INTRODUCTION
When patients, particularly older adults, and their families express concerns about “memory loss,” it’s crucial for clinicians to recognize that these concerns can encompass a wide spectrum of cognitive abilities and general cognitive decline, extending beyond just memory. While some degree of cognitive slowing is a natural part of aging, distinguishing between normal age-related changes and clinically significant cognitive impairment is the first critical step.
Dementia, clinically termed major neurocognitive disorder, is diagnosed when acquired cognitive impairment becomes severe enough to demonstrably impair an individual’s social and/or occupational functioning. Mild cognitive impairment (MCI), or mild neurocognitive disorder, represents an intermediate stage between normal cognition and dementia. In MCI, individuals experience cognitive decline, but their functional abilities remain essentially preserved.
This article aims to elucidate the diagnosis of dementia and MCI using the framework provided by the fifth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-5). The DSM-5 criteria for Major Neurocognitive Disorder (dementia) require evidence of substantial cognitive decline in one or more cognitive domains, significant enough to compromise independence in daily activities. Conversely, Mild Neurocognitive Disorder (MCI) is diagnosed when there is a modest decline in one or more cognitive domains, but the individual maintains independence in everyday activities, albeit with potentially increased effort. Crucially, the cognitive impairment in both conditions must represent a decline from a previous level of function, be documented by both patient history and objective assessment, and not occur exclusively during delirium or be better explained by another mental disorder.
Adapted from: American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association; 2013
Beyond diagnosing the syndrome of dementia or MCI, clinicians must also determine the underlying cause, or etiology, of the cognitive impairment. DSM-5 provides diagnostic criteria for various etiological subtypes of neurocognitive disorders, particularly relevant in older adults. Understanding these subtypes is essential for appropriate management and patient care.
IMPACT OF DEMENTIA: A GLOBAL HEALTH CONCERN
Neurocognitive disorders, especially dementias, have profound and far-reaching consequences. They impact individuals, families, healthcare systems, and economies worldwide. Alzheimer’s disease (AD), the most common cause of dementia, stands as a leading cause of death in the United States, significantly contributing to hospital admissions, skilled nursing facility placements, and the need for home health care. The financial burden associated with dementia is substantial and escalating, encompassing both direct healthcare costs and the indirect costs of unpaid caregiving provided by families. Furthermore, family caregivers often experience heightened emotional distress, increased rates of depression, and a decline in their own health. Globally, the scale of the problem is immense, with an estimated 35.6 million people living with dementia in 2010, a number projected to surge to 115.4 million by 2050. This escalating prevalence underscores the urgent need for effective diagnostic and management strategies.
DEMENTIA PREVALENCE AND INCIDENCE: UNDERSTANDING THE SCOPE
To fully grasp the public health challenge posed by dementia, it’s important to understand the concepts of prevalence and incidence. Prevalence refers to the proportion of a population affected by a disease at a specific time, offering a snapshot of the disease burden. Incidence, on the other hand, measures the rate at which new cases emerge in a population over a given period, reflecting the risk of developing the disease. Prevalence is influenced by both incidence and disease duration. Since most dementias are currently incurable, the duration is largely determined by how long individuals live after diagnosis. Therefore, the overall public health burden of dementia is shaped by both the emergence of new cases and the survival duration post-diagnosis. Populations with longer life expectancies will naturally exhibit higher dementia prevalence, even if the incidence rates are similar.
Prevalence Rates Across Populations
Dementia prevalence exhibits a striking exponential increase with age, approximately doubling every five years after the age of 65. In higher-income countries, prevalence rates in the 65+ age group typically range from 5% to 10%, with a tendency to be higher among women, largely due to their longer lifespan. Within the United States, studies indicate a higher prevalence in African American and Latino/Hispanic populations compared to non-Hispanic White populations. Global analyses suggest regional variations in prevalence, with potentially lower rates in sub-Saharan Africa and higher rates in Latin America compared to other parts of the world, as detailed in Table 2. The prevalence of MCI is more challenging to precisely quantify, as it varies depending on the specific definitions and MCI subtypes being studied.
Table 2. Prevalence of Dementia: Overall and Subtypes
| Authors | Country | Study type | Age | Regions | Overall Dementia | Alzheimer’s dementia | Vascular dementia | Parkinson’s dementia | Dementia with Lewy bodies | Fronto-temporal dementia |
|---|---|---|---|---|---|---|---|---|---|---|
| Prince et al., 2013 | Global | Meta-analysis + systematic review | >=60 | Latin America | 8.5% | |||||
| Sub-Saharan Africa | 5.0—7.0% | |||||||||
| Other world regions | 2.0–4.0% | |||||||||
| Matthews et al., 2013 | UK | Population survey | 65+ | Cambridgeshire, Newcastle, and Nottingham | 6.5% | |||||
| Gurland et al., 1999 | USA | Population survey | 65+ | Hispanic/Latino | 65–74 | 7.5% | ||||
| 75–84 | 27.9% | |||||||||
| 85+ | 62.9% | |||||||||
| African American | 65–74 | 9.1% | ||||||||
| 75–84 | 19.9% | |||||||||
| 85+ | 58.6% | |||||||||
| Non-Hispanic White | 65–74 | 2.9% | ||||||||
| 75–84 | 10.9% | |||||||||
| 85+ | 30.2% | |||||||||
| Hall et al., 2009 | USA | Population survey | 70+ | African Americans in Indianapolis | 7.45% | 6.77% | ||||
| Plassman et al. 2007 | USA | Population survey | 71–79 | Nationally representative sample | 4.97% | 2.32% | 0.98% | |||
| 80–89 | 24.19% | 18.1% | 4.09% | |||||||
| 90+ | 37.36% | 29.7% | 6.19% | |||||||
| Graves et al., 1996 | USA | Population survey | 65+ | Japanese Americans | 6.32% | 3.46% | 1.41% | |||
| CSHA Working Group, 1994 | Canada | Population survey | 65+ | Nationally representative sample | 8% | 5.1% | 1.5% | |||
| Aarsland et al.,2005 | Multi-national | Systematic review | 65+ | 0.15–0.5% | ||||||
| Zaccai et al.,2005 | Multi-national | Systematic review | 65+ | 0–5% | ||||||
| Rosso et al.,2003 | Netherlands | Population survey | Per 100,000 | 50–59 | 3.6 | |||||
| 60–69 | 9.4 | |||||||||
| 70–79 | 3.8 |
In all studies, prevalence % increases with age. Age-specific prevalence is reported in the original articles but omitted from this table.
With global life expectancy on the rise, particularly in low- and middle-income countries where population aging is accelerating, the prevalence of dementia is projected to increase significantly. However, some emerging evidence suggests a potential plateauing or even a decrease in dementia prevalence in high-income countries, possibly due to improved healthcare and lifestyle factors.
Incidence Rates and Trends
The incidence of dementia generally increases steadily with age until around 85 or 90, after which the rate of increase may slow down. Incidence rates are generally similar between men and women or slightly higher in women. Annual age-specific incidence rates can range from as low as 0.1% at ages 60-64 to as high as 8.6% at age 95. Understanding these trends is crucial for public health planning and resource allocation.
RISK AND PROTECTIVE FACTORS IN DEMENTIA
Identifying risk and protective factors is crucial for developing strategies to mitigate dementia risk. Risk factors are elements associated with an increased likelihood of developing dementia, while protective factors are linked to a reduced risk. It’s important to note that correlation does not equal causation; observed risk factors may not directly cause dementia, and protective factors may not entirely prevent it. These associations can be influenced by various biases, confounding factors, and the timing and duration of exposure, with mid-life often emerging as a critical period for many risk factors.
Demographic Risk Factors
Advancing age is unequivocally the strongest risk factor for dementia, and notably, it remains the most consistently identified risk factor even beyond the age of 80. While prevalence is often higher in women, this may be primarily attributable to their longer life expectancy, as incidence rates are not consistently higher. Lower levels of education have been consistently linked to higher dementia prevalence. Within the US, the reported higher prevalence in African American and Latino populations has been partially attributed to factors such as lower educational attainment and higher rates of cardiovascular disease within these communities.
Genetic Factors
While the majority of dementias are not directly inherited, genetics do play a role. A small subset of dementias is caused by deterministic autosomal dominant genes, which will be discussed in detail under specific dementia subtypes. For Alzheimer’s disease, several genes have been identified as susceptibility genes, with the Apolipoprotein E (APOE) polymorphism on Chromosome 19 being the most well-established. The APOE*4 allele, also associated with higher risks of hypercholesterolemia and heart disease, is linked to an increased risk of Alzheimer’s, Parkinson’s, Lewy Body, vascular, and frontotemporal dementias, particularly in men. Individuals homozygous for APOE*4 face a greater dementia risk than heterozygotes, while the APOE*2 allele appears to have a protective effect. It is crucial to remember that APOE*4 is a risk factor, not a definitive diagnostic marker for Alzheimer’s disease; its influence on risk seems to diminish after age 80.
Medical Risk Factors
Cardiovascular disease is increasingly recognized as a significant risk factor not only for vascular dementia but also for degenerative dementias, particularly Alzheimer’s disease. Heart disease has been associated with both Alzheimer’s and vascular dementia. Midlife cardiovascular risk factors, including hypertension, hypercholesterolemia, high body mass index (BMI), and diabetes mellitus, significantly increase the risk of late-life dementia, highlighting the long-term impact of midlife health. Conditions like heart failure and atrial fibrillation also elevate the risk of cognitive impairment and dementia. Cardiac disease can contribute to cerebral hypoperfusion, triggering cellular energy crises and cascades of events that lead to the production of toxic proteins implicated in dementia. Even in cognitively normal older adults, elevated pulse pressure has recently been linked to alterations in biomarkers suggestive of Alzheimer’s disease.
Inflammation and inflammatory markers (interleukins, cytokines, C-reactive protein) have been implicated in both Alzheimer’s and vascular dementias. Multiple mechanisms have been proposed for the role of inflammation in Alzheimer’s neuropathology.
Obstructive sleep apnea, which is associated with hypertension, heart disease, stroke risk, and white matter changes in the brain, is also linked to an increased risk of dementia. Stroke itself is a major risk factor for dementia.
Psychiatric Risk Factors
Depression and dementia share a complex and likely bidirectional relationship. Recurrent major depression in early adulthood appears to increase the risk of later-life dementia. Late-life onset depression is often considered a potential early manifestation of the underlying vascular or degenerative processes that cause dementia. Late-life anxiety is also associated with cognitive impairment and decline. Post-traumatic stress disorder (PTSD) has been reported as a risk factor for dementia. Certain lifelong personality traits, such as harm avoidance and a diminished sense of purpose, have also been observed as potential early indicators of Alzheimer’s disease.
Head Injury
Traumatic brain injury (TBI) is associated with an increased risk of dementia, particularly Alzheimer’s disease, with the severity of the injury correlating with the level of risk. Neurocognitive disorders can manifest immediately after a TBI or emerge later during recovery at any age. Chronic traumatic encephalopathy (CTE), previously known as dementia pugilistica, is a distinct condition diagnosed years after repeated concussive or subconcussive head impacts, presenting clinically similar to Alzheimer’s or frontotemporal lobar degeneration.
Lifestyle and Environmental Risk Factors
Various environmental and occupational exposures have been linked to neurodegenerative diseases. Smoking is associated with an elevated dementia risk, although some studies have paradoxically suggested a protective effect, potentially due to survival bias or cholinergic mechanisms. Heavy alcohol consumption increases dementia risk. Exposure to pesticides is associated with an increased risk of Parkinson’s disease, with a molecular mechanism identified.
Protective Factors Against Dementia
Protective factors are associated with a reduced incidence or risk of dementia, or a delayed onset. The concept of “reserve” has been proposed to explain why some individuals maintain cognitive function despite the presence of neuropathology typically associated with dementia. Brain reserve refers to the structural integrity and capacity of the brain, such as brain mass and neuron preservation. Cognitive reserve refers to the brain’s functional capacity, specifically the ability to utilize alternative neural networks and compensatory strategies.
Education and Cognitive Activity
Higher education is associated with a lower prevalence of dementia. This may reflect innate cognitive reserve or the cognitive stimulation provided by education itself, potentially through mechanisms like increased dendritic branching. Education may also correlate with socioeconomic status and access to better nutrition and healthcare. Bilingualism has been linked to delayed dementia onset, independent of education level, potentially offering specific protection against declines in attention and executive functions.
Lifelong engagement in cognitively stimulating activities and occupations is associated with a reduced risk of dementia. Leisure activities that are cognitively engaging also appear to lower dementia risk. Cognitive stimulation seems to have both protective and enhancing effects on cognitive function.
Pharmacological Factors
Observational studies have suggested that certain medications used for other conditions might be associated with a reduced dementia risk. However, clinical trials of these drugs for dementia prevention have generally been less conclusive. Timing and duration of exposure may be critical factors, as protective effects are often seen with prolonged use initiated years before dementia onset.
Non-steroidal anti-inflammatory drugs (NSAIDs) have shown mixed results regarding dementia risk. Some studies suggest a protective effect, but meta-analyses have raised concerns about bias in these findings. Lipid-lowering HMG Co-A reductase inhibitors (“statins”) have shown more consistent evidence of a protective effect against dementia in pooled analyses and meta-analyses.
Estrogen therapy, particularly hormone replacement therapy (HRT), has been extensively studied for dementia prevention. The Women’s Health Initiative Memory Study (WHIMS) trial in older women showed no protection and potentially increased risk with combination HRT. Meta-analyses generally conclude that hormones have no overall effect on dementia risk. However, some long-term observational studies suggest that the timing of hormone therapy initiation, specifically at menopause, might be a critical factor for potential protective effects.
Lifestyle Factors
Similar to cardiovascular disease, moderate alcohol consumption has been associated with a reduced risk of cognitive impairment and dementia in population-based studies. Adherence to a Mediterranean diet is linked to better cognitive function, lower rates of cognitive decline, and reduced Alzheimer’s disease risk. High levels of physical activity are consistently associated with a lower risk of neurodegenerative diseases. Interestingly, smoking shows a protective effect against Parkinson’s disease, possibly due to nicotine’s influence on cholinergic receptors.
Strong social networks and participation in mental, social, and productive activities in older women have been associated with a lower incidence of dementia. A combination of social, mental, and physical lifestyle components appears to be important for cognitive health, although reverse causality remains a possibility, as neuropathological changes often begin decades before clinical symptoms emerge.
CLINICAL ASSESSMENT: DIAGNOSING DEMENTIA AND MCI USING DSM-5
Clinical assessment is paramount in diagnosing dementia and MCI. The process is often initiated when patients or their families proactively express concerns about cognitive difficulties. In other cases, concerns may be elicited through direct questioning by the clinician. Occasionally, cognitive impairment may be observed by the clinician even when denied by the patient and without a reliable informant, particularly when the clinician has a strong prior knowledge of the patient’s cognitive baseline. Subtle clues, such as missed appointments, medication management errors, or confusion with simple instructions, can also alert clinicians. Experienced clinicians also recognize vagueness, evasiveness, or conversely, exaggerated reactions to minor issues as potential indicators of cognitive decline. In some instances, the initial presentation may not be cognitive complaints but rather changes in mood or behavior, such as apathy, anxiety, or depression.
Subjective Assessment: Gathering History and Functional Impact
Whenever feasible, obtaining a detailed history from both the patient and a reliable informant (family member, caregiver) is crucial. In milder cases, the patient may be more acutely aware of cognitive deficits than relatives. The clinical focus should be on changes in cognitive functioning as they manifest in everyday activities. Early deficits often become apparent in managing finances and medications. While well-learned routines may remain intact, difficulties may emerge in problem-solving, multitasking, and adapting to novel situations. Table 3 outlines the cognitive domains recognized by DSM-5 and corresponding examples of functional limitations in daily life.
Table 3. Functional limitations associated with impairment in different cognitive domains
| Cognitive domain | Examples of changes in everyday activities |
|---|---|
| Complex attention | Normal tasks take longer, especially when there are competing stimuli; easily distracted; tasks need to be simplified; difficulty holding information in mind to do mental calculations or dial a phone number |
| Executive functioning | Difficulty with multi-stage tasks, planning, organizing, multi-tasking, following directions, keeping up with shifting conversations |
| Learning and memory | Difficulty recalling recent events, repeating self, misplacing objects, losing track of actions already performed, increasing reliance on lists, reminders |
| Language | Word-finding difficulty, use of general phrases or wrong words, grammatical errors, difficulty with comprehension of others’ language or written material |
| Perceptual-motor/visuospatial function | Getting lost in familiar places, more use of notes and maps, difficulty using familiar tools and appliances |
| Social cognition | Disinhibition or apathy, loss of empathy, inappropriate behavior, loss of judgment |
Adapted from: American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association; 2013
It’s important to acknowledge that both patients and families may normalize cognitive decline as part of aging, dismissing concerns by comparing themselves to peers. Conversely, others may amplify minor changes and express undue fear of developing Alzheimer’s disease. While clinical observations are valuable, subjective concerns alone are insufficient for a definitive diagnosis.
Objective Assessment: Cognitive Testing and Standardization
Objective assessment requires the administration of standardized cognitive tests. Neuropsychological assessment, which provides detailed evaluation of specific cognitive domains, is preferred for both detecting subtle impairments and aiding in differential diagnosis, as outlined in Table 4. Detailed descriptions of neuropsychological assessments are readily available in specialized resources. When neuropsychological assessment is not accessible, global cognitive screening scales like the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), or the Mini-Cog can be utilized. These screening tools are generally sensitive enough to detect dementia but may be less sensitive to MCI. Crucially, test performance must be interpreted in the context of age, educational level, and ideally, cultural/linguistic background and regional norms to ensure accurate assessment.
Table 4. Examples of objective cognitive assessments, as noted in DSM-5
| Cognitive domains | Objective Assessment |
|---|---|
| Complex Attention | Maintenance of attention, e.g., press a button every time a tone is heard, over a period of time. Selective attention, e.g., hear numbers and letters, but count only the letters. Divided attention, e.g., tap rapidly while learning a story. Processing speed: carry out any timed task. |
| Executive Functioning | Planning: e.g., maze puzzles, interpret sequential pictures or arrange objects in sequence. Decision making with competing alternatives, e.g., simulated gambling. Working memory: hold information for a brief period and manipulate it, e.g. repeat a list of numbers backward. Feedback utilization: Use feedback on errors to infer rules to carry out tasks. Inhibition: Override habits; choose the correct but more complex and less obvious solution, e.g., read printed names of colors rather than naming the color in which they are printed. Cognitive flexibility: Shift between sets, concepts, tasks, rules, e.g., alternate between numbers and letters. |
| Learning and Memory | Immediate memory: Repeat a list of words or digits. Recent memory:– Free recall: recall as many items as possible from, e.g., a list of words, or a story, or a diagram. – Cued recall: with examiner providing cues, e.g., “recall as many food items as you can from the list.” – Recognition: with examiner asking, e.g., “was there an apple on the list?” Semantic memory: recall well-known facts. Autobiographical memory: recall personal events. Implicit (procedural) memory: recall skills to carry out procedures. |
| Language | Expressive language: confrontation naming of e.g., objects or pictures; fluency for words in a given category (e.g. animals) or beginning with a given letter, as many as possible in one minute. Grammar and syntax: omitting or incorrectly using articles, prepositions, helper verbs. Receptive language: comprehend /define words, carry out simple commands. |
| Perceptuomotor functioning | Visuoconstructional: e.g., Draw, copy, assemble blocks. Perceptuomotor: e.g., Insert blocks or pegs into appropriate slots. Praxis: Mime gestures such as “salute” or actions such as “use hammer.” Gnosis: e.g., recognize faces and colors. |
| Social cognition | Recognize emotions: Identify pictures showing e.g., happy, sad, scared, angry faces. Theory of mind: Consider another person’s thoughts, intentions when looking at story cards, e.g., “why is the boy sad?” |
Adapted from: American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association; 2013
Additional Assessments: Physical, Neurological, and Laboratory Evaluations
A comprehensive general physical and neurological examination, along with appropriate laboratory investigations, are essential components of the diagnostic process. These assessments serve to rule out treatable conditions that may contribute to cognitive impairment and to aid in differential diagnosis among various dementia subtypes.
The following sections will delve into the most prevalent etiological subtypes of neurocognitive disorders encountered in geriatric psychiatry settings, as classified by DSM-5.
ALZHEIMER’S DISEASE: THE MOST COMMON CAUSE OF DEMENTIA
Alzheimer’s disease (AD) stands as the most prevalent neurodegenerative disease, characterized by a progressive loss of synapses and neurons, accompanied by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, and significant cholinergic deficits. Typically diagnosed in the eighth or ninth decades of life, early-onset forms can manifest as early as the fifth decade. The average survival duration after dementia onset is approximately 10 years, but this can vary considerably based on factors like age of onset, severity of cognitive impairment, presence of comorbidities, and other individual factors.
In DSM-5, AD is categorized as an etiological subtype of both Major and Mild Neurocognitive disorders. The DSM-5 criteria align with the latest guidelines for Dementia and MCI due to AD published by the National Institute on Aging – Alzheimer’s Association (NIA-AA) Work Group. However, unlike the NIA-AA guidelines, DSM-5 criteria are primarily designed for clinical use, not research, and do not encompass preclinical AD stages. Diagnosing Dementia (Major NCD) due to Alzheimer’s disease using DSM-5 requires evidence of decline to substantial impairment in at least two cognitive domains, with memory impairment being mandatory in at least one. MCI (Mild NCD) due to Alzheimer’s disease is diagnosed when there is a decline to modest impairment in memory and potentially other cognitive domains. The cognitive decline should exhibit an insidious onset and a gradual, steady progression. Memory and executive function impairments typically emerge earlier in the disease course, while visuoconstructional/perceptual-motor, language, and social cognition impairments tend to appear later. However, non-amnestic presentations of AD do occur. Depression and apathy can be present throughout the disease spectrum. In the middle to later stages, psychotic features, irritability, agitation, combativeness, and wandering may develop. Very late in the illness, gait disturbances, dysphagia, incontinence, myoclonus, and seizures may become evident.
For a diagnosis of Probable AD-related neurocognitive disorder, DSM-5 requires either evidence of autosomal dominant familial AD or the absence of mixed etiology, meaning no other neurological, psychiatric, or systemic conditions that could account for the cognitive decline. In cases where mixed etiology cannot be definitively ruled out, a diagnosis of Possible AD is appropriate.
Genetics of Alzheimer’s Disease
Rare cases of early-onset familial AD are caused by autosomal dominant mutations in genes such as the amyloid precursor protein (APP) gene on Chromosome 21, the Presenilin 1 (PS1) gene on Chromosome 14, and the Presenilin 2 (PS2) gene on Chromosome 1. Individuals with Down Syndrome (Trisomy 21) invariably develop Alzheimer’s neuropathology if they live long enough. As previously discussed, the APOE*4 gene increases the risk of dementia but is not a diagnostic marker for AD.
Biomarkers in Alzheimer’s Disease Diagnosis
Biomarkers are increasingly playing a role in AD research and diagnosis. Evidence of cerebral amyloid deposition, detected through positron emission tomographic (PET) brain scans using amyloid tracers, and reduced levels of amyloid beta 42 in cerebrospinal fluid (CSF), are proposed as research biomarkers for AD. Markers of neuronal injury, such as hippocampal atrophy on magnetic resonance imaging (MRI), temporoparietal hypometabolism on fluorodeoxyglucose (FDG) PET scans, and elevated total tau and phospho-tau levels in CSF, are less specific to AD but are also considered research biomarkers. Currently, these biomarkers are primarily used in research settings and are not yet officially validated or approved for routine clinical diagnostic use under DSM-5.
In contrast to DSM-5, the NIA-AA guidelines describe a preclinical, asymptomatic stage of Alzheimer’s disease, where AD pathology is present as indicated by biomarkers, and subtle cognitive decline is detectable only through objective testing. This preclinical stage highlights the evolving understanding of AD’s long trajectory.
VASCULAR DEMENTIA (VASCULAR NEUROCOGNITIVE DISORDER)
Vascular neurocognitive disorder, also known as vascular dementia, is characterized by cognitive deficits primarily attributed to cerebrovascular disease. Terms like arteriosclerotic dementia, multi-infarct dementia, and vascular cognitive impairment are also used. It is the second most common cause of dementia and frequently coexists with Alzheimer’s disease (“mixed dementia”). Vascular dementia can result from both large and small vessel disease, with lesion location often being more critical than the overall volume of brain tissue damage. Given the variability in lesion type and location, the clinical presentation and disease course are often heterogeneous. Cognitive decline can manifest in an acute, stepwise pattern, a more gradual progression, or a fluctuating or rapid decline.
DSM-5 diagnostic criteria for vascular neurocognitive disorder require either a clear history of stroke or transient ischemic attacks (TIAs) temporally related to the cognitive decline, or neurological signs consistent with prior strokes. Cognitive impairment commonly affects complex attention and executive functions. Gait disturbances, urinary symptoms, and personality or mood changes, including emotional lability, are frequently observed. The depression associated with vascular neurocognitive disorder may present in late life and be characterized by psychomotor slowing and executive dysfunction, sometimes referred to as “vascular depression.”
Neuroimaging in Vascular Dementia
Neuroimaging, using CT or MRI, plays a crucial role in diagnosing vascular dementia by identifying evidence of significant parenchymal injury due to cerebrovascular disease. This may include one or more large vessel infarcts, a single strategically located infarct or hemorrhage, extensive lacunar infarcts beyond the brainstem, or extensive white matter lesions.
Genetics of Vascular Dementia
Rare autosomal dominant cerebrovascular disorders exist, such as CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a hereditary stroke form caused by Notch-3 mutations on Chromosome 19.
FRONTOTEMPORAL LOBAR DEGENERATION (FRONTOTEMPORAL DEMENTIA)
Frontotemporal dementia (FTD) is the third most common degenerative dementia, characterized by prominent atrophy of the frontal and temporal lobes of the brain. The underlying neuropathology involves protein inclusions, primarily composed of hyperphosphorylated tau or ubiquitin protein.
FTD typically has an earlier onset than AD, with a mean onset in the sixth decade of life, although 20–25% of individuals with FTD are over 65. It is a significant cause of early-onset dementia. Survival duration after symptom onset ranges from 6 to 11 years, and 3 to 4 years after diagnosis. FTD exhibits an insidious onset and gradual progression. Clinical subtypes, primarily the behavioral and language variants, correspond to specific patterns of brain atrophy.
The Behavioral Variant FTD is characterized by prominent changes in personality and behavior. These include loss of interest in personal affairs and responsibilities, social withdrawal, neglect of personal hygiene, and socially disinhibited behavior. Perseverative or compulsive motor behaviors, hyperorality (excessive eating), and dietary changes may also be present. Individuals with behavioral variant FTD are often initially seen in psychiatric settings and may be misdiagnosed with major depressive or bipolar disorder.
In addition to the behavioral variant, there are three Language Variants of FTD: (i) Semantic Variant Primary Progressive Aphasia (svPPA), presenting as fluent aphasia with impoverished content, paraphasic errors (word substitutions), but relatively preserved syntax and prosody. Emotional blunting, loss of empathy, and rigid behaviors can also be observed. (ii) Nonfluent Variant Primary Progressive Aphasia (nfvPPA), characterized by effortful, halting speech with grammatical errors. (iii) Logopenic Variant Primary Progressive Aphasia (lvPPA), marked by slow, word-finding pauses in speech, often affecting single-word retrieval.
Genetics of Frontotemporal Dementia
Familial FTD is linked to mutations in genes encoding proteins involved in fundamental cellular functions. These include microtubule-associated protein tau (MAPT), granulin (GRN), C9ORF72, transactive response DNA-binding protein of 43 kDa (TDP-43), valosin-containing protein (VCP), chromatin modifying protein 2B (CHMP2B), and fused in sarcoma protein (FUS).
Neuroimaging in Frontotemporal Dementia
Structural MRI or CT scans can reveal distinct patterns of regional cortical atrophy that correlate with the clinical variants of FTD, aiding in diagnosis and subtype differentiation.
DEMENTIA WITH LEWY BODIES
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. The underlying pathology is primarily characterized by the misfolding and aggregation of alpha-synuclein protein, forming pathognomonic Lewy bodies, also found in Parkinson’s disease. Symptom onset typically occurs between the sixth and ninth decades, with an average survival of 5–7 years.
DLB has an insidious onset and gradual progression. Cognitive deficits are most prominent in attention, visuospatial, and executive functions. Core diagnostic features include fluctuating cognition, recurrent visual hallucinations, and parkinsonism (motor symptoms similar to Parkinson’s disease). The key distinction between DLB and Parkinson’s disease dementia lies in the temporal sequence of cognitive and motor symptoms. In DLB, cognitive impairment precedes or occurs concurrently with parkinsonism, whereas in Parkinson’s disease dementia, cognitive impairment develops in the context of established Parkinson’s disease.
Suggestive features of DLB include REM sleep behavior disorder (RBD) and marked neuroleptic sensitivity (severe adverse reactions to antipsychotic medications). Reduced dopamine transporter (DaT) uptake in the basal ganglia, as demonstrated by SPECT or PET imaging, is also considered a suggestive feature. Supportive clinical features include repeated falls and syncope (fainting), transient unexplained loss of consciousness, severe autonomic dysfunction (e.g., orthostatic hypotension), hallucinations in other sensory modalities, systematized delusions, and depression.
Neuroimaging and Other Investigations in Dementia with Lewy Bodies
To differentiate Lewy body dementias (DLB and Parkinson’s disease dementia) from other dementias, dopamine transporter (DaT) PET or SPECT scans can be valuable. Generalized low uptake on SPECT and fluorodeoxyglucose PET, particularly with reduced occipital lobe activity, supports a DLB diagnosis. Additional supportive tests include low uptake on MIBG myocardial scintigraphy (suggesting cardiac sympathetic denervation) and prominent slow-wave activity on EEG with temporal lobe transient sharp waves.
NEUROCOGNITIVE DISORDERS DUE TO PARKINSON’S DISEASE
Neurocognitive disorders associated with Parkinson’s disease are diagnosed when gradual cognitive decline occurs in the context of a well-established diagnosis of Parkinson’s disease. Over the course of Parkinson’s disease, approximately 75% of individuals will develop a major neurocognitive disorder. The pattern of cognitive deficits is variable but often affects executive functions, memory, and visuospatial abilities, with a slowing of information processing suggestive of a “subcortical” cognitive profile. Associated features include psychiatric symptoms like depressed or anxious mood, apathy, hallucinations, delusions, or personality changes, as well as rapid eye movement sleep behavior disorder and excessive daytime sleepiness.
NEUROCOGNITIVE DISORDER DUE TO HUNTINGTON’S DISEASE
Huntington’s disease is a neurodegenerative disorder caused by an autosomal dominant mutation involving CAG repeats on Chromosome 4. The neurotoxic Huntingtin (HTT) protein initially damages the striatum of the basal ganglia but eventually affects the entire brain. Adult-onset Huntington’s disease typically manifests in the fourth or fifth decades, but patients have a median survival of 15–20 years after diagnosis and can present to geriatric services. A few individuals may develop initial symptoms at older ages even without a family history. Progressive cognitive impairment leading to dementia is inevitable in Huntington’s disease. Although cognitive deficits (executive function) and behavioral symptoms (depression, anxiety, apathy, obsessive-compulsive symptoms, and psychosis) often precede motor abnormalities (bradykinesia and chorea), clinical diagnosis is rarely made solely based on cognitive symptoms. A family history of Huntington’s disease should raise clinical suspicion, and genetic testing for the HTT mutation is diagnostic.
NEUROCOGNITIVE DISORDER DUE TO PRION DISEASE
Prion diseases are neurocognitive disorders caused by spongiform encephalopathies, resulting from transmissible misfolded protein particles called prions. Human prion diseases include kuru, sporadic Creutzfeldt-Jacob disease (CJD), familial CJD, iatrogenic CJD, Gerstmann-Stäussler-Scheinker disease, fatal insomnia, and variant CJD. Human transmission has been reported through infected growth hormone injections and corneal transplantation; cross-species transmission is exemplified by bovine spongiform encephalopathy (“mad cow disease”). Prion diseases are rapidly progressive and combine neurocognitive decline with motor features like myoclonus and ataxia. Variant CJD may initially present with mood changes, withdrawal, and anxiety. Individuals are typically diagnosed in their seventh and eighth decades, with a rapidly progressive course and survival typically under one year. Definitive diagnosis requires biopsy or autopsy. However, MRI with diffusion-weighted imaging or fluid-attenuated inversion recovery may show multifocal gray matter hyperintensities in subcortical and cortical areas. CSF analysis may reveal tau or 14-3-3 protein. Characteristic triphasic waves may be observed on EEG. Genetic testing can be useful in the 15% of cases with a family history suggestive of autosomal dominant mutation.
TREATMENT STRATEGIES FOR DEMENTIA
Etiology-Specific Treatment
When a neurocognitive disorder is diagnosed as being wholly or partially caused by a treatable condition (e.g., vitamin deficiency, thyroid disorder), treatment targeting the underlying condition is the primary approach. Currently, there are no disease-modifying therapies available for the major neurodegenerative dementias. However, symptomatic and supportive treatments can significantly improve quality of life and manage disease manifestations.
Symptomatic Treatment: Pharmacological Approaches
Cholinesterase Inhibitors: These medications enhance cholinergic neurotransmission in the synaptic cleft, potentially benefiting patients with cholinergic deficits, as seen in Alzheimer’s disease. Three cholinesterase inhibitors are currently approved in the US: donepezil, rivastigmine, and galantamine. For Alzheimer’s dementia, systematic reviews indicate that these drugs have comparable efficacy, providing modest improvements in cognitive function, daily activities, and behavior. Their effectiveness in advanced stages of dementia is debated. Evidence regarding their long-term impact on slowing functional decline or delaying institutionalization is mixed.
Rivastigmine is also approved for dementia in Parkinson’s disease, demonstrating meaningful improvements in cognition and daily functioning in clinical trials.
While expert consensus suggests cholinesterase inhibitors may be more effective in DLB than AD, for both cognitive and behavioral symptoms, robust evidence from large controlled trials is still needed.
In vascular dementia, the evidence for cholinesterase inhibitors is mixed. They are often prescribed due to the frequent co-occurrence of vascular and neurodegenerative pathology.
In frontotemporal dementia, cholinesterase inhibitors have not shown convincing benefits and may even worsen behavioral symptoms.
Evidence for the use of cholinesterase inhibitors in other neurocognitive disorders is limited.
Importantly, systematic reviews have found minimal evidence of benefit from cholinesterase inhibitors in mild cognitive impairment, either for symptom relief or delaying progression to dementia, and the limited benefits are outweighed by the risk of adverse effects, particularly gastrointestinal issues.
NMDA Receptor Antagonist: Memantine, an NMDA receptor antagonist, is approved for moderate to severe Alzheimer’s disease. It is believed to have neuroprotective effects against excitotoxicity in the cortex and hippocampus. Memantine is generally well-tolerated.
Systematic reviews show that memantine provides a small cognitive benefit at six months in moderate to severe AD, a marginal effect in mild to moderate AD, and minimal clinically detectable benefit in mild to moderate vascular dementia.
In frontotemporal dementia, memantine’s effectiveness is unclear. Preliminary evidence suggests potential benefits in DLB and Parkinson’s disease dementia, but there are reports of worsening delusions and hallucinations in DLB.
Serotonergic Agents: Selective serotonin reuptake inhibitors (SSRIs) antidepressants can be beneficial for managing behavioral and psychiatric symptoms in frontotemporal dementia, although they do not typically improve cognition.
Dopamine Blocking Agents (Neuroleptics/Antipsychotics): Neuroleptic drugs should be prescribed cautiously in dementia due to the risk of adverse cerebrovascular events. They should be avoided or used with extreme caution in DLB patients due to neuroleptic sensitivity. Second-generation antipsychotics are preferred when necessary. If the patient is already taking dopaminergic medications for Parkinsonism, dose reduction of the dopaminergic agent should be considered before introducing a dopamine-blocking agent.
Benzodiazepines: Benzodiazepines are generally avoided in neurocognitive disorders due to the risk of paradoxical agitation, falls, and further cognitive impairment. An exception may be the treatment of REM Sleep Behavior Disorder in DLB.
Psychosocial and Environmental Management: Non-pharmacological interventions, including psychosocial support, cognitive rehabilitation, environmental modifications, and caregiver support, are essential components of dementia care and are discussed in detail elsewhere.
SUMMARY: DSM-5 AND DEMENTIA DIAGNOSIS
Clinicians must possess a thorough understanding of the diverse neurocognitive disorders that significantly impact older adults. Accurate diagnosis relies on careful history taking, skilled clinical assessment utilizing DSM-5 criteria, and judicious use of laboratory investigations. Diagnostic imaging can be valuable when interpreted by experts familiar with these conditions. While biomarkers hold promise, they are still primarily research tools and not yet routinely recommended for clinical diagnosis in most dementia subtypes under DSM-5. Referral to specialists, such as neuropsychologists for detailed cognitive testing, neurologists for complex diagnoses, and geriatric psychiatrists for behavioral and psychological challenges, can be invaluable. Current drug treatments primarily offer symptomatic relief. Psychosocial and supportive therapies are crucial for comprehensive dementia management.
Key Points
- Knowledge of various neurocognitive disorders is crucial for clinicians managing older adults.
- Accurate dementia diagnosis using DSM-5 requires careful history, clinical assessment, and relevant lab tests.
- Diagnostic imaging aids diagnosis when interpreted by experts.
- Biomarkers are research tools, not yet routine clinical diagnostic tools for most dementias under DSM-5.
- Specialist referrals (neuropsychologists, neurologists, geriatric psychiatrists) enhance diagnosis and management.
- Current drug treatments are symptomatic; psychosocial and supportive therapies are essential.
Footnotes
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