Neurodevelopmental and Neurodegenerative Similarities and Interactions: A Point of View About Lifelong Neurocognitive Trajectories

Abstract

Neurodevelopmental and neurodegenerative disorders are both growing major public health topics with similarities and frequent complex interactions with each other. Taking these aspects into account can provide a new point of view on lifelong neurocognitive trajectories. Assessing both neurodevelopmental and neurodegenerative dimensions during cognitive and behavioral clinical assessments is challenging but might improve diagnostic accuracy and physiopathological understanding. It is therefore necessary to understand the lifelong specific neurocognitive trajectory of each patient in order to develop personalized precision cognitive medicine.

Keywords

Atypical dementia neurodegenerative disorders neurodevelopmental disorders

INTRODUCTION

Neurodevelopmental disorders are a group of syndromes that manifest early in the developmental period, leading to atypical brain functioning. Behavioral and cognitive deficits can produce personal, social, academic, and occupational functioning impairments [1]. Neurodevelopmental disorders are very common, with a prevalence of at least 15%in the general population [2]. They consist of a group of syndromes that includes many clinical presentations, such as specific learning disorder, attention-deficit hyperactivity disorder (ADHD), developmental language disorders, and autism spectrum disorders (ASD) [3]. Different neurodevelopmental syndromes frequently occur together (for example, patients with learning difficulties due to ADHD frequently also have a specific learning disorder with impaired reading due to a phonological deficit not explained by the ADHD cognitive deficit). These conditions are present throughout adulthood, as the associated atypical cognitive profiles and atypical brain structures and functioning remain [3 –5]. These lifelong conditions in people with neurodevelopmental disorders might also affect later aging and neurodegenerative processes, inducing different clinical presentations compared to the general population [6, 7].

On the other hand, neurodegenerative disorders, such as Alzheimer’s disease or frontotemporal dementia (FTP), which are influenced by many factors such as traumatic conditions and genetic and epigenetic factors, might begin very early in life, influencing the child’s developmental profile and leading to presymptomatic prodromal presentations [8, 9]. Because preventive therapeutic strategies might be the future of neurodegenerative disorder management, recognizing these early manifestations might help to identify at-risk populations [10].

Although these two kinds of disorder may appear to be conceptually very different, a growing number of papers suggest a link between these two apparently opposite conditions across a lifetime, likely with a bi-directional interaction. The objective of this article is to provide a short, non-exhaustive overview of this topic.

CLINICAL AND GENETIC INTER-ACTIONS BETWEEN NEURODEVELOP-MENTAL DISORDERS AND NEURODEGENERATIVE DISORDERS

Neurodevelopmental disorders and neurodevelopmental genetic factors modify the clinical expression of neurodegenerative disorders

Patients with Alzheimer’s disease who have a probable history of neurodevelopmental disorders since childhood (according to a short screening with a 30-Item Self-Report Questionnaire [11]) more frequently have an atypical clinical presentation such as a focal cortical atrophy syndrome (e.g., posterior cortical atrophy (PCA) or primary progressive aphasia (PPA)) [7]. It is interesting to note that the frequency of atypical clinical presentations of Alzheimer’s disease (i.e., non-amnesic presentations) is about 15%[12], which is similar to the frequency of neurodevelopmental disorders in the general population [2]. Neurodevelopmental disorders might be a risk factor for the development of atypical Alzheimer’s disease but cannot explain all atypical presentations because some patients in this category do not have any history of neurodevelopmental disorders. The interactions between neurodevelopmental disorders and Alzheimer’s disease are not fully understood in term of causality, risk factors, aggravating factors, or co-morbidities. This may be because the underlying physiopathological processes are not well known and are probably multifactorial and heterogeneous. Therefore, the reported inter-relationships are mainly descriptive and/or hypothetical (Figs. 1 –3).

Fig. 1

Mind map showing examples of complex anatomo-functional and genetic links between developmental dyslexia, left-handedness, and primary progressive aphasia (PPA). Green, neurodevelopmental processes; blue, cognitive similarities; orange, neurodegenerative processes; lvPPA, logopenic variant PPA; svPPA, semantic variant PPA.

Fig. 2

Mind map showing examples of the complex anatomo-functional links between attention-deficit hyperactivity disorder (ADHD) and neurodegenerative disorders such as posterior cortical atrophy (PCA) and Lewy body spectrum disorders. Green: neurodevelopmental processes; Blue, cognitive similarities; Orange, neurodegenerative processes; LBD, Lewy body disease.

Fig. 3

Mind map showing complex anatomo-functional and genetic links between neuro-visual developmental disorders, specific learning disorders (SLD) of mathematic skills, neurodevelopmental genes and posterior cortical atrophy (PCA). Green: neurodevelopmental processes; blue: cognitive similarities; orange: neurodegenerative processes; ASD, autism spectrum disorders.

Constitutive atypical brain structures and atypical cognitive profiles present later, and frequently atypically, in neurodegenerative disorders. Different kinds of neurodevelopmental disorder are associated with different clinical presentations of neurodegenerative disorders.

Specific learning disorder with impaired reading or developmental dyslexia (Fig. 1)

Developmental dyslexia, initially considered by Mesulam as a risk factor for primary progressive aphasia [13], is overrepresented in logopenic variant PPA [14], a syndrome that is frequently caused by Alzheimer’s disease neuropathology [15]. Left-hemisphere brain atrophy centered on posterior portions of the middle and superior temporal gyri was smaller in the PPA group with developmental dyslexia than in the PPA group without developmental dyslexia. The common cognitive deficit of the phonological loop involved in these two syndromes suggests that neurodegenerative impairments target neurodevelopmental cognitive weak points. In a neuropathological study of three patients presenting logopenic variant PPA with developmental dyslexia, cortical developmental abnormalities and most severe Alzheimer’s disease pathological changes co-occur and overlap in the left perisylvian region [16].

Some susceptibility genes involved in developmental dyslexia (KIAA0319 and CNTNAP2) are associated with a more pronounced left asymmetrical atrophy, which itself is associated with language network disorders in FTD [17, 18]. However, no influence on the clinical presentation of FTD was reported. The same proportion of susceptibility genes was observed in both PPA (i.e., language variant FTD) and behavioral variant FTD. Associations between language developmental disorders and left network vulnerability with decreased brain volume and impaired connectivity are also frequently reported in siblings of patients with PPA [19].

Interestingly, non-right-handedness is a condition that frequently co-occurs with developmental dyslexia [20], and might also be considered a developmental dyslaterality (i.e., a type of benign neurodevelopmental variant compared to the general right-handed population). Non-right-handedness is also more frequently observed in people with semantic variant PPA—a syndrome that is frequently caused by FTD—than in the general population [14]. The specific cognitive process involved in this association between laterality and semantic knowledge remains unclear. However, in non-right-handed subjects, the left hemisphere and left-right interactions, which are involved in language networks, might function atypically [21]. The complex interactions observed between developmental dyslexia, non-right-handedness, and neurodegenerative disorders such as Alzheimer’s disease and FTD are summarized in Fig. 1.

Attention-deficit/hyperactivity disorder (ADHD) (Fig. 2)

Patients with ADHD present attentional deficits and cognitive and behavioral executive disorders. Fronto-parietal dysfunction [22] and dopaminergic dysregulation hypotheses [23] are frequently discussed in ADHD physiopathology. ADHD is associated with Lewy body dementia (LBD) and Parkinson’s disease [6 –24]. Cognitive presentations of LBD and Parkinson’s disease frequently induce common cognitive deficits with ADHD, i.e., attentional and executive disorders [25]. LBD and Parkinson’s disease with dementia present dysfunctions of the frontoparietal network, which is the network impaired by ADHD. Moreover, a potential pathophysiological link might be the dopaminergic disorders observed in ADHD and synucleinopathies such as Parkinson’s disease and LBD [23 –26].

In addition, ADHD is frequently associated with PCA [7], a syndrome mainly caused by Alzheimer’s disease neuropathology. As visual attention is frequently impaired in ADHD [27], it might also be the cognitive weak point for neurodegenerative processes, which might induce neurovisual disorders. These may include space perception deficits and simultanagnosia, which are severe visual attention disorders observed in PCA presentation [28]. Parietal lobe abnormalities are reported in both ADHD and PCA. Interestingly, LBD also sometimes presents with PCA syndrome at onset, and are both associated with ADHD. These factors support the hypotheses of similarities and interactions between Alzheimer’s disease, LBD, PCA, and ADHD.

Neuro-visual developmental disorders and specific learning disorders of mathematic skills: interaction with PCA

Neuro-visual developmental disorder, which in children is also called cerebral visual impairment, is an umbrella term for all types of visual impairment (from visual field defect to higher visual functions such as agnosia or simultanagnosia). These impairments are caused by early damage or dysfunction of the visual pathways or visual centers in the brain, including the lateral geniculate bodies, the optic radiations, the occipital cortices and the visual associative areas, as well as the tectum and thalamus [29]. Neuro-visual developmental disorders and specific learning disorders of mathematic skills are frequently associated with posterior dysfunction, especially of the parietal lobe [29, 30]. These two neurodevelopmental disorders are frequently associated with PCA [31], in which neurovisual disorders, including perception deficit and simultanagnosia, are some of the predominant clinical manifestations, and other parietal lobe related deficits such as acalculia are frequently reported [28]. Neurodegenerative PCA processes, frequently due to Alzheimer’s disease, but sometimes involving LBD or corticobasal degeneration for example [28], might be focused on the potential parietal neurodevelopmental weak point.

Genetic factors involved in neurodegenerative PCA presentation due to Alzheimer’s disease compared to typical amnesic presentation include two genes involved in neurodevelopment: SEMA3C and CNTNAP5. SEMA3C is associated with cortical and hippocampal development, and CNTNAP5 is associated with two psychiatric disorders: bipolar disorder and autism, which are also frequently included in the neurodevelopmental disorder spectrum [32]. ASD are sometimes associated with neuro-visual developmental disorders, and these entities have many similarities, such as prematurity as a risk factor, central coherence deficit, and social cognition disorders [33]. Bipolar disorders and ADHD also present a clinical and genetic overlap [34]. These findings support links between neurodevelopmental disorders and PCA presentation.

Neurodevelopmental disorders might mimic neurodegenerative disorders during aging

Neurodevelopmental disorders, such as dyslexia [35] or ADHD [36], are frequently not diagnosed during childhood or even during adulthood. This is especially the case among the geriatric population because no screening was available in their youth. In addition, neurodevelopmental disorders are not frequently reported spontaneously as part of the patient’s medical history during memory evaluation at memory clinics for elderly people. The atypical cognitive functioning caused by neurodevelopmental disorders remains as the patient ages, and might slightly increase with the dysexecutive syndrome and decrease in processing speed that occur during physiological aging. For example, a more pronounced impaired processing speed is reported in aging developmental dyslexia [37], while ADHD symptoms are stable across lifespan [38]. Moreover, other general medical conditions present in the geriatric population (e.g., obstructive sleep apnea, iatrogenic disorders, or diabetes) might aggravate cognitive disorders in neurodevelopmental population [39]. Therefore, if neurodevelopmental disorders are not taken into account, the patient’s atypical cognitive profile might be erroneously considered a recent cognitive decline at risk of developing into a neurodegenerative disorder [25 , 41]. Some cognitive performances of patients with neurodevelopmental disorders are below the cognitive performances of the general population and might be considered a cognitive decline according to DSM international classifications of neurodegenerative disorders. They may be misclassified as a neurodegenerative syndrome such as mild cognitive impairment (MCI) or PPA depending on the initial clinical cognitive and behavioral presentation of the neurodevelopmental disorder (Fig. 4) [25]. Systematic exclusion of an ongoing neurodegenerative disorder is of course needed to diagnose an isolated aging neurodevelopmental disorder [42]. Thereby, some clinical presentations supposedly considered as a probable neurodegenerative syndrome such as MCI, PPA, PCA, and FTD are revealed to be non-evolutive during medical follow-up. These conditions are sometimes related to aging neurodevelopmental disorders instead of to neurodegenerative disorder onset. For example, the phenocopy syndrome of behavioral variant FTD, which corresponds to patients with neuropsychiatric symptoms mimicking behavioral variant FDT, but lacking neuroimaging abnormalities and not evolving to dementia during the follow-up, are sometimes neurodevelopmental disorders such as ADHD or ASD that are undiagnosed until memory clinic assessment [43]. Clinical and neuropsychological follow-ups are therefore important tools to diagnose a non-degenerative process and to screen for neurodevelopmental conditions.

Fig. 4

Examples of potential misclassification in memory clinics between neurodegenerative and neurodevelopmental disorders that share cognitive and/or behavioral symptoms.

THE CHALLENGE OF DIAGNOSING AGING NEURODEVELOPMENTAL DISORDERS, NEURODEGENERATIVE DISORDERS, OR BOTH ENTITIES

The unequivocal diagnosis of neurodevelopmental and neurodegenerative disorders is difficult and often requires a postmortem neuropathological examination or at least identification of a genetic mutation [44]. For the majority of cases, only probabilistic diagnoses (i.e., “possible” or “probable”) are available in vivo in clinical practice using clinico-radiological classifications. Only a few biomarkers exist to improve diagnostic accuracy.

A posteriori diagnosis of neurodevelopmental disorders, i.e., a long time after the developmental period, sometimes lacking witnesses to report the patient’s birth and acquisition capacity while at preschool, for example, is a challenging procedure. It requires an exhaustive evaluation, the development of specific tools such as questionnaire-based scales, semi-structured interviews, and specific exhaustive neuropsychological evaluations. Clinical and cognitive follow-up, showing the presence or absence of progressive cognitive decline, might play an important role in confirming or invalidating the diagnosis [39, 40]. Patients with neurodevelopmental disorders might have relatively stable cognitive performances during follow-up, while patients with neurodegenerative disorders might show progressive cognitive decline [45]. The development of neurodevelopmental disorder biomarkers in addition to neurodegenerative biomarkers is also needed to increase the accuracy of—and level of confidence in—these diagnoses [46, 47].

Misdiagnosis is a major problem in Alzheimer’s disease, with a rate of misdiagnosis at about 20–30%in research studies as well as in clinical series [48 –52]. A neurodevelopmental disorder might be a confounding factor and/or a differential diagnosis in some of these misdiagnoses [40 , 54]. Diagnostic accuracy might be improved by including neurodevelopmental disorder screening in neurodegenerative disorder assessments, even for the oldest patients. Having an overview of the patient’s cognitive trajectory throughout their life could therefore help in developing personalized precision medicine [11, 40].

Neurodegenerative disorders’ genetic factors and proteinopathy influence childhood cognitive profile

APOE

The controversial role of APOE gene variants, which are an important genetic risk factor for Alzheimer’s disease, in cognitive development has been the subject of debate in the literature. Many studies suggest that APOE genes influence processing speed [55], attentional performance, and intellectual abilities during childhood [56]. However, some negative studies raise questions about the role of APOE in the developmental period [57].

Amyloid pathway

Amyloid precursor protein (APP) and Presenilin 1 (PSEN1) gene variants also modulate intellectual abilities [58, 59]. Both of these genes are involved in early-onset autosomal dominant Alzheimer’s disease when mutated. Genes involved in the amyloid secretase pathway, an enzymatic complex playing an important role in the amyloid cascade of Alzheimer’s disease, have also been identified by a genome-wide association study as factors influencing attentional performance in children [60].

Down syndrome is associated with both neurodevelopmental and neurodegenerative disorders

Down syndrome is a fairly common genetic abnormality caused by the presence of a third copy of chromosome 21. It induces neurodevelopmental disorders with varying levels of intellectual disability. As chromosome 21 includes the APP gene, amyloid overexpression induced by extra copies of the APP gene is also observed, which contributes to the high risk of early-onset Alzheimer’s disease and amyloid angiopathy observed in Down syndrome. Many genetic studies have focused on the other genetic factors that modulate the risk of Alzheimer’s disease and may provide insight into research into innovative protective strategies [61]. Many genes involved in redox metabolism, cholesterol metabolism, amyloid processing and clearance, tau phosphorylation, mitochondrial dysfunction, inflammatory responses, and neuronal development might play a role in the interaction between Alzheimer’s disease and Down syndrome and modulate the pathogenicity of the extra APP gene [62]. Interestingly, microduplication of the APP gene induces Alzheimer’s disease and amyloid angiopathy but is not associated with intellectual deficiency, neurodevelopmental disorders, or other Down syndrome abnormalities [63]. This suggests that isolated amyloid overexpression due to the extra copy is not sufficient to affect neurodevelopment.

Some findings suggest a lifelong, complex, amyloid neurocognitive trajectory with the influence of many other genes that are involved the amyloid cascade and other neurotoxic and neurodevelopmental mechanisms [62, 64].

TAUOPATHY, WHICH INFLUENCES ATROPHY PATTERNS, AS A POTENTIAL LINK BETWEEN SOME NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS

The microtubule-associated protein tau (MAPT) gene—a gene coding the tau protein, which is involved in frontotemporal dementia and Alzheimer’s disease—is linked with intellectual skills [65], and its deletion results in intellectual disability [66]. In addition to the direct role of the MAPT gene, neurodevelopmental disorders frequently influence tau expression and sometimes present an abnormal tau aggregation, leading to tauopathy in early life [67]. Tauopathy is also a hallmark of the neurodegenerative process of producing neurofibrillary tangles, which are observed in Alzheimer’s disease and in other kinds of neuropathological lesions that are related to other neurodegenerative disorders, such as progressive supranuclear palsy, corticobasal degeneration, and some forms of frontotemporal dementia [68].

For example, nodding syndrome is a progressive neurological disorder occurring during childhood, primarily observed in East Africa. It is characterized by stereotypical head dropping movements, cognitive impairment, impaired growth, and seizures. Neuropathological study of the syndrome has shown a diffuse tauopathy [69]. Its classification into early-onset neurodegenerative disorders or neuroinfectious diseases due to Onchocerca volvulus remains debated [70]. This example might suggest that tauopathy might have an early onset, even during the developmental period and, in this case, may be induced by an environmental infectious factor.

It is interesting to note that tauopathy is present in greater quantities in atypical presentations of Alzheimer’s disease [71, 72]. Tauopathy localization is associated with atrophy localization in Alzheimer’s disease [73, 74]. Patients who have Alzheimer’s disease with neurodevelopmental disorders often have an atypical clinical presentation [8, 14], a more severe tauopathy, and different patterns of atrophy [74, 75].

These findings, which show a tauopathy link between neurodevelopmental and neurodegenerative disorders, in addition to the interaction between tauopathy and brain atrophy, support the previous clinical and radiological observations in which neurodevelopmental disorders are overrepresented in atypical presentations of Alzheimer’s disease [8, 14]. They also suggest a lifelong tau neurocognitive trajectory in addition to the amyloid one.

NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS SHARE SOME NON-GENETIC RISK FACTORS AS WELL AS GENETIC ONES

Environmental pollution, perinatal disorders, body growth, head circumference, head trauma, childhood socioeconomic status, and psychological stress are involved in both neurodevelopmental and neurodegenerative disorders, suggesting at least partially common pathophysiological mechanisms and potential common future preventive interventions for these two domains [76].

Many of these factors are involved in brain, cognitive, and neural reserves that are reported to provide protection from dementia [76]. Neurodevelopmental biological, environmental, epigenetic, and educational factors are important to build these reserves [77]. Neurodevelopmental disorders might therefore modify or affect these mechanisms [37]. However, the link between brain and cognitive reserves and dementia might be complex and bi-directional, with some genetic factors involved in dementia affecting early-life brain construction and cognitive performances and therefore limiting the endogenous “passive” biological part of brain and cognitive reserve development [78]. Conversely, environmental, epigenetic, and educational factors may be preserved and may partially help to protect against neurodegenerative disorder expression [8] and counterbalance this genetic frailty.

COMMON BRAIN STRUCTURES AND COGNITIVE FUNCTIONS AFFECTED BY NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS

Cognitive function in patients with Alzheimer’s disease declines in reverse order of the development of these abilities during normal childhood and adolescence. Similarly, brain structures are affected by neurodegenerative disorders in a stereotypical progression that inversely follows ontogenetic brain development in a neocortex of the temporal, parietal, and frontal lobes [78]. Newborn infants show high levels of phosphorylated tau because phosphorylation of microtubule-associated protein tau is a physiological way of destabilizing axons and promoting synaptic plasticity in the developing brain and during neuroplasticity [79]. The distribution of neurofibrillary tangles is concentrated on the structures that take the longest to mature during childhood and adolescence [80] and which retain a capacity of neuroplasticity in adulthood. These include the temporal and frontal lobes, which are involved in higher brain functions like language, memory, perception, self-awareness, and consciousness, which require a life-long brain plasticity [81]. In patients with both neurodevelopmental disorders and neurodegenerative disorders, such as Alzheimer’s disease or synucleinopathy, the same brain structures present cortical developmental abnormalities and neurodegenerative lesions [16 –82].

A PERSONALIZED LIFELONG NEUROCOGNITIVE TRAJECTORY POINT OF VIEW

The term “lifelong neurocognitive trajectories” can be used to summarize both neurodevelopmental and neurodegenerative conditions in a life-long overview that includes both brain and cognition history. It also takes into account the fact that many factors are involved and can induce many different possible trajectories. This complexity provides a good explanation for the occurrence and variability of clinical and biological presentations of neurodevelopmental and neurodegenerative disorders in different patients.

CONCLUSION

Neurodevelopmental and neurodegenerative disorders are both growing major public health topics with frequent but complex interactions with each other, contributing to a new point of view about lifelong neurocognitive trajectories. Taking into account both neurodevelopmental and neurodegenerative dimensions during cognitive and behavioral clinical assessments at any age, as well as during fundamental cognitive research and therapeutic trials, is challenging but might improve diagnostic accuracy and physiopathological understanding, potentially providing information about prognosis and guiding specific therapeutic management. A broader perspective on lifelong neurocognitive trajectories is needed if we are to develop personalized precision cognitive medicine. For example, the overexpression of tauopathy and/or amyloidopathy in some subtypes of the neurodevelopmental disorder population who also have Alzheimer’s disease might modify therapeutic decisions, such as by leading to the prescription of a higher dose, or a combination of future anti-tau and/or anti-amyloid medications.

Footnotes

ACKNOWLEDGMENTS

Thanks to Jennifer Dobson for proofreading the article.

The author’s disclosure is available online (https://www.j-alz.com/manuscript-disclosures/20-1207r1).

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