Considering learning disabilities and attention-deficit hyperactivity disorder when assessing for neurodegenerative disease

Abstract

Purpose of review

When evaluating an older adult for a possible neurodegenerative disease, the role of premorbid specific learning disabilities or attention-deficit hyperactivity disorder (ADHD) should be considered. These neurodevelopmental conditions can manifest as lifelong weaknesses and variability in cognitive functions that complicate assessment of cognitive decline. There is also accumulating evidence that certain neurodevelopmental disorders may entail greater risk for specific neurodegenerative disorders.

Recent findings

We describe clinical cases where diagnosis of neurodegenerative disease was influenced by preexisting neurodevelopmental disorders. We also present a questionnaire to assist with screening for premorbid learning disabilities and ADHD in older adults.

Summary

This article offers clinical guidance for practicing neurologists in the identification and assessment of neurodevelopmental disorders in older adult patients, which informs management and treatment. Consideration of lifetime functioning has become increasingly important with research linking neurodevelopmental disabilities to increased risk of specific neurodegenerative diseases.

When older adults present for evaluation of neurocognitive functioning, neurodevelopmental conditions are rarely considered, although learning disabilities (LDs) and attention-deficit hyperactivity disorder (ADHD) are common and associated with atypical brain maturation patterns. Current epidemiologic studies estimate that 5%–15% of school-aged children have LDs, which are known to persist into adulthood.¹ However, prevalence rates of LDs in adults are less well characterized, likely due to changes in diagnostic criteria over time and the fact that LDs were not routinely identified and tracked in the United States before 1975, when the federal government implemented what is now known as the Individuals with Disabilities Education Act.² The rate of ADHD in adulthood has been estimated to be approximately 2.5%,³ with high rates of persistence from childhood to adulthood in both men and women.⁴ There is also a high degree of comorbidity between LDs and ADHD.^5,6

These neurodevelopmental disorders are defined by the presence of specific weaknesses in cognitive skills that may be formally assessed in older adults to determine whether there has been a decline in functioning relative to a presumed baseline. Thus, the presence of premorbid LDs and/or ADHD can complicate diagnosis of a neurocognitive disorder in an older adult. Lack of knowledge about the individual's long-standing learning disability or ADHD may lead to the erroneous conclusion that there has been a decline in cognitive functioning when the observed weaknesses are developmental in origin. Similarly, if new cognitive difficulties are accurately detected, differential diagnosis may be unduly biased by the presence of old cognitive difficulties if those are incorrectly judged to be new.

There is also increasing evidence linking specific neurodevelopmental disorders to the onset of neurodegenerative disorders later in life.^7–12 Higher rates of language-based LDs, especially dyslexia, have been associated with the logopenic subtype of primary progressive aphasia (PPA).^7,9 Similar links have been established between mathematical and visuospatial LDs with posterior cortical atrophy (PCA)¹² and ADHD with Lewy body dementia (LBD).⁸ These correlations raise the possibility that there may be common underlying biological processes (e.g., genes) in neurodevelopmental and neurodegenerative disorders.¹² Lending support to this hypothesis is the recent characterization of fragile X-associated tremor/ataxia syndrome, a neurodegenerative condition presenting in those with a family history of neurodevelopmental conditions associated with fragile X.¹³ Alternatively, neurodevelopmental disorders may be associated with decreased reserve within a specific network once a neurodegenerative process begins. Similar hypotheses have been discussed in regard to the influence of cognitive reserve on diagnosis with neurodegenerative disease (i.e., high cognitive reserve is associated with delayed diagnosis of dementia, whereas lower cognitive reserve is associated with earlier diagnosis).¹⁴

From a clinical perspective, knowledge of a premorbid learning disability or ADHD is critical in assessing whether there has been pathologic cognitive decline. Premorbid neurodevelopmental conditions may complicate differential diagnosis and thus influence clinical management. In the early stages of cognitive decline, standard cognitive screening measures (e.g., Montreal Cognitive Assessment, Mini-Mental Status Examination) may not have sufficient specificity or sensitivity to differentiate between preexisting and new-onset cognitive variability.^15,16 Referral for a full neuropsychological evaluation should be considered to characterize specific cognitive domains. Convergent data from additional diagnostic tools (e.g., neuroimaging) may also be needed. Furthermore, serial neuropsychological evaluations may differentiate between lower cognitive abilities that are stable over time (developmental) from those that are progressive (neurodegenerative) and to assess response to interventions (e.g., medications). Below, we describe 3 clinical vignettes to illustrate these principles.

Case vignette: developmental dyslexia

Case 1 is a 66-year-old, left-handed man with a 1-year history of progressive memory decline with insidious onset. He reported that he easily forgets recent events, has greater difficulty multitasking, and struggles to find words in conversation. When navigating, he sometimes has difficulty remembering his destination but denied frank route-finding difficulties. His wife reported that he is slightly more irritable but otherwise, personality is unchanged. He is fully independent in basic and instrumental activities of daily living.

Medical history is remarkable for cerebrovascular risk factors (hyperlipidemia, hypertension, history of a remote myocardial infarction), and sleep apnea (continuous positive airway pressure-compliant). Psychiatric history is unremarkable. Family history is notable for cerebrovascular disease and cancer with no known history of neurodegenerative disease.

English is his first and only language. He has a master's degree in engineering and retired as a high-level manager within a large company. Developmental history is notable for early reading difficulties, and he received tutoring in elementary school. He also described poor spelling and early concerns about vulnerability to inattention.

Dyslexia is a common neurodevelopmental disorder characterized by deficits in phonological processing that interfere with the acquisition of reading skills. Neuroanatomical and imaging studies have revealed atypical development of brain areas involved in language processing.¹⁷ In addition to deficits in reading, there may be associated difficulties with spelling, math (word problems and math fluency), and achieving proficiency in a second language.^18–20

On formal neuropsychological testing, intellectual functioning is generally within normal limits. Language abilities are usually variable with weaknesses in skills related to phonological processing, including rapid naming, phonemic fluency, and speed on measures that involve orthographic coding or number and letter sequencing. Auditory working memory may also be suppressed, presumably because of a reduced capacity within the phonological loop, and this can contribute to weaker encoding of verbal material. Vocabulary and fund of general knowledge may be reduced due to the cumulative impact of academic difficulties.²¹

Based on his reported occupational history and results of formal testing, premorbid intellectual ability was estimated to fall in the high average range for age. Consistent with reported concerns, there were considerable memory difficulties, characterized by reduced encoding (learning) and retrieval of new information (auditory and visual) and possibly rapid forgetting (Wechsler Memory Scale [WMS] Logical Memory and Visual Reproduction, Free and Cued Selective Reminding Test). There were also language difficulties. Speech was fluent and grammatical but with circumlocutions. On a measure of single word reading used to estimate premorbid intellectual ability (Test of Premorbid Functioning), his performance fell at the 10th percentile with difficulty pronouncing irregular words. Confrontation naming was poor (Boston Naming Test), and verbal fluency was reduced (Controlled Oral Word Association), with phonemic fluency weaker than semantic fluency. A narrative writing sample was notable for grammatical and spelling errors.

This case illustrates that exclusive use of language-based measures (e.g., word reading) to establish premorbid intellectual functioning may result in underestimation in cases in which dyslexia is suspected. Other nonverbal measures correlated with premorbid intellectual functioning were definitively higher. In this context, markedly reduced encoding and retrieval of new auditory and visual material raises concern about systems involving the frontal lobes, which is not unexpected, given his history of cerebrovascular risk factors and history of sleep apnea. Reduced confrontation naming and possibility of mild forgetting of verbal material raises additional concern about medial temporal involvement and Alzheimer pathology; current consensus criteria for Alzheimer disease identify anterograde amnesia (impairment in learning and recall of recently learned information) as the most common syndromic presentation.²² PPA might also be included in the differential diagnosis, given that diagnostic criteria for semantic variant PPA require impaired confrontation naming and may include surface dyslexia and that diagnostic criteria for logopenic PPA include impaired single-word retrieval in spontaneous speech and naming.²³ However, in the context of possible developmental dyslexia, only impaired confrontation naming is suspicious for a clear change relative to his baseline.

To aid in differential diagnosis and clinical management, additional evaluative studies were considered, including neuroimaging and biomarkers. Neuropsychological reevaluation in 1–2 years was also recommended if there was further progression of his clinical symptoms. Neuropsychological evaluations should include assessment of language skills that may differentiate the recognized forms of PPA from developmental dyslexia, including speech fluency, grammaticism of language output, repetition, confrontation naming, and language comprehension (at the single word and syntactic level). If PPA is strongly suspected following these studies, speech and language therapy could also be considered, given recent research suggesting that this may be beneficial for those with PPA.²⁴

Case vignette: math and visuospatial difficulties

Case 2 is a 72-year-old, right-handed woman who presented with a 1-year history of progressive memory decline with insidious onset. She described difficulty retaining recent information, occasional temporal confusion, increased distractibility, and difficulties with multitasking. She was reading less because of difficulties following the plot. There had been a decline in her handwriting and spelling abilities. Basic and instrumental activities of daily living were largely intact, although she was taking fewer speaking roles at church and voluntarily stopped driving about 6 months ago.

Medical history is remarkable for a remote history of migraine headaches and osteoarthritis. She described long-standing vulnerability to anxiety and had recently begun taking medication for this. There is no other history of psychiatric services. Elemental neurologic examination was within normal limits. A head CT was notable for possible moderate to severe white matter disease.

She is a college graduate, and English was her first and only language. When asked about her developmental history, she reported having “dyslexia.” However, on further questioning, she reported having always been an avid reader and excellent at spelling. In contrast, she had greater difficulty in math, particularly with spatial concepts (e.g., geometry and fractions). She also described lifelong difficulty with spatial navigation and left-right discrimination, as well as vulnerability to anxiety, particularly in social situations, and mild clumsiness.

Figure. MGH learning disabilities screen.

Case 2 clearly describes a developmental history of uneven cognitive skill development. Although she used the term “dyslexia,” her reported developmental history is notable for math and spatial weaknesses that overlap with what has been described as a Nonverbal Learning Disability (NLD).²⁵ NLD is not a recognized learning disability and is a controversial construct for reasons discussed elsewhere,²⁶ but the salient and specific constellation of weaknesses can be seen in idiopathic developmental conditions, as well as in some genetic syndromes.²⁷ From a clinical perspective, this case also illustrates that in older adults, self-reported LDs should be elicited by focusing on symptoms rather than reported diagnostic labels.

On formal neuropsychological testing, intellectual functioning is generally within normal limits with selective weaknesses in spatial skills (e.g., navigation, mental rotation, constructing puzzles, and judging line angles), poor left-right discrimination, weaknesses in graphomotor skills (e.g., drawing and handwriting) and/or coordination, and slower processing speed. Math skills, specifically those requiring quantitative reasoning and “number sense,” are often areas of difficulty, whereas calculation skills may be intact. There may also be weaknesses in processing speed and a tendency to exhibit a concrete or detail-oriented reasoning style. Accompanying social and emotional difficulties have been described.^25,27

Neuropsychological testing revealed average premorbid intellectual abilities and intact memory and semantic access. There were prominent difficulties with aspects of executive function, including reduced auditory working memory (Digit Span), difficulty with mental tracking and set-shifting (serial 7s, Trail Making Test), slow processing speed (Coding), and a tendency to generate concrete responses on reasoning tasks (Similarities). Visuospatial skills were reduced. She could not accurately copy overlapping pentagons or a cube. Her clock drawing was poorly planned and organized. She was unable to generate block designs (Block Design) and had difficulty identifying objects that were presented as “puzzle pieces” (Hooper Visual Organization Test). She struggled to perform calculations that involved regrouping or the alignment of columns.

Marked difficulties with visuospatial, constructional, and math skills raise concern about PCA. PCA is a progressive neurodegenerative disease that typically affects those in their mid-50s and early 60s, and current diagnostic criteria require the presence of prominent cognitive dysfunction consistent with posterior cortices (e.g., constructional dyspraxia, left/right disorientation, environmental agnosia, acalculia, apperceptive prosopagnosia, and agraphia) with relatively spared anterograde memory, speech/language functions, executive functions, and behavior/personality.²⁸ Although the observed visuospatial deficits overlap with diagnostic criteria for PCA, given the elicited developmental history, the degree to which her current performances represent a decline from her premorbid baseline is unclear. The prominent difficulties with executive function are also unexpected in the early stages of PCA. The possibility that the neuropsychological profile reflects the combination of progressive executive dysfunction secondary to the cumulative impact of white matter disease noted on neuroimaging and a stable preexisting learning disability should be considered. Anxiety may be a contributing component, but given that her symptoms are currently well managed, unlikely to fully account for her executive dysfunction. Neuroimaging and biomarkers may assist with differential diagnosis and clinical management, especially given that PCA can sometimes reflect atypical Alzheimer disease, but there are individuals with the PCA syndrome who are negative for AD pathophysiologic biomarkers (e.g., in cases in which the clinical syndrome is associated with LBD, corticobasal degeneration, or previous disease).²⁸

On the other hand, the possibility of preexisting weaknesses in visuospatial skills and mathematics does not preclude diagnosis of PCA. As discussed above, higher rates of similar LDs have been associated with PCA. In a single study, the clinical presentations of patients with PCA with and without preexisting LDs were quite similar, with only neuroimaging showing different patterns of atrophy for the 2 groups (i.e., patients with PCA with a history of LD had a right-lateralized pattern with prominent intraparietal sulcal involvement, whereas those without LD had a more bilateral pattern with prominent middle and superior occipital gyri involvement).¹² Thus, additional evaluative studies with serial neuropsychological evaluations were recommended.

Case vignette: ADHD

Case 3 is an 83-year-old, right-handed man who presented with a 1- to 2-year history of progressive memory decline with insidious onset. He reported difficulties recalling recent events. Although he benefits from prompts, his recall is not as detailed as in the past. He also endorsed occasional word finding difficulties in conversation. He is independent for basic and instrumental activities of daily living.

Medical history is remarkable for hyperlipidemia. Neuroimaging (brain MRI) was notable for mild asymmetric volume loss of the right hippocampus, mild global volume loss, and mild nonspecific T2 hyperintensities (more in subcortical than periventricular areas). Psychiatric history is notable for mild depressive episodes and vulnerability to anxiety throughout his life but not requiring formal psychiatric services.

He is a college graduate who ran a successful manufacturing business until his retirement approximately 5 years ago. When asked about developmental history, he reported that he had wondered whether he had “ADD” (attention-deficit disorder). He described lifelong difficulty staying focused, especially on topics that were not interesting to him. There were early concerns about academic underachievement, but he did well in college once he was able to take courses that he enjoyed. He has always been disorganized and relied on his wife and administrative assistant to keep track of his schedule and important details.

ADHD is the most common neuropsychiatric disorder treated in children and adolescents, affecting 5%–12% of school-aged children. Approximately 30% of individuals will continue to meet diagnostic criteria for ADHD in adulthood.²⁹ Individuals who have ADHD may be very high functioning, but there are also higher rates of specific LDs, anxiety, depression, and substance use.⁶ From a neurologic perspective, atypical development of networks involving the frontal lobes has been proposed.³⁰ On formal neuropsychological testing, ADHD is sometimes associated with weaknesses in sustained attention and aspects of executive function. Specifically, relative to other skills, individuals who have ADHD may exhibit slower processing speed, reduced working memory capacity, trouble with set-shifting and multitasking, and demonstrate reduced efficiency in their approach to tasks (e.g., poor self-monitoring and disorganization). These may contribute to reduced encoding (learning) on memory testing, especially when information is presented without context.^31,32

Neuropsychological testing indicated high average to superior premorbid intellectual functioning. In this context, there were prominent memory difficulties for new auditory and visual information. He exhibited major difficulty with encoding (learning) and milder difficulties with spontaneous retrieval. The possibility of mild rapid forgetting of visual material could not be entirely ruled out (WMS Logical Memory, WMS Visual Reproduction, Free and Cued Selective Reminding Test). There was also mild executive dysfunction, characterized by difficulty with set-shifting, mental tracking, self-monitoring, and task persistence (e.g., Trail Making and serial 7s). Language, including semantic access, and visuospatial functions were intact.

Testing suggests multiple processes contributing to current cognitive difficulties. The nature of his memory concerns (poor encoding and retrieval) coupled with weaknesses in executive function is concerning for disruption of frontal lobe networks. Although the degree of difficulty on testing most certainly represents a decline from his high premorbid baseline and may reflect the cumulative effect of cerebrovascular disease, the magnitude of this decline is difficult to estimate in the context of lifelong ADHD symptoms. Rapid forgetting of visual information is clearly concerning, as this is most certainly a change from baseline and consistent with asymmetric hippocampal volume loss noted on neuroimaging (right > left). From a diagnostic perspective, Alzheimer disease should be strongly suspected, given evidence for anterograde amnesia for visual material and a likely decline in executive functions. From a clinical management perspective, the presence of biomarkers for Alzheimer disease would provide confirmatory evidence, and it would be reasonable to consider cognitive-enhancing medications while continuing to manage cerebrovascular risk factors.

TAKE-HOME POINTS

• → Screening for neurodevelopmental disorders should be performed when considering a neurodegenerative disorder diagnosis. This may be accomplished through a series of brief and targeted questions (figure).

• → Patients who have LDs and/or ADHD may have had variable cognitive skills throughout their lives. This should be taken into account when estimating functional decline from a presumed baseline. Formal neuropsychological testing is recommended in these cases, as cognitive screening measures (e.g., MMSE and MoCA) may not have adequate sensitivity when there is variability among cognitive domains.

• → Certain learning disorders are overrepresented in individuals with certain neurodegenerative disorders. There are established links between dyslexia and the logopenic variant of PPA, math and visuospatial disabilities and PCA, and ADHD and LBD.

Appendix. Authors

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Disclosure

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