Neuroimaging Biomarkers of Neurodegenerative Diseases
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, affecting more than 5 million individuals in the United States, mostly age 65 or older, and that number is expected to more than triple by 2050. The earliest clinical symptoms are memory impairments, particularly in episodic and semantic domains, as well as deficits in language and executive functioning. Patients with AD also show a significant impairment in daily functioning with disruption or cessation of the ability to perform complex activities and later more simple tasks. Clinicians and researchers have recently updated AD diagnostic criteria for use in clinical practice and research. Currently, the diagnosis of AD is made clinically, based on cognition and the relative impact of impairments on daily activities. Attempts to diagnose AD at an earlier stage have led to the development of a clinical syndrome termed amnestic mild cognitive impairment (MCI). Recently, new criteria for diagnosis of MCI in clinical and research settings have been published. Patients with MCI typically show deficits in episodic memory that fall more than 1 standard deviation below age and education adjusted and culturally appropriate normative levels. More recently, researchers have proposed dividing MCI into an earlier stage (early MCI [E-MCI]) and a later stage (late MCI [L-MCI]), with E-MCI patients showing a 1 to 1.5 standard deviation memory deficit and L-MCI showing a greater than 1.5 standard deviation deficit. This classification has only recently been introduced and future studies will help to elucidate differences between these MCI subgroups. The most common presentation of MCI features memory impairment (amnestic MCI), but can co-occur with other cognitive deficits such as executive function or language deficits (multidomain MCI). Amnestic MCI is widely considered to be a prodromal form of AD, as nearly 10 to 15% of amnestic L-MCI patients convert to probable AD each year, relative to only 1 to 2% of the general older adult population. Recently, researchers and clinicians have been attempting to detect AD-related changes and predict progression even earlier than MCI (e.g., pre-MCI or preclinical AD). A conceptual framework for identifying preclinical AD patients has been presented in a recent article.
Alzheimer's disease is characterized by two neuropathological hallmarks: amyloid plaques and neurofibrillary tangles. Amyloid plaques are extracellular aggregations of the amyloid-β (Aβ) peptide that are found throughout the brain of AD patients. Neurofibrillary tangles result from the hyperphosphorylation of the microtubule-associated protein tau, which forms insoluble filamentous structures that combine to create paired helical filaments, a key component of the neurofibrillary tangles seen in the brains of patients with AD. The temporal relationship and direct link between amyloid plaques and neurofibrillary tangles is not completely elucidated at this time. Current theories suggest that amyloid plaque formation precedes neurofibrillary tangles, with amyloid accumulation occurring during a long preclinical period lasting years to decades. The biochemical processes involved in Alzheimer's disease development ultimately converge upon widespread cell death and neuronal loss, likely through apoptosis. The first regions of the brain to show neuronal loss associated with AD are in the medial temporal lobe (MTL), including the entorhinal cortex, hippocampus, amygdala, and parahippocampal cortex, as well as cholinergic innervations to the neocortex from the nucleus basalis of Meynert. By the time a patient has reached a diagnosis of AD, neurodegeneration is usually found throughout the neocortex and subcortical regions, with significant atrophy of the temporal, parietal, and frontal cortices, but relative sparing of the primary occipital cortex and primary sensory–motor regions.
Although the majority of AD cases represent late-onset or sporadic AD, nearly 5% of AD cases are caused by dominantly inherited genetic mutations, usually in one of three genes: amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2). Often featuring an onset of symptoms that is at an earlier age than sporadic AD patients (i.e., before age 65), these cases are referred to as familial AD or early-onset AD. Although these diseases can show somewhat different symptomology and pathology than late-onset AD, the major AD hallmarks (i.e., amyloid plaques, neurofibrillary tangles) are present. Therefore, these patients may represent a useful sample for studying early changes in biomarkers, particularly because the age of symptom onset tends to be consistent across generations. Therefore, using an estimated age of symptom onset (EAO), changes in neuropathology and cognition can be assessed using biomarkers decades before onset of disease. Other diseases associated with AD neuropathology show atypical presentation, including posterior cortical atrophy (PCA) and logopenic aphasia. Posterior cortical atrophy is a disorder of higher visual function that causes significant visual dysfunction in the absence of ocular disease, as well as constructional apraxia, visual field deficits, and environmental disorientation. This disorder is primarily thought to be associated with changes in posterior brain regions, including the parietal and occipital lobes. Logopenic aphasia is a type of primary progressive aphasia (PPA) associated with AD (i.e., amyloid) rather than frontotemporal dementia- (FTD-) like pathology and features impaired word retrieval and sentence repetition in the absence of motor speech or grammatical abnormalities. Cerebral amyloid angiopathy (CAA) is also associated with AD-like amyloid pathology. However, amyloid deposits are largely observed in the walls of small cerebral arteries and capillaries in CAA. Patients with CAA often show cognitive decline, seizures, headaches, and stroke-like symptoms.
Vascular dementia and vascular-associated cognitive impairment (VCI), a form of cognitive impairment with notable cerebrovascular pathology and/or risk factors, can be identified using self-reports of stroke and/or other vascular events or diseases (myocardial infarction, atherosclerosis, hypertension, etc.), neurologic and psychometric evaluation, and/or structural and functional imaging techniques. The major requirements for a diagnosis of vascular dementia or vascular-associated MCI include the presence of clinically significant cognitive impairments, which can be in any cognitive domain, but are commonly observed in executive function and/or memory, and the presence of significant cerebrovascular pathology and/or risk factors, assessed using clinical or neuroimaging techniques. Beyond these requirements, patients are diagnosed by clinical severity and the impact on activities of daily living (ADLs), similar to the diagnosis of AD. Specifically, patients diagnosed with vascular-associated MCI must show a cognitive deficit, but no significant impairment in ADLs, whereas a diagnosis of vascular dementia requires significant impairment in both clinically assessed cognitive status and ADLs.
Frontotemporal dementia (FTD) is an overarching diagnosis that encompasses multiple disorders with varying symptoms. Behavioral variant FTD (bvFTD) is characterized by a change in personality and behavior, disinhibition, apathy, loss of empathy, obsessive–compulsive behaviors, and changes in appetite. Behavioral variant FTD is most commonly associated with pathological tau accumulation, such as seen in Pick's disease, but can also feature accumulation of a TAR-DNA-binding protein called TDP-43. Primary progressive aphasia (PPA) is another form of FTD, which is divided into two forms: semantic dementia (SD) and progressive nonfluent aphasia (PNFA). Semantic dementia features fluent aphasia, anomia, and single-word comprehension deficits and later in the disease course behavioral symptoms similar to those seen bvFTD. Pathologically, TDP-43 accumulation usually underlies SD, but rare cases featuring tau pathology associated with Pick's disease have been observed. Progressive nonfluent aphasia features speech production difficulties with agrammatism and apraxia of speech, as well as phonemic errors, anomia, and impairments in sentence comprehension. Progressive nonfluent aphasia typically features changes due to tau pathology, although mutations in the progranulin gene (GRN) resulting in TDP-43 pathology, can cause PNFA symptoms, but without apraxia of speech. Frontotemporal dementia can also feature motor dysfunction and motor neuron disease (MND). These disorders have been linked to Parkinson's-like symptoms, such as those seen in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), which feature tau pathology, or changes due to TDP-43 pathology, which presents as FTD-MND with Lewy body-like pathology or FTD associated with amyotrophic lateral sclerosis (FTD-ALS). Clinically, the Parkinson's-like FTD dementias (CBD and PSP) can show either behavioral-type symptoms (i.e., those seen in bvFTD) or language-type symptoms (most commonly PFNA-like symptoms), along with executive dysfunction, in the presence of cortical and extrapyramidal motor dysfunction. Patients with FTD associated with TDP-43 (FTD-ALS, others) most commonly present with behavioral symptoms (bvFTD-like) in the presence of motor dysfunction. Amyotrophic lateral sclerosis can also occur without behavioral symptoms, although non-FTD ALS patients commonly still have subthreshold cognitive changes.
Parkinson's disease (PD) is caused by deposition of inclusions of α-synuclein called Lewy bodies and feature spontaneous motor parkinsonism, visual hallucinations, and potentially changes in cognition; 70 to 80% of patients with PD develop cognitive impairment and/or dementia over the course of the disease. Two types of Parkinson's dementias have been defined, including Parkinson's disease dementia (PDD), in which patients develop cognitive symptoms more than 1 year after motor symptoms, and dementia with Lewy bodies (DLB), in which patients develop cognitive symptoms concurrent with or within a year of motor symptoms. Cognitive symptoms in PDD and DLB are variable, but often feature impairments in visual spatial functioning, executive function, language, and/or memory. However, whether PDD and DLB actually represent separate disorders is under debate. Thus, in the present article, PDD and DLB will be discussed together.
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative condition caused by trinucleotide repeates (CAG) in the gene coding for the protein huntingtin (HTT). Pathological features include progressive degeneration of striatal GABAergic interneurons. Clinical symptoms of HD include motor symptoms, such as chorea, bradykinesia, dystonia, and incoordination, and cognitive symptoms, including changes in visuomotor function, executive function, and memory. Because HD is an autosomal dominant disorder, prodromal phases of this disease can be studied (i.e., prior to clinical onset in mutation carriers) to assess disease development and progression.
Multiple sclerosis (MS) is a neurodegenerative condition featuring degeneration of the myelin sheaths that surround neuronal axons, which results in significant impairment in neuronal transmission. Although the exact cause of MS is unknown, it is thought to be the result of either an autoimmune syndrome in which inflammatory cells attack the myelin or a dysfunction of the myelin-producing cells. Multiple sclerosis typically presents either as discrete attacks (relapsing-remitting) or progressive over time (progressive MS). Symptoms of MS can vary dramatically, as MS lesions can occur throughout the cortical white matter, but the most common are autonomic, visual, motor, and sensory problems. Cognitive symptoms usually include behavioral and emotional changes (i.e., depression), as well as impairments in executive functioning, attention, and memory.
HIV-associated neurocognitive disorders (HAND) can be classified into three types based on severity: (1) asymptomatic neurocognitive impairment (ANI), which features cognitive impairment 1 SD below age and education adjusted norms in two cognitive domains but no functional impairment; (2) HIV-associated mild neurocognitive disorder (HMD; also referred to as mild cognitive motor dysfunction [MCMD]), which features cognitive impairment 1 SD below adjusted norms in two cognitive domains and mild impairment in daily functioning; (3) HIV-associated dementia (HAD; also known as AIDS dementia complex [ADC]), which is characterized by cognitive impairment 2 SD or more below age- and education-adjusted norms in at least two cognitive domains and significant impairment in daily functioning. In the present review, we will combine these three severity categories into one group (HAND). Although these classifications may represent stages of disease, further study is needed for this determination. Approximately 22 to 55% of patients with acquired immunodeficiency syndrome (AIDS) show cognitive dysfunction. Symptoms include disorientation, mood disturbances, and impairment in executive function, speed of information processing, attention and working memory, motor speed, and new learning and retrieval. However, long-term and semantic memory, language, and visuospatial function remain relatively intact. Some patients also show motor symptoms. However, symptoms can vary significantly across individuals.
Prion-associated diseases are rare neurodegenerative disorders caused by abnormal processing of the prion protein, which leads to lethal transmissible spongiform encephalopathies (TSEs). Prion-associated diseases can either be sporadic (sporadic Creutzfeldt-Jakob disease [sCJD]; sporadic fatal insomnia [SFI]), genetic (genetic CJD; Gerstmann-Straussler-Scheinker diseases [GSS]; fatal familial insomnia [FFI]), or acquired through infectious transmission of tissue carrying the misfolded prion protein (Kuru; iatrogenic CJD [iCJD]; variant CJD [vCJD]). The different variants of prion-associated dementia show somewhat different symptoms, including varying rates of progression and ages of onset, but the majority feature significant motor and sensory dysfunction, cognitive impairment, and personality changes or psychiatric disorders.
Degenerative Diseases and Dementias
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, affecting more than 5 million individuals in the United States, mostly age 65 or older, and that number is expected to more than triple by 2050. The earliest clinical symptoms are memory impairments, particularly in episodic and semantic domains, as well as deficits in language and executive functioning. Patients with AD also show a significant impairment in daily functioning with disruption or cessation of the ability to perform complex activities and later more simple tasks. Clinicians and researchers have recently updated AD diagnostic criteria for use in clinical practice and research. Currently, the diagnosis of AD is made clinically, based on cognition and the relative impact of impairments on daily activities. Attempts to diagnose AD at an earlier stage have led to the development of a clinical syndrome termed amnestic mild cognitive impairment (MCI). Recently, new criteria for diagnosis of MCI in clinical and research settings have been published. Patients with MCI typically show deficits in episodic memory that fall more than 1 standard deviation below age and education adjusted and culturally appropriate normative levels. More recently, researchers have proposed dividing MCI into an earlier stage (early MCI [E-MCI]) and a later stage (late MCI [L-MCI]), with E-MCI patients showing a 1 to 1.5 standard deviation memory deficit and L-MCI showing a greater than 1.5 standard deviation deficit. This classification has only recently been introduced and future studies will help to elucidate differences between these MCI subgroups. The most common presentation of MCI features memory impairment (amnestic MCI), but can co-occur with other cognitive deficits such as executive function or language deficits (multidomain MCI). Amnestic MCI is widely considered to be a prodromal form of AD, as nearly 10 to 15% of amnestic L-MCI patients convert to probable AD each year, relative to only 1 to 2% of the general older adult population. Recently, researchers and clinicians have been attempting to detect AD-related changes and predict progression even earlier than MCI (e.g., pre-MCI or preclinical AD). A conceptual framework for identifying preclinical AD patients has been presented in a recent article.
Alzheimer's disease is characterized by two neuropathological hallmarks: amyloid plaques and neurofibrillary tangles. Amyloid plaques are extracellular aggregations of the amyloid-β (Aβ) peptide that are found throughout the brain of AD patients. Neurofibrillary tangles result from the hyperphosphorylation of the microtubule-associated protein tau, which forms insoluble filamentous structures that combine to create paired helical filaments, a key component of the neurofibrillary tangles seen in the brains of patients with AD. The temporal relationship and direct link between amyloid plaques and neurofibrillary tangles is not completely elucidated at this time. Current theories suggest that amyloid plaque formation precedes neurofibrillary tangles, with amyloid accumulation occurring during a long preclinical period lasting years to decades. The biochemical processes involved in Alzheimer's disease development ultimately converge upon widespread cell death and neuronal loss, likely through apoptosis. The first regions of the brain to show neuronal loss associated with AD are in the medial temporal lobe (MTL), including the entorhinal cortex, hippocampus, amygdala, and parahippocampal cortex, as well as cholinergic innervations to the neocortex from the nucleus basalis of Meynert. By the time a patient has reached a diagnosis of AD, neurodegeneration is usually found throughout the neocortex and subcortical regions, with significant atrophy of the temporal, parietal, and frontal cortices, but relative sparing of the primary occipital cortex and primary sensory–motor regions.
Although the majority of AD cases represent late-onset or sporadic AD, nearly 5% of AD cases are caused by dominantly inherited genetic mutations, usually in one of three genes: amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2). Often featuring an onset of symptoms that is at an earlier age than sporadic AD patients (i.e., before age 65), these cases are referred to as familial AD or early-onset AD. Although these diseases can show somewhat different symptomology and pathology than late-onset AD, the major AD hallmarks (i.e., amyloid plaques, neurofibrillary tangles) are present. Therefore, these patients may represent a useful sample for studying early changes in biomarkers, particularly because the age of symptom onset tends to be consistent across generations. Therefore, using an estimated age of symptom onset (EAO), changes in neuropathology and cognition can be assessed using biomarkers decades before onset of disease. Other diseases associated with AD neuropathology show atypical presentation, including posterior cortical atrophy (PCA) and logopenic aphasia. Posterior cortical atrophy is a disorder of higher visual function that causes significant visual dysfunction in the absence of ocular disease, as well as constructional apraxia, visual field deficits, and environmental disorientation. This disorder is primarily thought to be associated with changes in posterior brain regions, including the parietal and occipital lobes. Logopenic aphasia is a type of primary progressive aphasia (PPA) associated with AD (i.e., amyloid) rather than frontotemporal dementia- (FTD-) like pathology and features impaired word retrieval and sentence repetition in the absence of motor speech or grammatical abnormalities. Cerebral amyloid angiopathy (CAA) is also associated with AD-like amyloid pathology. However, amyloid deposits are largely observed in the walls of small cerebral arteries and capillaries in CAA. Patients with CAA often show cognitive decline, seizures, headaches, and stroke-like symptoms.
Vascular dementia and vascular-associated cognitive impairment (VCI), a form of cognitive impairment with notable cerebrovascular pathology and/or risk factors, can be identified using self-reports of stroke and/or other vascular events or diseases (myocardial infarction, atherosclerosis, hypertension, etc.), neurologic and psychometric evaluation, and/or structural and functional imaging techniques. The major requirements for a diagnosis of vascular dementia or vascular-associated MCI include the presence of clinically significant cognitive impairments, which can be in any cognitive domain, but are commonly observed in executive function and/or memory, and the presence of significant cerebrovascular pathology and/or risk factors, assessed using clinical or neuroimaging techniques. Beyond these requirements, patients are diagnosed by clinical severity and the impact on activities of daily living (ADLs), similar to the diagnosis of AD. Specifically, patients diagnosed with vascular-associated MCI must show a cognitive deficit, but no significant impairment in ADLs, whereas a diagnosis of vascular dementia requires significant impairment in both clinically assessed cognitive status and ADLs.
Frontotemporal dementia (FTD) is an overarching diagnosis that encompasses multiple disorders with varying symptoms. Behavioral variant FTD (bvFTD) is characterized by a change in personality and behavior, disinhibition, apathy, loss of empathy, obsessive–compulsive behaviors, and changes in appetite. Behavioral variant FTD is most commonly associated with pathological tau accumulation, such as seen in Pick's disease, but can also feature accumulation of a TAR-DNA-binding protein called TDP-43. Primary progressive aphasia (PPA) is another form of FTD, which is divided into two forms: semantic dementia (SD) and progressive nonfluent aphasia (PNFA). Semantic dementia features fluent aphasia, anomia, and single-word comprehension deficits and later in the disease course behavioral symptoms similar to those seen bvFTD. Pathologically, TDP-43 accumulation usually underlies SD, but rare cases featuring tau pathology associated with Pick's disease have been observed. Progressive nonfluent aphasia features speech production difficulties with agrammatism and apraxia of speech, as well as phonemic errors, anomia, and impairments in sentence comprehension. Progressive nonfluent aphasia typically features changes due to tau pathology, although mutations in the progranulin gene (GRN) resulting in TDP-43 pathology, can cause PNFA symptoms, but without apraxia of speech. Frontotemporal dementia can also feature motor dysfunction and motor neuron disease (MND). These disorders have been linked to Parkinson's-like symptoms, such as those seen in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), which feature tau pathology, or changes due to TDP-43 pathology, which presents as FTD-MND with Lewy body-like pathology or FTD associated with amyotrophic lateral sclerosis (FTD-ALS). Clinically, the Parkinson's-like FTD dementias (CBD and PSP) can show either behavioral-type symptoms (i.e., those seen in bvFTD) or language-type symptoms (most commonly PFNA-like symptoms), along with executive dysfunction, in the presence of cortical and extrapyramidal motor dysfunction. Patients with FTD associated with TDP-43 (FTD-ALS, others) most commonly present with behavioral symptoms (bvFTD-like) in the presence of motor dysfunction. Amyotrophic lateral sclerosis can also occur without behavioral symptoms, although non-FTD ALS patients commonly still have subthreshold cognitive changes.
Parkinson's disease (PD) is caused by deposition of inclusions of α-synuclein called Lewy bodies and feature spontaneous motor parkinsonism, visual hallucinations, and potentially changes in cognition; 70 to 80% of patients with PD develop cognitive impairment and/or dementia over the course of the disease. Two types of Parkinson's dementias have been defined, including Parkinson's disease dementia (PDD), in which patients develop cognitive symptoms more than 1 year after motor symptoms, and dementia with Lewy bodies (DLB), in which patients develop cognitive symptoms concurrent with or within a year of motor symptoms. Cognitive symptoms in PDD and DLB are variable, but often feature impairments in visual spatial functioning, executive function, language, and/or memory. However, whether PDD and DLB actually represent separate disorders is under debate. Thus, in the present article, PDD and DLB will be discussed together.
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative condition caused by trinucleotide repeates (CAG) in the gene coding for the protein huntingtin (HTT). Pathological features include progressive degeneration of striatal GABAergic interneurons. Clinical symptoms of HD include motor symptoms, such as chorea, bradykinesia, dystonia, and incoordination, and cognitive symptoms, including changes in visuomotor function, executive function, and memory. Because HD is an autosomal dominant disorder, prodromal phases of this disease can be studied (i.e., prior to clinical onset in mutation carriers) to assess disease development and progression.
Multiple sclerosis (MS) is a neurodegenerative condition featuring degeneration of the myelin sheaths that surround neuronal axons, which results in significant impairment in neuronal transmission. Although the exact cause of MS is unknown, it is thought to be the result of either an autoimmune syndrome in which inflammatory cells attack the myelin or a dysfunction of the myelin-producing cells. Multiple sclerosis typically presents either as discrete attacks (relapsing-remitting) or progressive over time (progressive MS). Symptoms of MS can vary dramatically, as MS lesions can occur throughout the cortical white matter, but the most common are autonomic, visual, motor, and sensory problems. Cognitive symptoms usually include behavioral and emotional changes (i.e., depression), as well as impairments in executive functioning, attention, and memory.
HIV-associated neurocognitive disorders (HAND) can be classified into three types based on severity: (1) asymptomatic neurocognitive impairment (ANI), which features cognitive impairment 1 SD below age and education adjusted norms in two cognitive domains but no functional impairment; (2) HIV-associated mild neurocognitive disorder (HMD; also referred to as mild cognitive motor dysfunction [MCMD]), which features cognitive impairment 1 SD below adjusted norms in two cognitive domains and mild impairment in daily functioning; (3) HIV-associated dementia (HAD; also known as AIDS dementia complex [ADC]), which is characterized by cognitive impairment 2 SD or more below age- and education-adjusted norms in at least two cognitive domains and significant impairment in daily functioning. In the present review, we will combine these three severity categories into one group (HAND). Although these classifications may represent stages of disease, further study is needed for this determination. Approximately 22 to 55% of patients with acquired immunodeficiency syndrome (AIDS) show cognitive dysfunction. Symptoms include disorientation, mood disturbances, and impairment in executive function, speed of information processing, attention and working memory, motor speed, and new learning and retrieval. However, long-term and semantic memory, language, and visuospatial function remain relatively intact. Some patients also show motor symptoms. However, symptoms can vary significantly across individuals.
Prion-associated diseases are rare neurodegenerative disorders caused by abnormal processing of the prion protein, which leads to lethal transmissible spongiform encephalopathies (TSEs). Prion-associated diseases can either be sporadic (sporadic Creutzfeldt-Jakob disease [sCJD]; sporadic fatal insomnia [SFI]), genetic (genetic CJD; Gerstmann-Straussler-Scheinker diseases [GSS]; fatal familial insomnia [FFI]), or acquired through infectious transmission of tissue carrying the misfolded prion protein (Kuru; iatrogenic CJD [iCJD]; variant CJD [vCJD]). The different variants of prion-associated dementia show somewhat different symptoms, including varying rates of progression and ages of onset, but the majority feature significant motor and sensory dysfunction, cognitive impairment, and personality changes or psychiatric disorders.