms in patients with pathologically verified disease. The FDG-PET profiles in life were consistent with the PM diagnosis.

Having a parent affected with late-onset Alzheimer's disease (AD) is a risk factor for developing AD among cognitively normal subjects. We examined whether cognitively normal subjects with a parental family history of AD show cerebral metabolic rate of glucose (CMRglc) reductions consistent with AD as compared with those without a family history and whether there are parent gender effects. Fortynine 50-to 80-year-old normal subjects were examined who received clinical, neuropsychological, and 2-[ 18 F]fluoro-2-deoxy-D-glucosepositron emission tomography examinations, including 16 subjects with a maternal (FHm) and eight with a paternal (FHp) family history of AD and 25 with no family history (FH ؊ ). FH groups were comparable for demographic and neuropsychological measures. As compared with both FH ؊ and FHp groups, FHm subjects showed CMRglc reductions in the same regions as clinically affected AD patients, involving the posterior cingulate cortex/precuneus, parietotemporal and frontal cortices, and medial temporal lobes (P < 0.05, corrected for multiple comparisons). These effects remained significant after accounting for possible risk factors for AD, including age, gender, education, apolipoprotein E genotype, and subjective memory complaints. No CMRglc differences were found between FHp and FH ؊ subjects. This study shows a relationship between reduced CMRglc in AD-vulnerable brain regions and a maternal family history of AD in cognitively normal individuals.A fter advanced age, the most significant risk factor for late-onset Alzheimer's disease (AD) is a family history of AD (1). Normal individuals with a first-degree relative affected by AD, especially a parent, are at a 4-to 10-fold higher risk for developing AD as compared with individuals with a negative family history (2-4). Apart from the rare early-onset form of familial AD related to autosomal dominant genetic mutations, genes with a clear Mendelian pattern of transmission for lateonset familial AD have not been identified. To date, the 4 allele of the apolipoprotein E (ApoE) gene is the only established genetic risk factor for late-onset AD and is found in Ϸ40% of late-onset AD cases with a positive family history (1). The ApoE-4 genotype has, however, no clear familial pattern of transmission and appears to act as a risk modifier by lowering the age at onset of clinical symptoms, rather than as a genetic determinant (see ref. 5 for review), indicating that other factors contribute to the etiology and phenotypic expression of disease. The biological mechanisms through which family history of AD confers increased susceptibility to late-onset AD are not known.A consistent feature of AD is the marked reduction of the cerebral metabolic rate of glucose (CMRglc) as measured by using positron emission tomography (PET) imaging with 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) as the tracer (FDG-PET). FDG-PET studies demonstrate a specific pattern of CMRglc impairment in AD, involving the parietotemporal, posterior cingulate, and to a lesser extent frontal cort...

Atrophic changes of the hippocampus are typically regarded as an early sign of Alzheimer’s dementia (AD). Using the radial distance atrophy mapping approach, we compared the longitudinal MRI data of 10 cognitively normal elderly subjects who remained normal at 3-year and 6-year follow-up (NL-NL) and 7 cognitively normal elderly subjects who were diagnosed with mild cognitive impairment (MCI) 2.8 (range 2.0–3.9) and with AD 6.8 years (range 6.1–8.2) after baseline (NL-MCIAD). 3D statistical maps revealed greater hippocampal atrophy in the NL-MCIAD relative to the NL-NL group at baseline (left p = 0.05; right p = 0.06) corresponding to 10–15% CA1, and 10–25% subicular atrophy, and bilateral differences at 3-year follow-up (left p = 0.001, right p < 0.02) corresponding to 10–30% subicular, 10–20% CA1, and 10–20% newly developed CA2-3 atrophy. This preliminary study suggests that excess CA1 and subicular atrophy is present in cognitively normal individuals predestined to decline to amnestic MCI, while progressive involvement of the CA1 and subiculum, and atrophy spreading to the CA2-3 subfield in amnestic MCI, suggests future diagnosis of AD.

Background:At cross-section, cognitively normal individuals (NL) with a maternal history of late-

Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimer's disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL = 18, 69.9 ± 6.7 years) and subjects with mild cognitive impairment (MCI = 15, 74.9 ± 8.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL = 17, MCI = 7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (q = À0.41, P = 0.049) and global cortical (q = À0.46, P = 0.02) vasoreactivity to hypercapnia (VR h ). The FCRP-VR h relationships were most pronounced in the MCI group: hippocampus (q = À0.77, P = 0.04); global cortex (q = À0.83, P = 0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VR h was lower in MCI than in NL subjects (Z = À2.0, P = 0.047). This difference persisted after age and FCRP correction (F [3,20] = 4.6, P = 0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VR h is more sensitive to vascular burden than either resting CBF or brain volume.

The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to the subtle brain changes that occur in the preclinical stage of the disease. Reductions in the cerebral metabolic rate of glucose (CMRglc), a measure of neuronal function, have proven to be a promising tool in the early diagnosis of AD. In vivo brain 2-[18F]fluoro-2-Deoxy-D-glucose-positron emission tomography (FDG-PET) imaging demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. There is increasing evidence that hypometabolism appears during the preclinical stages of AD and can predict decline years before the onset of symptoms. This review will give an overview of FDG-PET results in individuals at risk for developing dementia, including: presymptomatic individuals carrying mutations responsible for early-onset familial AD; patients with Mild Cognitive Impairment (MCI), often a prodrome to late-onset sporadic AD; non-demented carriers of the Apolipoprotein E (ApoE) ε4 allele, a strong genetic risk factor for late-onset AD; cognitively normal subjects with a family history of AD; subjects with subjective memory complaints; and normal elderly followed longitudinally until they expressed the clinical symptoms and received post-mortem confirmation of AD. Finally, we will discuss the potential to combine different PET tracers and CSF markers of pathology to improve the early detection of AD.

Background-Epidemiology and imaging studies showed that cognitively normal (NL) individuals with a maternal history (MH) of late-onset Alzheimer's disease (LOAD) may be at increased risk for AD compared to NL with a paternal history (PH) and NL with a negative family history of LOAD (NH). Using a panel of cerebrospinal fluid (CSF) markers, this study examined whether NL MH showed evidence for AD pathology compared to PH and NH.

BackgroundPrevious studies at single academic institutions have identified variations in the prevalence of photodermatoses among racial groups. The purpose of the study was to compare the distribution of photodermatoses between Whites and Blacks at four academic medical centers in the USA.MethodsA retrospective chart review was performed at four institutions’ general dermatology clinics using diagnoses consistent with the International Classification of Disease (ICD), Ninth and Tenth Revisions, codes related to photodermatoses between August 2006 and August 2016. A total of 9736 charts were manually reviewed and classified. Analyses were performed analyzing the frequency of photodermatoses between Whites and Blacks in the pooled data.ResultsThere were 1,080 patients with photodermatoses identified. Statistically significant differences in the frequency of photodermatoses between Whites and Blacks were identified for polymorphous light eruption (more common in Blacks), photoallergic contact dermatitis, phototoxic drug eruption, phytophotodermatitis, porphyria, and solar urticaria (more common in Whites). The most commonly diagnosed photodermatoses were polymorphous light eruption (total 672), and photodermatitis not otherwise specified (total 189).ConclusionOur study demonstrated significantly higher proportions of polymorphous light eruption in Blacks, and higher proportions of photoallergic contact dermatitis, phototoxic drug eruptions, phytophotodermatitis, porphyrias, and solar urticaria in Whites.