Table 2 Human neuroimaging studies

MCI/AD

Imaging: FDG-PET for 66 AD, 23 early AD, 22 ctrl subjects

Aimed to investigate cerebral glucose metabolism in early AD

• Glucose uptake in PCC↓ MMSE scores↓

[42]

Imaging: FDG-PET and DTI with 20 early AD, 18 ctrl subjects

Aimed to explore the association among hippocampal structural integrity, whole brain glucose metabolism and episodic memory with early AD subjects and ctrl

• DTI diffusivity in anterior hippocampus↑ Glucose uptake in the anterior hippocampus, parahippocampal gyrus and the PCC↓ Episodic memory assessed by DVR↓

[43]

Imaging: FDG- and 11C-acetoacetate-PET for glucose and ketone metabolism with 51 MCI, 13 AD, 14 ctrl subjects

Aimed to quantify both glucose and ketone metabolism in specific white matter fascicles associated with MCI and AD compared to ctrl

• AD: Glucose uptake in the left posterior cingulate segment↓

• AD: Ketone uptake in the left fornix and right parahippocampal segment of the cingulum↑

[44]

Imaging: MRI, FDG-PET, and PiB-PET for 40 noncarriers and 88 PSEN1, PSEN2, APP mutation carriers

Aimed to use data from longitudinal study to identify pathophysiological biomarkers

• Mutation carriers 10–15 yrs before AD: Bilateral hippocampal atrophy, Precuneus glucose uptake↓ Episodic memory↓

[45]

Imaging: fMRI, FDG-PET, and PiB-PET with 13 MCI (PiB +), 24 ctrl (12 PiB + and 12 PiB negative) older subjects

Aimed to determine whether MCI elder individuals with increased amyloid burden have disruptions in the functional whole-brain connectivity in cortical hubs and if these disruptions are associated with dysfunctional glucose metabolism

• Cortical hubs: Whole-brain connectivity↓ Glucose uptake↓

[46]

Imaging: FDG-PET of 12 relatives with APOE4, 19 relatives without APOE4, 7 AD subjects

Aimed to determine if APOE4 is associated with brain function decline in relatives at risk for familial AD

• APOE4 carriers at risk for AD: Parietal glucose uptake↓ Left–right metabolic asymmetry↑ • Dementia patients: Parietal glucose uptake↓↓

[47]

Imaging: FDG-PET and MRI with 11 AD and 54 non-demented subjects including 27 APOE4 and 27 non-carriers

Aimed to find if the combination of cerebral metabolic rates and genetic risk factors can predict cognitive decline in AD

• Non-demented APOE4 carriers: Glucose uptake in inferior parietal, lateral temporal, and posterior cingulate area↓ → (2 yrs later) Glucose uptake↓↓ Cognition↓

[48]

Imaging: FDG-PET and MRI of 11 APOE4 homozygotes, 22 ctrls without APOE4 allele

Aimed to find whether the brain regions where glucose metabolism declines are also affected in subjects homozygous for the APOE4 allele before the onset of cognitive impairment

• APOE4 homo carriers: Glucose uptake in the parietal, temporal, and prefrontal regions↓ PCC↓↓ Neuropsychological tests↓

[49]

Imaging: DTI with 61 ctrls, 56 MCI, 53 probable AD patients without a vascular component

Aimed to report a comprehensive whole-brain study of diffusion tensor indices and probabilistic tractography obtained from healthy controls, MCI and probable AD subjects

• Affected white matter in AD (vs ctrl): Cingulum bundle, the uncinate fasciculus, the entire corpus callosum and the superior longitudinal fasciculus

• Affected white matter in MCI (vs ctrl): Crossing fibers in the centrum semiovale

[50]

Imaging: DTI with 63 autosomal-dominant AD PSEN1 & 2, or APP mutation carriers (32 asymptomatic and 31 symptomatic) and noncarriers (44 asymptomatic, 1 symptomatic)

Aimed to identify the white matter pattern changes before detectable dementia in AD using early-onset autosomal-dominantly inherited AD subjects

• AD mutation carriers 5–10 yrs before symptom: Structural integrity in posterior parietal and medial frontal regions of the white matter↓

[51]

Imaging: DTI, neurite orientation dispersion and density imaging (NODDI), q-space imaging with 40 cognitively normal ctrls, 38 subjective cognitive decline, and 22 MCI

Aimed to use complementary diffusion metrics (i.e.,DTI, NODDI, and q-space) to study white matter alterations in early-stage AD

Altered white matter tracts (cingulum, thalamic radiation, and forceps major) in MCI subjects:

• Fractional anisotropy↓ (loss of fiber organization)

• Radial diffusivity↑ (myelin degeneration or cell membrane deterioration)

[52]

Imaging: FDG-PET co-registered with T1-MRI

(81 cognitively normal, 21 MCI, 15 AD);

Louvain algorithm; Pearson correlation

Aimed to determine if the strength of the brain metabolic network connectivity can predict the prognosis of MCI and AD and if it is modified by AD-risk gene expression

• Subjects 5 yrs prior to AD diagnosis: Metabolic correlation between brain regions↓ (Female > male)

• Expression of AD risk gene correlates with metabolic alteration in AD vulnerable regions

[32]

PD

Imaging: FDG-PET and CT with 17ctrl and 23 PD subjects

Aimed to evaluate the utility of the PD Related Pattern (PDRP) previously identified by FDG-PET and machine learning techniques, as a biomarker of early-stage PD

• Glucose uptake in parieto-occipital and prefrontal regions↓

• Glucose uptake in cerebellum, pons, thalamus, paracentral gyrus, and lentiform nucleus↑

[53]

HD

Imaging: MRI and FDG-PET with 71 HD mutation carriers (24 pre-symptomatic and 47 symptomatic) and 30 ctrls

Aimed to correlate anatomical and functional changes in various brain areas with the course of HD progression, estimated with a given expanded triplet number

• Pre-symptomatic and symptomatic subjects: Gray- and white-matter volumes↓ Glucose uptake in frontal, temporal lobes, caudate and putamen↓

• Pre-symptomatic: Progressive reduction of white matter

[54]

FTLD/ALS

Imaging: FDG-PET with 22 C9ORF72 mutation carriers with FTLD, 22 non-carriers with FTLD, and 23 ctrls

Previous MRI studies found changes in the thalamus and the cerebellum in C9ORF72-associated FTLD (C9FTLD). Here they aimed to examine functional changes

• Mutation carriers: Glucose uptake in thalamus↓↓ Glucose uptake in frontal and temporal areas, cingulate cortex, Rolandic operculum, caudate nuclei↓

• Non-carriers: Glucose uptake in right thalamus↓ Glucose uptake in frontal and temporal areas, right supplementary motor area, right supramarginal gyrus, right insula, right cingulate gyrus, right caudate nucleus, right postcentral gyrus, and right inferior parietal lobule↓

[55]

Imaging: FDG-PET with 32 ALS (13 with bulbar and 19 with spinal onset), 22 ctrls

• Patients of both groups: Glucose uptake in the amygdalae, midbrain, pons, and cerebellum↑

• Bulbar group (vs Spinal group): Glucose uptake in the large prefrontal and frontal regions↓ Neuropsychological tests score↓

[56]