Key points

Introduction

In recent years, with important advances in molecular genetics, neuroimaging has emerged as a potentially valuable tool to link individual differences in the human genome to structure and functional variation into brain system. This allows narrowing the gaps in the casual chain from a given genetic variation to a brain disorder. Considering that the effect of genes are not usually expressed directly at the level of mental behavior, but rather are mediated by their molecular and cellular effects, molecular imaging could play a key role on this regard.

This article reviews the literature using molecular imaging as an intermediate phenotype and/or biomarker for illness related to certain genetic alterations. Focus is on the two most common neurodegenerative disorders, Alzheimer’s disease (AD) and Parkinson disease (PD).

Introduction

In recent years, with important advances in molecular genetics, neuroimaging has emerged as a potentially valuable tool to link individual differences in the human genome to structure and functional variation into brain system. This allows narrowing the gaps in the casual chain from a given genetic variation to a brain disorder. Considering that the effect of genes are not usually expressed directly at the level of mental behavior, but rather are mediated by their molecular and cellular effects, molecular imaging could play a key role on this regard.

This article reviews the literature using molecular imaging as an intermediate phenotype and/or biomarker for illness related to certain genetic alterations. Focus is on the two most common neurodegenerative disorders, Alzheimer’s disease (AD) and Parkinson disease (PD).

Alzheimer’s disease

AD is the most important cause of dementia and affects 1 in 10 individuals over the age of 65. By 2050, there will be an estimated 1 million new cases per year in the United States, increasing health care costs by around 85%. Even if a prevention therapy has only a modest effect, it could provide an extraordinary public health benefit. For instance, a therapy that delays by 5 years the onset of this disorder could reduce the risk of it by one half. It is estimated that in almost 50 years, a treatment modestly helpful, could reduce the prevalence of AD from 16 to 9 million cases and reduce costs from $750 to $425 billion per year.

Amyloid plaques and neurofibrillary tangles are the most common neuropathologic hallmarks of AD and occur decades before symptoms. It is well known that the clinical diagnosis is not possible until a more advanced pathologic stage of disease is reached. Therefore, there is a need to shift the paradigm from late intervention (where treatment comes too late in the course of the disease) to prevention, targeting at-risk asymptomatic patients with disease-modifying drugs, when the potential for preservation of function is the greatest, and before irreversible synaptic and neuronal injury. Thus, it is necessary to identify individuals who are still cognitively normal, or who present mild symptoms (mild cognitive impairment) and have either a high risk for developing AD or are in a presymptomatic stage of disease.

Over one half of the risk for developing AD is owing to genetic factors, with heritability estimates in the range of 58% to 74%. Case-control genome-wide association revealed a large number of genetics variants that have now been consistently associated with AD, and have been disclosed by meta-analyses of large number of studies worldwide. Molecular neuroimaging, especially with fluoro-[ ¹⁸ F]-deoxyglucose positron emission tomography (FDG-PET) and with amyloid-β peptides (Aβ) PET ligands have provided evidence for phenotypic differences in cognitively normal individuals under some genetics or heritable risks for AD. For instance, FDG-PET has been successfully used to demonstrate signs of AD pathology, predicting patients with mild cognitive impairment who will decline in cognition. The FDG-PET pattern in AD demonstrates specific reductions in the cerebral metabolic rate of glucose (CMRglc) in the parietotemporal areas, posterior cingulate cortex (PCC) and medial temporal lobe, whereas cerebellum, striatum, basal ganglia, and primary visual and sensorimotor remain preserved. AD can be divided into 2 groups by age of onset: Early onset, at less than 65 years (EOAD) and late onset, at greater than 65 years (LOAD), each having some known gene mutations.

Molecular Imaging and Early Onset Alzheimer’s Disease

EOAD is very rare, accounting for approximately 1% of AD in the general population. Different autosomal-dominant genetic mutations located in 3 different genes have been firmly linked to this form: Amyloid precursor protein on chromosome 21, presenilin (PSEN1) on chromosome 14, and presenilin 2 (PSEN2) on chromosome 1. Although rare, these mutations have full penetrance in early age of onset, usually before 65 years old. Some FDG-PET studies on cognitively normal individuals carrying these genetic mutations showed a slightly different AD pattern, characterized by global reductions of CMRglc, being more pronounced on parietotemporal, PCC, and medial temporal lobe ( Table 1 ).

Table 1

FDG-PET studies on normal individuals carrying genetic mutations

Author, Year	N	Gene	Clinical Characteristics	Imaging Findings
Kennedy et al, 1995	24	APP PSEN1	Mean MMSE, 29/30 (range, 25–30) Mean age, 44.7 y (range, 31–60)	↓CMRglc parietotemporal with additional minor dorsolateral prefrontal
Perani et al, 1997	7	APP	Mean age, 34.6 y (range, 18–55) All subjects APOE 3/3	Significant ↓CMRglc parietotemporal and additional to dorsolateral prefrontal Thalamic impairment was seen
Mosconi et al, 2006	7	PSEN1	Age range, 35–49 y MMSE range, 25–30 (5/7 with 30)	AD ↓CMRglc pattern preceding MRI signs of atrophy
Nikisch et al, 2008	1	PSEN2	3-Year follow-up of a 48-year-old woman who had MMSE dropping from 28 to 0	At first presentation, MRI showed subtle changes, whereas FDG-PET showed marked ↓CMRglc on left parietal and precuneus cortex

Abbreviations: AD, Alzheimer’s disease; APOE, apolipoprotein E; APP, amyloid precursor protein; CMRglc, cerebral metabolic rate of glucose; FDG-PET, fluoro-[ ¹⁸ F]-deoxyglucose positron emission tomography; MMSE, Minnesota Mini Mental State Examination; PSEN, presenilin.

In addition to the typical AD pattern on FDG-PET, cognitively normal individuals carrying amyloid precursor protein mutations also present additional prefrontal CMRglc impairment (mild intensity). The reductions in CMRglc in cognitively normal individuals carrying PSEN1 mutations not only precede clinical symptoms and structural brain changes, but also can be present up to 13 years before the onset of symptoms ( Fig. 1 ).

A 56-year-old male, presenilin carrier presented with subjective memory complaint but not meeting criteria for mild cognitive impairment. The fluoro-[ ¹⁸ F]-deoxyglucose positron emission tomography image shows severe hypometabolism in the parietal, temporal, precuneus, and posterior cingulate cortex at the baseline study. No MRI signs of atrophy are identified on the corregistered images at this time. The same plane slices in a 2-year follow-up show greater glucose metabolism impairment of these cortex regions in addition to structural signs of sulci enlargement on MRI.

In symptomatic or cognitively normal individuals carrying amyloid precursor protein or PSEN mutations, Pittsburg Compound B (PiB) retention is seen predominately in the striatum and PCC. Unlike the situation in sporadic AD, these patients do not have as much as Aβ burden in the frontal and parietotemporal lobes, as well as the PCC ( Table 2 ).

Table 2

Symptomatic or normal individuals carrying APP or PSEN mutations

Author, Year	N	Gene	Clinical Characteristics	Imaging Findings
Klunk et al, 2007	5	PSEN1	Age range, 35–45 y None of the patients were symptomatic	Increased striatum uptake with a relative lack of PiB retention in cortical areas
Remes et al, 2008	2	APP	49-year-old man with MMSE 22/30 and 60-year-old woman with MMSE 17/30	Increased striatum and PCC uptake
Koivunen et al, 2008	4	PSEN1	One woman and 3 men (mean age ± SD, 53.0 ± 5.5 y) MMSE were 14, 16, 24, and 27/30	Increased striatum, PCC and anterior cingulate gyrus
Knight et al, 2011	7	PSEN1	Presymptomatic and mildly affected (MMSE ≥20)	Increased thalamus uptake; increased striatum uptake were seen, but in a minor intensity compared with previous studies

Abbreviations: AD, Alzheimer’s disease; APP, amyloid precursor protein; MMSE, Minnesota Mini Mental State Examination; PCC, posterior cingulate cortex; PiB, Pittsburg Compound B; PSEN, presenilin.

Molecular Imaging and Late-Onset Alzheimer’s Disease

The evidence from EOAD individuals with genetic mutation studies provided not only important data about preclinical AD-related brain impairment, for instance, supporting the key role for Aβ in this disease, as well served as resource for studying the relationship between genetic and phenotypic expression of this disorder.

Different from the EOAD, LOAD represents the majority of the AD cases (99%) and does not seem to be associated with clearly discernible genetic mutations. LOAD has a complex polygenic (risk alleles), and nongenetic background (sociodemographic background [education level], lifestyle [diet, environmental], and medical history [medication, vascular disease], etc), which modifies not only age at onset, but also the course of disease. In most cases, genetic influence seems to be predominant.

Molecular Imaging and apolipoprotein E ε4–associated genetic risk for late-onset Alzheimer’s disease

The epsilon 4 allele (ε4) of apolipoprotein E (APOE) gene located in chromosome 19, is a well-recognized risk factor for LOAD, and not only accounts for the majority of LOAD cases, but is associated with an earlier age of onset compared with other genotypes. Indeed, the ε4 gene dose (ie, number of alleles in a person’s APOE genotype) is associated with higher risk for developing AD. Individuals with a double dose of the ε4 have a 35-fold increase risk of developing the disease.

Several FDG-PET studies have demonstrated the association between metabolic impairment in cognitively normal individuals carrying at least 1 ApoE ε4 allele compared with ε4 noncarriers. This metabolic impairment is characterized by a significant reduction on CMRglc in PCC/precuneus, parietotemporal, and prefrontal regions, the same as clinically affected AD patients. Moreover, APOE ε4 homozygote carriers have significantly lower CMRglc in each of these brain regions, when compared with APOE ε4 heterozygotes and noncarriers, which shows that gene dose is a putative risk for brain metabolism impairment as well. Even young adults (20–39 years old) who are ε4 carries have been detected to have low rates of CMRglc bilaterally in the posterior cingulate, parietotemporal, and prefrontal cortex, which may be the earliest brain abnormalities described, several decades before the possible onset of dementia. Longitudinal studies showed that in cognitively normal late-middle-aged ε4 carries, the CMRglc impairment is progressive and correlates with future cognitive decline. From a prevention research perspective, this leads to a paradigm for testing the potentials of treatment to prevent this disorder, without having to study thousands of subjects or wait many years to determine whether or when treated individuals develop symptoms.

Imaging Aβ burden PET ligands through PiB in middle-aged to old cognitively normal individuals revealed that fibrillar Aβ is significantly associated with the APOE ε4 carrier status and ε4 gene dose in AD-affected mean cortical, frontal, temporal, PCC, precuneus, and basal ganglia ( Fig. 2 ). Of interest, the homozygote ε4 carriers with mild cognitive impairment had an even greater fibrillar Aβ burden, comparable with the average in patients with probable AD.

An 84-year-old woman with apolipoprotein E e3/e4 genotype presented with mild cognitive impairment. The Pittsburgh compound B positron emission tomography axial slices through the brain show high amyloid burden in the anterior and posterior cingulate cortex, parietotemporal, and frontal cortices.

( Courtesy of Dr G.K. von Schulthess and Dr F. Buck, Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland; and Dr C. Hock, Psychiatry, University Hospital Zurich, Zurich, Switzerland.)

Molecular Imaging and family history risk for late-onset Alzheimer’s disease

After advanced aged, family history (FH) is the second greatest risk factor for LOAD, even in the absence of known genetic mutations. Children of affected parents are especially at high risk of AD. Although having one parent with AD is per se a major risk factor for developing AD in the offspring, maternal transmission may have a major impact than the paternal transmission.

Recent FDG-PET studies showed phenotypic differences in CMRglc between cognitively normal individuals with a maternal FH (FHm), paternal FH (FHp), or negative FH for AD. Reductions in CMRglc were seen in the medial temporal lobe, parietotemporal, PCC, and frontal cortex, similar to the findings detected in clinical AD patients. Interestingly, this difference in CMRglc remained significant after accounting for potential risk factors, such as APOE ε4 genotype or the presence of subjective memory complaints. AD glucose metabolism pattern was found within the group of FHm subjects, irrespective of their APOE status. APOE ε4 FHm noncarriers had CMRglc reductions compared with the APOE ε4 noncarriers with an AD father and those with no parents affected. Moreover, FHm subjects have a progressive decline on CMRglc in the parietotemporal, PCC, and MTC as compared with FHp and no FH. Again, this decline remained significant after accounting for potential risk factors as APOE ε4 genotype or the presence of subjective memory complaints. These findings on FHm raise the hypothesis that a combination of defective mitochondrial function, increased oxidative stress, and possible mitochondrial DNA mutations leads to the CMRglc alterations. The fact that mitochondrial DNA is entirely maternally inherited in humans support this hypothesis.

A PiB-PET study showed that cognitively normal subjects with LOAD parents have high Aβ burden in brain regions typically affected in clinical AD, such as anterior and PCC, precuneus, parietotemporal, occipital, and frontal cortices compared with cognitively normal subjects with no FH. However, FHm subjects have increased and more widespread PiB retention than FHp subjects. Moreover, although both the FHp and FHm subjects showed increased PiB retention in the PCC and medial frontal gyrus, only FHm showed PiB retention in the lateral neocortex, which according to Braaks’s neuropathologic staging seems to be a sign of a more advanced stage of brain amyloidosis than FHp subjects.