Update on Major Neurocognitive Disorders

The initial evaluation and diagnoses of dementia should include a thorough clinical assessment with a collateral history, if available; a neurological examination with assessment of mental status; selective labs to rule out metabolic and physiologic abnormalities; and structural brain imaging, preferably with magnetic resonance imaging (MRI) instead of computed tomography (CT) because these images generate a higher resolution image of cortical structures, enabling a more detailed assessment of atrophy (15). Collateral informants may include spouses, adult children, or other primary caretakers who can attest to the natural progression of symptoms and functional changes over the course of months or years. Having this additional information can be vitally important, especially if, because of degree of clinical severity, the patient is unable to give a thorough history or lacks insight into their impairments. Common labs important to a dementia workup include basic chemistries, a thyroid panel, a B12-folate test, and a vitamin D test. On the basis of the patient’s clinical history, additional tests may be warranted, including Treponemal pallidum antibody or venereal disease research laboratory, human immunodeficiency virus-ab, antinuclear antibody, erythrocyte sedimentation rate, and a heavy-metal screen. T1-weighted structural MRI is very useful in detecting focal loss of gray matter volume loss, otherwise indicated as atrophy, which is a common feature of neurodegenerative dementias (16).

The emphasis of the clinical interview should be placed on establishing a thorough patient history backed by reliable collateral sources, when available, and creating a detailed timeline of clinical symptoms and functional decline. This timeline should include the rate of symptom onset (e.g., rapid vs. gradual) and the pace of symptom progression (e.g., decline over months vs. years) (15). For example, human prion diseases, such as Creutzfeldt-Jakob disease, typically progress quite rapidly, over weeks to months. In contrast, dementias caused by Alzheimer’s disease, diffuse Lewy body disease, and frontotemporal diseases progress much slower, over a period of years. As a result of the rapid or gradual cognitive decline, patients also lose the ability to perform complex instrumental activities of daily living (IADLs) and eventually basic activities of daily living (ADLs). For example, patients who have progressed to moderate and severe stages of dementia have marked impairments in cognitive function and have usually lost the ability to carry out most IADLs (17). At these stages, the accurate reporting of symptoms and functional decline will necessitate the use of reliable caretakers or family members. Accurately measuring functional loss is important because the nature and extent of functional losses associated with disease progression help determine the type and level of care needed, ranging from medication management in early stages to full-time care or institutionalization in later stages (18).

A detailed mental status examination should assess several cognitive domains, including attention, memory, executive functioning, and visuospatial ability. Several instruments have been developed to help clinicians assess the presence and severity of cognitive impairment. Tools such as the 30-point Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are more commonly used and are helpful in assessing the presence and severity of dementia. The MoCA offers a broader assessment of cognitive domains and can be more sensitive than the MMSE for early detection of neurodegenerative diseases. Although commonly still used, the MMSE has a ceiling effect for higher functioning older adults and is poorly sensitivity for distinguishing mild cognitive impairment (MCI), which increases the likelihood that people in predementia stages will score within the normal range (≥24) (19–21). Full neuropsychological testing may be helpful in instances in which screening tests and clinical impression remain ambiguous.

Alzheimer’s disease remains one of the leading causes of progressive dementia; moreover, as the number of Americans ages 65 and older continues to increase, the cases of Alzheimer’s disease and other dementias will also continue to grow. In 2020, an estimated 5.8 million Americans ages 65 and older were living with the disease; 80% were ages 75 or older (7). Out of the total U.S. population, one in 10 people (10%) ages 65 and older has Alzheimer’s disease; moreover, the percentage of people with Alzheimer’s disease increases with age: 3% of people ages 65–74, 17% of people ages 75–84, and 32% of people ages 85 and older (7, 9). It is also important to note that people younger than age 65 can also develop Alzheimer’s disease, but it is much less common.

The Alzheimer’s disease continuum reflects the progression from brain changes that are not noticed by the affected person to brain changes that cause problems with memory and eventually physical disability. The continuum has three phases: preclinical Alzheimer’s disease, MCI due to Alzheimer’s disease, and dementia due to Alzheimer’s disease. Each of these phases is further broken down into mild, moderate, or severe stages that reflect the impact of the disease on an individual’s daily function. How long individuals spend in each part of the continuum varies and can be influenced by age, genetics, gender, and other factors (22).

During the preclinical Alzheimer’s disease phase, individuals have the earliest signs of the disease, which are detectable with biomarkers; however, they have yet to develop symptoms such as memory loss or change in functionality. Biomarkers, the earliest measurable brain changes, include measures of beta-amyloid (Aβ) deposition and glucose metabolism in the brain. Positron emission tomography (PET) scans use an Aβ-specific ligand, known as Pittsburgh compound B, to detect levels of cerebral load in the brain. Analysis of cerebrospinal fluid (CSF) can detect drops in Aβ levels, indicating a reduced clearance of Aβ into the CSF and increased aggregation of the peptide into amyloid plaques in the brain (23). PET imaging with the 2-deoxy-2-fluoro-D-glucose (FDG) tracer measures the cerebral metabolism of glucose and has a specific topographic distribution pattern: bilateral reduction in FDG uptake in the temporal and parietal regions and especially in the cingulate cortex (23). It is important to note that not all individuals with evidence of Alzheimer’s disease–related brain changes go on to develop symptoms of MCI or dementia due to Alzheimer’s disease (24).

Individuals with MCI due to Alzheimer’s disease have biomarker evidence of brain changes plus subtle changes in memory and thinking that do not interfere with overall daily function. These changes occur when the brain can no longer compensate for the damage and nerve cell death caused by Alzheimer’s disease. Eventually, these patients can progress to full Alzheimer’s dementia, with several studies indicating a range of conversion rates anywhere from 15% to nearly 40% within 2–5 years of initial MCI diagnosis (25–27). The 2018 study by Petersen et al. (25) demonstrated a cumulative dementia incidence of 14.9% over 2 years in individuals with MCI older than age 65. In some cases, MCI will revert to normal or remain stable over time.

Patients diagnosed as having dementia due to Alzheimer’s disease have biomarker evidence of brain changes with very clear changes in memory, thinking, or behavior that affect an individual’s daily function. They can exhibit multiple symptoms that progress over years and reflect the degree of nerve cell damage in different parts of the brain. The rate at which dementia symptoms progress varies from person to person but is generally categorized in stages ranging from mild, moderate, to severe. In mild stages of Alzheimer’s disease, many people can function independently in many areas but typically require assistance with some activities to optimize safety and independence. In moderate stages of Alzheimer’s disease, which tend to last the longest, individuals may have trouble with communication and performing routine tasks, such as ADLs. Some may develop incontinence at times. Others may start to demonstrate personality and behavioral changes, which are often some of the first symptoms recognized by family members or caretakers that will prompt their desire for a clinical evaluation by a medical professional. In severe stages, individuals need help with ADLs 24 hours per day, 7 days per week, and the effects of Alzheimer’s disease on their general health become apparent. Damage to areas of the brain that control movement lead to patients being more at risk for falls and becoming bed bound, which makes them more vulnerable to blood clots, bed sores, infections, and even sepsis. Damage to the areas of the brain that control swallowing leads to increased risk of aspiration, which can cause aspiration pneumonia.

Most people who develop dementia caused by Alzheimer’s disease do so at age 65 or older, which is often referred to as late onset. Several risk factors exist for late-onset Alzheimer’s disease, which is not thought to be related to any singular cause. Overall, age is the greatest risk factor for late-onset Alzheimer’s disease; moreover, the percentage of people with dementia caused by Alzheimer’s disease increases dramatically with age, as previously mentioned (7). Genetics is another risk factor, and researchers have found several genes that increase the risk of Alzheimer’s disease, with the apolipoprotein (APOE) e4 gene conferring the strongest impact on risk. Everyone inherits one of the three forms of the APOE gene from each parent, resulting in six possible pairs: e2-e2, e2-e3, e2-e4, e3-e3, e3-e4, and e4-e4. Having the e4 allele of APOE increases the risk of developing dementia in comparison with having the e3, but it does not guarantee that an individual will necessarily develop Alzheimer’s disease. Having the e2 form may decrease risk compared with having the e3 form. Those with just a single copy of the e4 allele have three times the risk of developing Alzheimer’s disease than those with two copies of the e3 form. Individuals who have two copies of the e4 allele are eight to 12 times more likely to develop Alzheimer’s disease (28–30). Finally, family history confers a risk on developing Alzheimer’s disease. Individuals who have a first-degree relative with Alzheimer’s disease are more likely to develop the disease, with an even higher risk for those who have more than one first-degree relative with the disease (28, 31). Of course, when diseases run in families, shared nongenetic factors such as access to healthy foods and habits related to physical activity may also play a role.

Although age, genetics, and family history are considered nonmodifiable, certain risk factors can be changed or modified to reduce the risk of dementia. According to the 2019 published recommendations by the World Health Organization (32), cognitive impairment and dementia are associated with lifestyle-related risk factors, such as physical inactivity, tobacco use, unhealthy diets, and harmful use of alcohol. In addition, certain medical conditions, including hypertension, diabetes, hypercholesterolemia, obesity, and depression, also confer an increased risk of developing dementia. Other potentially modifiable risk factors include social isolation and cognitive inactivity.

Less commonly, patients can develop dementia due to Alzheimer’s disease before age 65, sometimes as early as age 30. This manifestation is called early-onset Alzheimer’s disease, which occurs in less than 1% of Alzheimer’s disease cases and develops from mutations to any three specific genes (33). Mutations in the genes for amyloid precursor protein, presenilin 1 protein, or presenilin 2 protein virtually guarantee the development of Alzheimer’s disease during a normal life span. Amyloid precursor protein and presenilin 1 mutations are associated with complete penetrance, whereas mutations in presenilin 2 are associated with a 95% penetrance (34). Each of the Alzheimer’s disease genes plays a role in the production, trafficking, and clearance of Aβ, where its deposition into amyloid plaques, along with neurofibrillary tangles, plays a major role in the pathologic process of Alzheimer’s disease.

FTD is a heterogenous spectrum of neurodegenerative disorders with diverse clinical presentations, genetic attributes, and neuropathological characteristics (39). They are linked by the selective degeneration of the frontal and temporal lobes. In the past considered to be a rare disease, FTD has been shown to be more frequent than previously thought, with an estimated lifetime risk of one in 742 by recent epidemiological studies and updated clinical criteria (39, 40). FTD has been established as the second most common cause of dementia for people younger than age 65, with a prevalence that approximates that of Alzheimer’s disease (40–42). However, the overall prevalence increases beyond age 65, with a rate doubling that of those ages 40–64 (40, 42).

Clinically, FTD is characterized by behavioral abnormalities, language impairment, and deficits of executive function. In accordance, the current revised diagnostic criteria list two different clinical forms: behavioral variant of FTD (bvFTD) and primary progressive aphasia (PPA; the two most common forms include the semantic variant of PPA [svPPA] and the agrammatic variant of PPA [avPPA]). Frequently thought of as a tauopathy, or a neurodegenerative disease involving aggregation of tau protein in the brain, the heterogeneity in both the clinical presentations and the neuropathological hallmarks of FTD subtypes are all primarily related to neuronal protein tau or transactive response DNA-binding protein 43 (TDP-43) depositions.

Frontotemporal dementia can be caused by a highly heritable group of neurodegenerative disorders, with nearly 30% of patients having a strong family history (58). Autosomal dominant transmission accounts for the majority of heritability, with mutations in the C9ORF72, progranulin, and microtubule-associated protein tau genes. However, other genes are associated with rare FTD cases, such as valosin-containing protein mutations, charged multivesicular body protein 2B, fused in sarcoma (FUS) protein, TDP-43, sequestosome 1 protein, TANK-binding kinase 1 protein, and ubiquilin 2 protein (39). C9ORF72 seems to be the most common worldwide cause of genetic FTD, followed by progranulin and then microtubule-associated protein tau genes (58). In each of the gene groups with amyotrophic lateral sclerosis, bvFTD is most common; among C9ORF72 carriers, bvFTD is also common.

Frontotemporal pathology in FTD is characterized by severe focal atrophy of frontal and temporal regions, subcortical gliosis, and neuronal loss (43). Neuroimaging studies, such as MRI and FDG-PET, can show gray matter atrophy and hypometabolism at least 10 years before symptom onset (58). Initially, pathological diagnosis was based on atrophy and neuronal and glial cell inclusions of hyperphosphorylated tau protein; however, more than 50% of patients with FTD proved to be tau negative but ubiquitin positive (59). Most FTD-ubiquitin inclusions are composed of TDP-43. The remaining 5% are tau and TDP-43 negative with inclusions of FUS protein, referred to as FTD-FUS (59).

Because of its heterogeneity, the diagnostic process in FTD can be fraught with difficulty; moreover, having a correct diagnosis is essential to the future of clinical trials for disease-modifying treatments. Great efforts have been made over the last 2 decades to identify biomarkers sensitive to FTD, with a predominant focus on fluid biomaterial and neuroimaging.

FTD studies have primarily focused on structural changes assessing gray matter atrophy and hypometabolism, which have been fairly consistent and validated diagnostic biomarkers between studies. However, white matter changes are probably more sensitive for the earliest changes in FTD than gray matter changes (60). Studies within the last 5–10 years have examined white matter integrity using diffusion tensor imaging. This technique measures the microstructural integrity of white matter by determining the rate of diffusion in different directions; the changes in different diffusion tensor imaging metrics are thought to reflect different pathological changes in microstructure. In FTD, white matter diffusivity has been found to precede gray matter atrophy and with a more widespread distribution in the brain. Four potential areas of application have been identified: differentiating between individuals with FTD, individuals with other types of dementia, and individuals without dementia; differentiating between subtypes of FTD; disease monitoring; and detection of early changes before disease onset (60).

A combination of fluid biomarkers in the CSF are likely to yield more information than single markers. For example, phosphorylated TDP-43 constitutes one of the major pathological subtypes of FTD; moreover, neurofilaments are a major constituent of the neuroaxonal cytoskeleton and play an important role in axonal transport and in the synapse (61). Neurofilament light chain blood and CSF levels are 2.5–11 higher among patients with FTD than among control groups and are thought to reflect axonal damage (62–66).

No treatments are available that will change the course of FTD, so the focus of medical therapy is on symptomatic relief using pharmacological and nonpharmacologic methods. Nonpharmacologic interventions should focus on patient safety and well-being. Discussions with family should include management of financial accounts and credit cards, driving safety, and environmental factors to ensure physical safety. Exercise and physical therapy can be helpful for patients with motor problems. Among patients with hyperorality, special attention to diet should be made by caretakers to avoid excessive weight gain.

No FDA-approved pharmacologic interventions exist for any of the FTD subtypes. Anticholinesterase inhibitors are not recommended because no evidence supports a deficit of acetylcholine in this disease (67). Studies in bvFTD have shown serotonergic network disruption, with decreased serotonin levels and 5-HT1A and 5-HT2A receptors in frontotemporal regions and neuronal loss in the raphe nuclei (68, 69). Evidence suggests that selective serotonin reuptake inhibitors (SSRIs) are effective in helping with various symptoms of FTD, including disinhibition, impulsivity, repetitive behaviors, and eating disorders (69–71). Evidence also exists for dopaminergic disruption, with low levels of dopamine metabolites and severely reduced presynaptic dopamine transporters in the putamen and caudate of patients with FTD (70, 72). Some patients with bvFTD will require the use of antipsychotics for the treatment of severe neurobehavioral symptoms; however, they are usually reserved if no success was achieved with nonpharmacologic interventions or SSRIs. These patients tend to be more sensitive to extrapyramidal side effects because of diminished dopaminergic function; therefore, agents with less D2 receptor antagonism, such as quetiapine, are preferred (73).

As in all of the neurodegenerative disorders discussed previously, no cure exists for dementia caused by either PD or LBD. Symptomatic treatment remains the focus of medical interventions.

Patients with PDD or DLB have significant cholinergic deficits; therefore, AChEIs such as donepezil or rivastigmine represent the logical choice for pharmacological treatment of dementia in both cases. Donepezil is the most widely used AChEI in the treatment for dementia, and it selectively inhibits acetylcholinesterase (AChE). Rivastigmine is unique in that it has both AChE and butylcholinesterase inhibitory activity. In 2012, the FDA approved rivastigmine for mild to moderate dementia associated with PD on the basis of the 2004 study by Emre et al. (93), a large, randomized, double-blind, placebo-controlled study of rivastigmine lasting 24 weeks among 541 patients with mild to moderate dementia that developed at least 2 years after receiving a clinical diagnosis of PD. Patients treated with rivastigmine had a mean improvement of 2.1 points on the 70-point Alzheimer’s Disease Assessment Scale, with a baseline score of 23.8, compared with a 0.7-point worsening in the placebo group, with a baseline score of 24.3 (p<0.001). The study also demonstrated clinically meaningful improvements in the scores for the Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change; improvements were observed in 19.8% of patients in the rivastigmine group and 14.5% of those in the placebo group, and clinically meaningful worsening was observed in 13.0% and 23.1%, respectively (mean score at 24 weeks=3.8 and 4.3, respectively; p=0.007).

When the psychotic symptoms of DLB and PDD become more distressful or threatening, the use of low doses of second-generation antipsychotics with low D2 potency, such as quetiapine, should be considered to minimize motor side effects. Pimavanserin, a novel antipsychotic drug that is a selective 5-HT2A receptor inverse agonist, was recently approved by the FDA for the treatment of psychosis in PD (94). It has negligible effects on dopamine and histamine receptors; therefore, it avoids the motor and sedative side effects common with other antipsychotics. However, risks are still associated with pimavanserin, especially the prolongation of the QT interval. Like other antipsychotics, risk of death is increased with pimavanserin among elderly patients with dementia.