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Published in final edited form as: Am J Geriatr Psychiatry. 2020 Jul 27;29(4):375–383. doi: 10.1016/j.jagp.2020.07.011

The Role of Neuropsychiatric Symptoms in Research Diagnostic Criteria for Neurodegenerative Diseases

Jeffrey Cummings 1
PMCID: PMC7855689  NIHMSID: NIHMS1622822  PMID: 32819825

Abstract

Neuropsychiatric syndromes and symptoms play increasingly important roles in research diagnostic criteria for neurodegenerative disorders. Diagnostic criteria were reviewed including those for: dementia, Alzheimer’s disease, mild cognitive impairment, mild behavioral impairment, prodromal Alzheimer’s disease, dementia with Lewy bodies, prodromal dementia with Lewy bodies, Parkinson’s disease, multiple system atrophy, frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy, corticobasal degeneration, traumatic encephalopathy syndrome, Huntington’ disease, amyotrophic lateral sclerorsis. All contemporary research diagnostic criteria for neurodegenerative disorders expect those for Parkinson’s disease, primary progressive aphasia, and multisystem atrophy include neuropsychiatric phenomena as core diagnostic criteria. There are no disease-specific neuropsychiatric symptoms; apathy and disinhibition are common in tauopathies, and rapid-eye-movement sleep behavioral disorder occurs almost exclusively in synucleinopathies. Neuropsychiatric symptoms and syndromes are increasingly integrated into research diagnostic criteria for neurodegenerative disorders; they require clinician skills for recognition; their biology is better understood as their relationships to cognitive, motor, and autonomic symptoms of neurodegenerative disorders are studied.

Keywords: Neurodegenerative disorders, neuropsychiatric syndromes, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, frontotemporal dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, traumatic encephalopathy syndrome, multiple system atrophy. depression, psychosis, apathy, agitation

Introduction

Research diagnostic criteria for neurodegenerative disorders (NDD) allow more precise patient diagnosis and management and facilitate research. Research diagnostic criteria lead to the identification of relatively homogenous patient populations that can be enrolled in pharmacologic and nonpharmacologic interventional research as well as in natural history studies. Research diagnostic criteria rapidly transcend research applications and are incorporated into clinical practice. They are periodically updated to reflect advances in scientific understanding of the diagnosis, differential diagnosis, management, and underlying biology of NDD.

NDD affect multiple brain regions and are characterized clinically by combinations of cognitive, neuropsychiatric, motoric, and autonomic changes that comprise the phenotype of the disorders and are integrated in diagnostic criteria. In some cases, such as in the criteria for dementia with Lewy bodies (DLB), biomarkers may be included (1).

Characteristic neuropsychiatric manifestations of NDD contribute importantly to many of the diagnostic criteria, facilitate accurate diagnosis, represent key symptoms that must be managed in the course of the illness, and contribute to an evolving understanding of the biological underpinnings of neuropsychiatric symptoms and syndromes. There has been progress in defining neuropsychiatric syndromes occurring in NDD and these more rigorous definitions contribute to the implementation of the diagnostic criteria. For example, the definition of apathy (2, 3) assists in defining the apathetic syndrome that comprises part of the diagnostic criteria for frontotemporal dementia (FTD) (4).

This review addresses the role of neuropsychiatric symptoms and syndromes in diagnosis of NDD as reflected in current research diagnostic criteria. A key implication of this discussion is that diagnosticians and investigators working with NDD must be knowledgeable about the behavioral aspects of NDD as well as about the cognitive, motoric, and autonomic features. The review draws attention to the shared biology of cognition and behavior and to the evolving understanding of the biology of behavior facilitated by NDD criteria.

Review Methodology

This review is based on a PubMed search for research diagnostic criteria for NDD including dementia, AD, DLB, Parkinson’s disease (PD), FTD, primary progressive aphasia (PPA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), traumatic encephalopathy syndrome (TES), multiple system atrophy (MSA), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Current diagnostic criteria were identified, and the presence of behavioral features in the criteria was reviewed. Corresponding definitions of the neuropsychiatric symptoms and syndromes including disinhibition, apathy, delusions, hallucinations, psychosis, and depression noted in the criteria were identified and are discussed. Derivative references were reviewed to determine if the neuropsychiatric components of the definitions were assessed in follow-up studies of the criteria.

Research Diagnostic Criteria for Neurodegenerative Disorders

Dementia

The Diagnostic and Statistical Manual, 5th ed.(5) uses the terms Major Neurocognitive Disorder and Mild Neurocognitive Disorder for the clinical syndromes labeled dementia and mild cognitive impairment (MCI) in other approaches. Major Neurocognitive Disorder is defined as exhibiting decline from past cognitive ability manifested by memory impairment, language abnormalities, visuospatial disturbance, executive dysfunction, attention impairment, and abnormal social cognition. The functional changes must be sufficient to interfere with activities of daily living and not exclusively explained by a delirium or some other mental disorder. Decline in social cognition is recognized as lack of empathy and sympathy, reduced insight, poor social judgment, impaired recognition of social cues, and inappropriate social behavior (6, 7). With these criteria, Major Neurocognitive Disorder can be diagnosed on the basis of the presence of one cognitive deficit plus changes in social cognition.

The Diagnostic and Statistical Manual, 5th ed.(5) does not include changes in behavior as part of the definition of Mild Neurocognitive Disorder.

In 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) advanced criteria for dementia and MCI as well as preclinical AD, MCI due to AD, and AD dementia (8). The NIA-AA approach defines all-cause dementia as having at least two of the following features: memory impairment; impaired reasoning and complex thinking; impaired visuospatial abilities; impaired language; or changes in personality, behavior, or comportment (9). Examples of the latter include uncharacteristic mood fluctuations such as agitation, impaired motivation, reduced initiative, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviors, and socially unacceptable behaviors. This approach to dementia allows “changes in personality, behavior, or comportment” plus change in one cognitive domain to be the basis of identifying a dementia syndrome. The changes must be sufficiently severe to interfere with work or activities, represent a decline from the individual’s previous level of function, and are not better explained by delirium or a psychiatric disorder. The NIA-AA syndrome of dementia is similar to the Diagnostic and Statistical Manual(5) in recognizing behavioral changes to be as important as cognitive changes in defining the dementia syndrome, allowing identification based on change in one aspect of cognition plus change in personality, behavior, or comportment.

NIA-AA criteria for MCI do not include reference to behavioral or neuropsychiatric changes (10).

Alzheimer’s Disease

After providing criteria for Major Neurocognitive Disorder, the Diagnostic and Statistical Manual advances more specific criteria for the diagnosis of Major Neurocognitive Disorder due to AD(5). This diagnosis requires the gradually progressive decline of memory impairment plus at least one of: language abnormalities, visuospatial disturbance, executive dysfunction, attention impairment, or social cognition. Gradually compromised social cognition plus memory impairment with appropriate exclusions of delirium and major psychiatric disorders would allow fulfillment of the clinical criteria for Major Neurocognitive Disorder due to AD. As in the criteria for dementia, behavioral changes are as important as cognitive abnormalities in diagnosis.

The NIA-AA criteria define AD dementia by the presence of a dementia syndrome as previously defined presenting with insidious onset and gradual worsening. The disorder may have either an amnestic or a non-amnestic presentation. Building on the NIA-AA criteria for dementia allows behavior to be one of two key elements sufficient for a diagnosis of AD dementia (9).

NIA-AA criteria for MCI due to AD do not include reference to behavioral or neuropsychiatric changes(10).

The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) associated with the AA, has proposed criteria for Mild Behavioral Impairment (MBI) that can occur with or without MCI and is the harbinger of a progressive dementia syndrome(11, 12). MBI identification requires at least one of the following: decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, or abnormal perception or thought content.

The International Work Group (IWG) is devoted to developing a clinical-biological definition of AD. Their approach to AD allows a typical or an atypical phenotype along with biological evidence of AD based on amyloid imaging, cerebrospinal fluid amyloid/tau protein measures, or presence of a mutation known to be associated with autosomal dominant AD (13). The typical phenotype of AD features an episodic type memory impairment. Several atypical presentations are described including a frontal variant that is defined by the presence of early, predominant and progressive behavioral changes featuring apathy or behavioral disinhibition. Neuropsychological assessment of patients with the frontal variant reveals marked executive dysfunction. In this approach, a frontal-type behavioral syndrome plus biological evidence of AD is sufficient for a diagnosis of AD. If functional changes are minor, prodromal AD is the appropriate diagnosis; if functional changes are prominent, AD dementia is the appropriate diagnosis.

Criteria for neuropsychiatric syndromes occurring in AD and other neurocognitive disorders have been developed including psychosis in AD (14, 15), depression in AD (16), agitation in AD and cognitive disorders (17), and apathy in AD and other dementias (2). These criteria were typically developed to apply to AD as the most common late-life dementia; they state that the syndromic criteria can be applied to other dementias as they are not uniquely associated with AD.

Frontotemporal Dementia

FTD includes the behavioral variant (bvFTD), nonfluent primary progressive aphasia (nfPPA), and semantic variant primary progressive aphasia (svPPA) (4). Behavioral variant FTD is the only NDD that requires the presence of behavioral changes to establish the diagnosis(4). The patient must have at least two of the following behavioral symptoms: early behavioral disinhibition; early apathy or inertia; early loss of sympathy or empathy; early perseverative, stereotyped or compulsive/ritualistic behavior; or hyperorality and dietary changes. If neuropsychological abnormalities (especially executive function deficits) are not present, the patient must have three of the categories of behavioral changes to support a diagnosis. The behavioral changes of bvFTD represent the core diagnostic features. The publication describing the criteria includes a glossary with definitions of disinhibition, apathy or inertia, loss of sympathy or empathy, compulsive behavior, and hyperorality/dietary changes (4). These definitions can apply to the behavioral changes seen in other NDD.

Nonfluent primary progressive aphasia and svPPA do not include specific reference to behavioral features that contribute to meeting the diagnostic criteria (18). Many patients with svPPA develop behavioral changes similar to those of bvFTD including disinhibition, irritability, lack of empathy, mental inflexibility, compulsions, and food taste changes (e.g., preference for sweet foods) (19). In some cases, nfPPA progresses to PSP (see below) with the behavioral features of PSP and depression(20).

Dementia with Lewy Bodies

In addition to the presence of progressive dementia, DLB has four core clinical features: fluctuating cognition, recurrent visual hallucinations, rapid eye movement (REM) sleep behavior disorder, and parkinsonism (1). Probable DLB is diagnosed if two core features are present; alternatively, one core and one indicative biomarker (reduced dopamine transporter signal in the basal ganglia demonstrated by single photon emission tomography or positron emission tomography; abnormally low uptake on 123idoine- metaiodobenzylguanidine (MIBG) myocardial scintigraphy; polysomnographic confirmation of REM sleep without atonia) are sufficient for a diagnosis of probable DLB. Visual hallucinations are present in a majority (62–77%) of patients meeting criteria for DLB (21, 22). REM sleep behavior disorder occurs in 40–50% of patients with DLB(23). Neuropsychiatric features are a prominent component of the criteria for DLB, accounting for two of the four core criteria.

Possible DLB can be identified in a patient with dementia and 1 core clinical feature such as visual hallucinations (1).

Criteria for prodromal DLB focus on patients with MCI. The presence of MCI plus 2 of 4 core features of DLB or 1 core feature plus 1 of the biomarkers leads to the diagnosis of prodromal DLB (24). Visual hallucinations or REM sleep behavior disorder occurring a patient with MCI allow the diagnosis of prodromal DLB.

The prodromal DLB criteria provide provisional guidelines for identification of psychiatric-onset DLB describing neuropsychiatric symptoms that may prior to cognitive manifestations. Late onset visual hallucinations, hallucinations in other sensory modalities, systematized delusions including Capgras syndrome, apathy, anxiety, and depression are suggested as possible presenting features of psychiatric-onset DLB.

Parkinson’s Disease Dementia

Parkinson’s disease dementia is characterized by impairment in attention, memory, executive and visuo-spatial functions (25). The criteria identify behavioral symptoms (apathy, depressed or anxious mood, hallucinations, delusions, excessive daytime sleepiness) as supportive of the diagnosis. Behavioral changes are not identified as core diagnostic criteria.

Criteria for PD MCI do not explicitly identify a role for neuropsychiatric symptoms or behavioral changes in diagnosis (26).

Although neuropsychiatric symptoms do not play a role in the diagnosis of PD, behavioral changes are common among PD patients and criteria for depression in PD (27) and psychosis in PD have been developed (28).

Multiple System Atrophy

Multiple system atrophy (MSA) is characterized by parkinsonian features, cerebellar ataxia, autonomic failure, urogenital dysfunction, and corticospinal abnormalities. The presenting motor disorder most commonly consists of parkinsonism with bradykinesia, rigidity, and gait instability; cerebellar ataxia is the initial motor disorder in a substantial minority of patients. MSA diagnostic criteria do not identify behavioral features useful in diagnosis (29). REM sleep behavioral disorder is common in MSA and is the most common presenting manifestation of the disorder(30). Cognitive impairment including abnormalities of attention, working memory, information retrieval, and visuospatial deficits commonly occur with disease progression (31).

Corticobasal Degeneration

Core diagnostic criteria for CBD include asymmetric limb rigidity or bradykinesia, asymmetric limb dystonia, asymmetric limb myoclonus, orobuccal or limb apraxia, cortical sensory deficit, and alien limb phenomenon(32). Diagnosis is supported by two features of the core CBD syndrome or by a frontobehavioral disorder plus at least one corticobasal feature. The criteria require that the individual be 50 years of age or older with insidious onset and gradual progression of the behavioral and cognitive changes. Symptoms must be present for a minimum of one year. With this approach, a behavioral-type of frontobehavioral syndrome plus one corticobasal syndrome feature is sufficient for a diagnosis of CBD. Apathy or a bvFTD-type disinhibition syndrome are the behavioral features identified as manifestations of the frontobehavioral syndrome (33).

Progressive Supranuclear Palsy

Three levels of certainty have been identified in current PSP criteria (34). Behavioral abnormalities do not meet criteria for Level 1 certainty, but the criteria do allow behavioral abnormalities (frontal cognitive/behavioral presentation) to achieve a Level 2 diagnostic certainty. Apathy is present in 60% of those with PSP and disinhibition is present in 50%; these symptoms comprise the principal elements of the frontal-behavioral presentation (35).

Traumatic Encephalopathy Syndrome

The relationship of TES to the neuropathologic diagnosis of chronic traumatic encephalopathy (CTE) is under investigation and most studies suggest that current TES criteria have good sensitivity and low specificity. CTE is a progressive neurodegenerative disorder characterized by aberrant deposits of phosphorylated tau protein identified at autopsy(36). The current clinical criteria for TES require progressive cognitive impairment with delayed onset following repetitive head trauma (37, 38). Emotional dysregulation, behavioral, and motor disturbance are included as core features(38) or supportive features(37).

Huntington’s Disease

The Movement Disorder Society reviewed the criteria for diagnosis of HD and concluded that application of Diagnostic and Statistical Manual, 5th ed.(5) terms Major Neurocognitive Disorder and Mild Neurocognitive Disorder was appropriate for characterizing the cognitive and behavioral changes o HD provided the individual has confirmatory genetic testing(39).

Amyotrophic Lateral Sclerosis

The diagnostic criteria for ALS depend on electromyographic documentation of motor neuron disease and do not include behavior or psychological criteria(40, 41).

Discussion

Neuropsychiatric syndromes and symptoms contribute importantly to the diagnosis of NDD and are incorporated into the diagnostic criteria of most (Table 1).

Table 1.

Neuropsychiatric syndromes and symptoms included in diagnostic criteria for NDD.

Neurodegenerative Disorder Neuropsychiatric Symptoms and Syndromes Included in Diagnostic Criteria
Major neurocognitive disorder (DSM) Social cognition including recognition of emotions, theory of mind, and insight
Dementia (NIA-AA) Changes in personality, behavior, or comportment
Mild neurocognitive disorder (DSM) None
Mild cognitive impairment (NIA-AA) None
Major neurocognitive disorder due to Alzheimer’s disease (DSM) social cognition including recognition of emotions, theory of mind, and insight
Alzheimer’s disease dementia (NIA-AA) Changes in personality, behavior, or comportment
Mild cognitive impairment due to Alzheimer’s disease (NIA-AA) None
Mild Behavioral Impairment (MBI) Decreased motivation; affective dysregulation; impulse dyscontrol; social inappropriateness; abnormal perception or thought content
IWG AD dementia; frontal variant Apathy, disinhibition
IWG prodromal AD; frontal variant Apathy, disinhibition
Dementia with Lewy bodies Recurrent visual hallucinations
Prodromal dementia with Lewy bodies Recurrent visual hallucinations
Psychiatric onset dementia with Lewy bodies Visual hallucinations, hallucinations in other sensory modalities, systematized delusions including Capgras syndrome, apathy, anxiety, and depression
Parkinson’s disease dementia None
Parkinson’s disease mild cognitive impairment None
Behavioral variant frontotemporal dementia Behavior disinhibition; apathy/inertia; loss of sympathy or empathy; perseverative, stereotyped, or compulsive/ritualistic behavior; hyperorality and dietary changes
Nonfluent primary progressive aphasia None
Semantic variant primary progressive aphasia None
Progressive supranuclear palsy Frontal cognitive/behavioral syndrome
Corticobasal degeneration Frontotemporal syndrome
Traumataic encelphalopathy syndrome Behavioral dysregulation; mood changes
Huntington’s disease Social cognition including recognition of emotions, theory of mind, and insight (from DSM)
Amyotrophic lateral sclerosis None
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DSM – Diagnostic and Statistical Manual of Mental Disorders, 5th edition; IWG – International Work Group; NIA-AA – National Institute on Aging – Alzheimer’s Association

There are no neuropsychiatric symptoms or syndromes that are unique to a specific NDD. Apathy, psychosis, depression, agitation, and sleep disturbances occur across NDD albeit at different frequencies. The role of neuropsychiatric syndromes in diagnosis is as a part of a constellation of signs and symptoms that comprise the phenotype characteristic of each NDD and its unique molecular signature and neuro-geographic distribution (42).

The important role played by neuropsychiatric syndromes in NDD diagnosis has several implications. First, assessment and recognition of the neuropsychiatric symptoms and syndromes is essential to accurate diagnosis. Improved interview approaches and rating scales may assist clinicians in detection, characterization, and diagnosis of NDD. Criteria for psychosis, agitation, depression, and apathy occurring in NDD are helpful in recognizing these disorders accurately (2, 14–17). Second, the increasing recognition of behavioral changes in the course of NDD informs understanding of the biology of these syndromes and symptoms. For example, the very high prevalence of neuropsychiatric disorders in DLB implies that the specific molecular, pathological, and circuit changes of this disease create a cerebral ecology uniquely provocative of these symptoms. Apathy and impulsivity are common in bvFTD but also occur in other frontotemporal lobar degeneration syndromes including PSP, CBD, CTE, and some patients with PPA(43). This group of disorders shares a common underlying biology, with tauopathy as the key pathological change. REM sleep behavior disorder occurs almost exclusively in disorders characterized pathologically by alpha-synuclein aggregation including PD, DLB and MSA (44). The criteria for NDD and the inclusion of neuropsychiatric phenomena is facilitating study of the neurobiology of these behaviors.

This review addresses the role of neuropsychiatric syndromes in diagnosing NDD. Similar approaches to incorporating neuropsychiatric syndromes into diagnostic frameworks are seen with other dementias. Criteria for vascular cognitive impairment (VCI) require onset of the clinical syndrome following a cerebrovascular event and evidence of decline in frontal executive functioning, plus one of the following: gait disturbance, urinary symptoms, or personality and mood changes. There must also be evidence on computerized tomography or magnetic resonance imaging of cerebrovascular disease. With this approach, personality and mood changes contribute to meeting the criteria for diagnosis of VCI (45).

An important trend in diagnostic criteria is facilitation of early diagnosis based on behavioral changes. This is evident in the criteria for MBI that may occur with or without MCI and represent the initial manifestations of a progressive disorder (11, 12) and the criteria for prodromal DLB(24).

Review of the literature on neuropsychiatric syndromes in NDD demonstrates that the criteria are typically based on expert opinion experienced with the specific NDD. The criteria are periodically revised and updated as new knowledge accrues. In some cases, sensitivity, specificity, and positive and negative predictive value are examined in follow-up studies. It is rare for the specific contribution of the behavioral changes to these parameters or inter-rater reliability of the assessments to be studied. Similarly, there are few clinicopathologic studies of the behavioral changes in patients who succumb to their illness and come to autopsy. An assessment of the criteria for depression in AD conducted after publication of the criteria, found them to perform effectively in detection of important mood changes in AD (46, 47). A re-examination of the criteria for psychosis in AD encouraged allowing diagnosis of the syndrome in prodromal and preclinical AD as the presenting manifestation of the disorder (15). There were few changes in the core criteria.

Biomarkers play an increasingly important role in diagnosis of NDD and are being integrated into some sets of diagnostic criteria (1, 24, 48). Identifying biomarkers associated with specific behavioral symptoms and syndromes would further strengthen diagnostic criteria and the role of neuropsychiatric symptoms in support of diagnosis (49, 50).

An important role for diagnostic criteria is their application in clinical trials and regulatory interactions. For clinical trials of disease-modifying therapies, criteria allow the construction of trial populations that have greater diagnostic homogeneity. Reduction of neuropsychiatric symptoms or reduction in the emergence of new symptoms will be key aspects of the success of disease modifying treatments of NDD. When neuropsychiatric symptoms and syndromes occurring as part of NDD are the focus of trials, criteria facilitate recruitment of trial populations with homogeneous behavioral changes. There are currently several trials for agitation in AD using research diagnostic criteria for AD and for agitation (51). Some trials recruit across NDD using a common neuropsychiatric endophenotype such as the trial of pimavansarin for dementia-related psychosis (52). These trials are based on the assumption that the test agent influences circuits affected across multiple NDDs.

In summary, neuropsychiatric phenomena play an increasingly important role in diagnostic criteria for NDD. Accurate recognition of neuropsychiatric phenomena improves detection and recognition of NDD. NDD criteria have facilitated studying the neurobiology of behavioral changes in NDD. The criteria and the integrated neuropsychiatric phenomena facilitate clinical trials and the development of new therapies for NDD and their behavioral manifestations. Neuropsychiatric aspects of NDD criteria support nonpharmacologic research and assist clinicians in diagnosis and management of NDD.

Highlights.

Review questions: What is the role of neuropsychiatric symptoms and syndromes in research diagnostic criteria for neurodegenerative disorders?

Main finding: Neuropsychiatric symptoms and syndromes are included in research diagnostic criteria for dementia, Alzheimer’s disease, prodromal Alzheimer’s disease, dementia with Lewy bodies, prodromal dementia with Lewy bodies, frontotemporal dementia, corticobasal degeneration, and progressive supranuclear palsy.

Key meaning of the finding: Awareness of behavioral changes is essential to accurate diagnosis of neurodegenerative disorders. Inclusion of neuropsychiatric symptoms and syndromes in research diagnostic criteria facilitates study of the neurobiology of these disorders.

Acknowledgements

JC is supported by Keep Memory Alive (KMA); NIGMS grant P20GM109025; NINDS grant U01NS093334; and NIA grant R01AG053798.

Footnotes

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Conflicts of Interest and Source of Funding

JC has provided consultation to Acadia, Actinogen, Alkahest, Allergan, Alzheon, Annovis, Avanir, Axsome, BiOasis, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Third Rock and United Neuroscience pharmaceutical and assessment companies. JC owns the copyright of the Neuropsychiatric Inventory. JC is supported by KMA; NIGMS grant P20GM109025; NINDS grant U01NS093334; and NIA grant R01AG053798.

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