Mutations in the mitochondrial genome can impair normal metabolic function in the central nervous system (CNS) where cellular energy demand is high. Primary mitochondrial DNA (mtDNA) mutations have been linked to several mitochondrial disorders that have comorbid psychiatric, neurologic, and cognitive sequelae. Here, we present a series of cases with primary mtDNA mutations who were genotyped and evaluated across a common neuropsychological battery. Nineteen patients with mtDNA mutations were genotyped and clinically and cognitively evaluated. Pronounced deficits in nonverbal/visuoperceptual reasoning, verbal recall, semantic word generativity, and processing speed were evident and consistent with a “mitochondrial dementia” that has been posited. However, variation in cognitive performance was noteworthy, suggesting that the phenotypic landscape of cognition linked to primary mtDNA mutations is heterogeneous. Our patients with mtDNA mutations evidenced cognitive deficits quite similar to those commonly seen in Alzheimer's disease and could have clinical relevance to the evaluation of dementia.

Introduction

Mitochondria are structural organelles that regulate fundamental cellular energy in the central nervous system (CNS). Metabolic energy in the brain is essential for neurotransmitter release and synaptic plasticity (Brierley, Johnson, Lightowlers, James, & Turnbull, 1998; McFarland, Taylor, & Turnbull, 2002). Genetic mutation to DNA in the mitochondrial (mtDNA) genome, although rare [estimated to be ∼1 in 5,000 (Bannwarth et al., 2013)], can be highly penetrant in the CNS (Abramov et al., 2010). Human cognition is especially susceptible to mitochondrial dysfunction given the strong metabolic requirements of normal brain function. Certain allelic variants in mtDNA genes often lead to cognitive impairments, and a “mitochondrial dementia” has even been posited (Finsterer, 2008).

The current study is a case-series presentation of individuals with primary mtDNA mutations who underwent comprehensive neuropsychological testing to better characterize the cognitive deficits (or lack thereof) associated with a variety of mtDNA mutations. Data are presented both case-by-case and groupwise. The sample is unique in that it includes both related and unrelated individuals across the developmental spectrum who were assessed using several neuropsychological measures germane to dementia and Alzheimer's disease specifically.

Methods

Participants

Nineteen patients (68% female) from Hungary with primary mtDNA alterations were evaluated. Patients were 35.3 years old on average (±12.2 years; range: 17–61 years) and educated for approximately 12.9 years (±1.2 years). Most patients had symptomatology typical of mtDNA mutation syndromes (e.g., hypoacusis, myopathy, and ataxia), but no patients had severe ptosis, visual loss, or hearing impairment that affected their performance based on their medical history on intake. Diagnosis of primary mitochondrial disorders was based on clinical, myopathological, and biochemical investigations following international criteria, and confirmed by genetic testing (DiMauro & Hirano, 2005). Psychiatric symptomatology in these patients has been reported previously (Inczedy-Farkas et al., 2012).

A sample of 13 demographically similar healthy controls (mean age: 33.76 years; 69% female) was also recruited for the purpose of normalizing the raw neuropsychological data to standardized metrics (e.g., z-scores). We elected to norm the patient data to a Hungarian control sample rather than to norms developed in English speaking samples. Because our patient group lacked genetic homogeneity in terms of the type(s) of mtDNA mutations included in the study, we resultantly had inadequate statistical power to compare patients with controls employing traditional parametric statistics. However, we provide estimates of effect size in the form of Cohen's d in Table 1 to give a general sense of the magnitude of impairment across measures.

Table 1.

Magnitude of deficit in mtDNA patients relative to controls for individual neuropsychological tests

  Domain
 
Test Cohen's d Verbal Nonverbal 
Trails A −5.7  Nonverbal processing speed 
WAIS object assembly −3.3  Visuoconstruction 
WAIS PIQ −3.2  Nonverbal/fluid intelligence 
WAIS digit symbol −3.1  Nonverbal processing speed 
Semantic fluency total −2.9 Verbal processing speed  
Category fluency (animals) −2.8 Verbal processing speed  
WAIS FSIQ −2.6 General intelligence 
RAVLT short-delay free recall −2.5 Verbal recall  
RAVLT long-delay free recall −2.4 Verbal recall  
WAIS block design −2.3  Visuoconstruction 
RAVLT trial 2 −1.9 Verbal encoding  
RAVLT total words trials 1–5 −1.8 Verbal encoding  
Trails B −1.8  Nonverbal processing speed 
RAVLT trial 1 −1.7 Verbal encoding/attention  
RAVLT list B −1.7 Verbal encoding  
RAVLT trial 5 −1.7 Verbal encoding  
WAIS picture completion −1.6  Visuoconstruction 
WAIS VIQ −1.6 Verbal/crystallized intelligence  
Stroop color naming −1.6 Mixed processing speed 
Category fluency (shopping) −1.6 Verbal processing speed  
Stroop color-word −1.5 Mixed processing speed/inhibition 
RAVLT trial 4 −1.5 Verbal encoding  
WAIS comprehension −1.5 Verbal reasoning  
Letter fluency (S) −1.4 Verbal processing speed  
WAIS longest digit span backward −1.3 Mixed working memory 
Letter fluency total (FAS) −1.3 Verbal processing speed  
Stroop word reading −1.2 Verbal processing speed  
RAVLT trial 3 −1.2 Verbal encoding  
Category fluency (fruit) −1.1 Verbal processing speed  
WAIS information −1.1 Verbal reasoning  
WAIS digit span −1.0 Verbal working memory  
Letter fluency (F) −1.0 Verbal processing speed  
WAIS picture arrangement −0.9  Visuoconstruction 
Letter fluency (A) −0.9 Verbal processing speed  
WAIS arithmetic −0.8 Mixed working memory 
WAIS similarities −0.8 Verbal reasoning  
Stroop interference T-score −0.7 Mixed inhibition 
WAIS longest digit span forward −0.4 Basic attention  
Mean −1.8 −1.5 −2.7 
  Domain
 
Test Cohen's d Verbal Nonverbal 
Trails A −5.7  Nonverbal processing speed 
WAIS object assembly −3.3  Visuoconstruction 
WAIS PIQ −3.2  Nonverbal/fluid intelligence 
WAIS digit symbol −3.1  Nonverbal processing speed 
Semantic fluency total −2.9 Verbal processing speed  
Category fluency (animals) −2.8 Verbal processing speed  
WAIS FSIQ −2.6 General intelligence 
RAVLT short-delay free recall −2.5 Verbal recall  
RAVLT long-delay free recall −2.4 Verbal recall  
WAIS block design −2.3  Visuoconstruction 
RAVLT trial 2 −1.9 Verbal encoding  
RAVLT total words trials 1–5 −1.8 Verbal encoding  
Trails B −1.8  Nonverbal processing speed 
RAVLT trial 1 −1.7 Verbal encoding/attention  
RAVLT list B −1.7 Verbal encoding  
RAVLT trial 5 −1.7 Verbal encoding  
WAIS picture completion −1.6  Visuoconstruction 
WAIS VIQ −1.6 Verbal/crystallized intelligence  
Stroop color naming −1.6 Mixed processing speed 
Category fluency (shopping) −1.6 Verbal processing speed  
Stroop color-word −1.5 Mixed processing speed/inhibition 
RAVLT trial 4 −1.5 Verbal encoding  
WAIS comprehension −1.5 Verbal reasoning  
Letter fluency (S) −1.4 Verbal processing speed  
WAIS longest digit span backward −1.3 Mixed working memory 
Letter fluency total (FAS) −1.3 Verbal processing speed  
Stroop word reading −1.2 Verbal processing speed  
RAVLT trial 3 −1.2 Verbal encoding  
Category fluency (fruit) −1.1 Verbal processing speed  
WAIS information −1.1 Verbal reasoning  
WAIS digit span −1.0 Verbal working memory  
Letter fluency (F) −1.0 Verbal processing speed  
WAIS picture arrangement −0.9  Visuoconstruction 
Letter fluency (A) −0.9 Verbal processing speed  
WAIS arithmetic −0.8 Mixed working memory 
WAIS similarities −0.8 Verbal reasoning  
Stroop interference T-score −0.7 Mixed inhibition 
WAIS longest digit span forward −0.4 Basic attention  
Mean −1.8 −1.5 −2.7 

Notes: Cohen's d = (PATIENTmean − CONTROLmean)/CONTROLsd; WAIS, Wechsler Adult Intelligence Scale; PIQ, Performance intelligence quotient; VIQ, Verbal intelligence quotient; FSIQ, Full-scale intelligence quotient; RAVLT, Rey auditory verbal learning test.

Written informed consent was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki, and approved by the Research and Ethics committee of Semmelweis University, Hungary.

Medical History

Patients underwent a comprehensive neurologic assessment completed by a trained neurologist. A chart review was conducted to determine duration of disease, medication history and results obtained from prior brain scans (e.g., CT or MRI). The global severity index (GSI) of the Symptom Checklist-90-R (SCL-90-R) was administered to determine the presence and severity of psychiatric symptoms for the purpose of generating a GSI score (Derogatis, 1994). Daily functional activities (e.g., dressing, eating, and maintaining hygiene) were assessed using the Stanford Health Assessment Questionnaire 20-item Disability Index (HAQ-DI) (Ponyi et al., 2005).

Genotyping

DNA was extracted from blood cells and skeletal muscle tissue were obtained by Qiagen DNA extraction kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions in cases where no mutation was found in blood cells but suspicion was high for mitochondrial disease. We used PCR-RFLP standard methods to screen for mutations in the mtDNA hot spots (m.3243 A>G, m.8344 A>G, A8356G, m.8993 T>C and m.8993 T>G) and the long-PCR methodology to look for mtDNA common deletions. In cases negative for the common mutations, the entire mtDNA was sequenced using standard methods.

Cognitive Evaluation

All patients underwent neuropsychologic testing with measures validated in Hungarian, and administered and scored according to standard methodology (Maruta, Guerreiro, de Mendonça, Hort, & Scheltens, 2011). Wechsler Adult Intelligence Scale (WAIS). Ten subtests from the WAIS were administered to assess intellectual abilities: information, comprehension, digit span, arithmetic, similarities, digit symbol coding, picture arrangement, picture completion, block design, and object assembly. Rey Auditory Verbal Learning Test (RAVLT). We focused on verbal encoding, short- and long-term recall, and proactive and retroactive interference from the RAVLT to assess learning and memory. Stroop Color-Word Test. The Stroop was used to gauge verbal processing speed and susceptibility to interference. Trail Making Test. Basic psychomotor speed and visual attention were assessed with Trails A and more complex psychomotor control was assessed with Trails B. Verbal Fluency. Phonemic fluency was assessed with letter cues (FAS) and semantic fluency assessed with categorical cues (animals, fruits/vegetables, and shopping items).

Results

Genotypes

Four major types of mtDNA alterations were identified (Supplementary material online, Table S1). Nine patients had mutations in genes coding for mitochondrial transfer RNA (tRNA). Three patients had mutations in genes that code for mitochondrial proteins. Three patients had large mtDNA deletions. Finally, four patients had multiple polymorphisms, some of which have previously been described in association with various diseases (www.mitomap.org).

Clinical Outcomes

On average, the duration of mtDNA-related disease in this cohort was 17.9 years (±6.3 years; range: 4–30 years). As shown in Supplementary material online, Table S1, the most common neurological complications identified were hypoacusis, ataxia, myopathy, neuropathy, and exercise intolerance. Various structural brain abnormalities were detectable on neuroimaging; however, several patients (ID 4, 6, 9, 11–14, 17 and 19) had normal scans. Four patients (ID 1–4) harbored the m.3243 A>G substitution that is classic for MELAS syndrome; however, none had a history of stroke-like episodes, a core feature of MELAS. Among patients harboring the classic MERRF m.8344 A>G substitution (ID 5–8), only ID 7–8 (monozygotic twin brothers) had the classic symptomatology characterized by myoclonus epilepsy. The classic NARP genotype (m.8993 T>C) was present in a mother and her son (ID 9–10), but only the son was symptomatic. Of the three patients with mtDNA deletions, two had CPEO (ID 11–12) and one had KSS (ID 13).

Neuropsychological Findings

On average, IQ scores were within normal limits but variable (FSIQ = 101, SD = 23), and performance IQ scores were lower than verbal IQ scores. Object assembly, digit symbol coding, and block design were the most impaired. Learning and memory performance was mixed such that additional words were learned with each repetition, but overall encoding was below average (d = −1.8 for total words recalled across RAVLT trials 1–5). Notably, patients generally had difficulty recalling what they had learned and were susceptible to retroactive interference (Fig. 1). Furthermore, both immediate recall (d = −2.5) and delayed recall (d = −2.4) were differentially more impaired than learning/encoding. Word reading (d = −1.2), color naming (d = −1.6), and color-word reading (d = −1.5) were all below average on the Stroop but susceptible to interference was minimal once color-word performance was adjusted for basic word reading speed and color naming speed (d = −0.7). Performance on Trails A (d = −5.7) was more impaired than Trails B (d = −1.8) although five patients could not complete Trails B within 300 s so the task was stopped and not scored. Patients were differentially slower at rapidly generating verbal responses to semantic (category) cues compared with phonemic (letter) cues such that categorical fluency (d = −2.9) was more than two-fold worse than letter fluency (d = −1.3). Lastly, duration of disease and functional disability on the HAQ-DI were significantly correlated with performance on most neuropsychological measures, but general psychopathology on SCL-90-R GSI was not (Supplementary material online, Table S2).

Fig. 1.

Rey Auditory Verbal Learning Test (RAVLT). Patients were more susceptible to retroactive interference and performed differentially worse on recall than on learning. Note: SDFR, short-delay free recall; LDFR, long-delay free recall; ±standard error of the mean is reflected in error bars.

Fig. 1.

Rey Auditory Verbal Learning Test (RAVLT). Patients were more susceptible to retroactive interference and performed differentially worse on recall than on learning. Note: SDFR, short-delay free recall; LDFR, long-delay free recall; ±standard error of the mean is reflected in error bars.

Discussion

In this case-series report, we identified a general pattern of moderate to severe cognitive dysfunction across 19 patients with primary mtDNA mutations. However, there was clear individual-level variation in cognitive performance and several patients were intact. Still, pronounced deficits were evident on tests of nonverbal processing speed and visuoperceptual/visuoconstructional ability. Verbal memory/recall was impaired relative to verbal encoding/learning, and susceptibility to retroactive interference was evident. Semantic fluency was differentially impaired relative to phonemic fluency. Test performance correlated significantly with functional disability and duration of disease. As expanded upon below, these deficits are consistent with cognitive decline seen in subcortical dementias and AD.

Administration of 10 WAIS subtests revealed deficits in nonverbal/fluid ability approximately twice as pronounced as verbal/crystallized intelligence, especially visually-mediated perception, integration, and construction. Similar findings of significant impairment in visuospatial processing have been reported in patients with a variety of mitochondrial diseases (Bosbach, Kornblum, Schroder, & Wagner, 2003; Sartor, Loose, Tucha, Klein, & Lange, 2002; Turconi et al., 1999). Thus, mtDNA mutations seem to differentially impair cognitive processes involving complex visuospatial integration and the nondominant cerebral hemisphere.

Memory performance was variable in our mtDNA patients. Serial encoding of semantically unrelated information was generally lower than average, although patients did learn new words with each trial. The encoding/learning component of the RAVLT therefore does not seem to represent a core area of impairment. By contrast, patients forgot an average of three words following short and long delay periods when asked to freely recall what had previously been learned. Notably, no proactive interference effect was evident such that both controls and patients remembered one less word on list B than trial 1. The patients, however, were susceptible to retroactive interference. Specifically, controls recalled the same number of words after the 5-min delay as they recalled on trial 5, whereas patients recalled three fewer words after the same delay. Combined deficits in retroactive interference and in retaining material over time are indicative of impairments in memory storage, likely of mesial temporal origin and similar to deficits common to AD (Ahn et al., 2011).

Across tasks, patients evidenced severe impairments in processing speed in both verbal and nonverbal modalities. Trails A and digit symbol coding were the most impaired. Semantic fluency (a putative subcortical task) was twice as impaired as phonemic fluency (a putative frontal task) (Baldo, Schwartz, Wilkins, & Dronkers, 2006). Speed on all three Stroop conditions was well below average, but interference control was relatively intact. However, half of our patients were treated with CNS medications that could have interfered with their ability to rapidly process information to some extent (Supplementary material online, Table S1).

Although we did not subgroup patients based on mutation type in a formal way, a few interesting patterns are worth noting. Patients harboring mitochondrial tRNA mutations performed neuropsychological testing the worst relative to other classes of mtDNA mutation. The tRNA group comprised four individuals with the m.3243 A>G mutation, four with the m.8344 A>G mutation, and a patient with two tRNA mutations (m.8332 A>G and m.8270 C<T). Only three of these nine patients had normal neuroimaging workups, and four of them showed cortical and cerebellar atrophy. Patients with the m.8344 A>G/MERRF mutation evidenced fewer cognitive deficits, and their duration of disease (12 years) was shorter than individuals with other tRNA variants (average disease duration of 19 years). Two of the three carriers of mutations in genes that code for mitochondrial proteins performed in the impaired range on most neuropsychological measures, and only one had a normal neuroimaging workup. Of note, a mother with the m.8993 T>C mutation had superior intellectual ability (ID9: FSIQ = 122), whereas her son with the same mutation had a moderate intellectual disability (ID10: FSIQ = 55). As a group, the three patients with large mtDNA deletions (ID 11–13) were the least impaired cognitively, and all three had normal neuroimaging workups. Finally, the group of four patients with multiple mtDNA polymorphisms performed intermediate to controls and the most impaired probands.

A mitochondrial dementia has been posited to describe the substantial cognitive impairments that often arise from mutations in the mitochondrial genome (Finsterer, 2008). Mitochondrial dysfunction has been implicated in AD before (Grazina et al., 2006; Onyango et al., 2006). Dementia is defined as the development of multiple cognitive deficits in which memory impairment is core in conjunction with aphasia, apraxia, agnosia, or executive dysfunction. In DSM-5, dementia is now termed major or minor “neurocognitive disorder (NCD),” and the criteria has broadened so that NCD encompasses a decline in any of the following areas: complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5], 2013). Our patients evidenced severe deficits in several domains, especially memory recall, complex visuospatial processing, nonverbal reasoning, semantic fluency, and processing speed. Thus, these data broadly support the notion of a mitochondrial dementia. Notably, deficits in digit symbol coding, short-delay free recall, and semantic fluency, which were the core findings in our sample, are all significant predictors of developing dementia (Tierney, Moineddin, & McDowell, 2010).

Subcortical brain regions such as the temporal lobes and cerebellum appear to be particularly susceptible to mtDNA mutation. For example, the m.8344 A>G mutation disrupts function of Purkinje cells and neurons in the dentate nucleus and inferior olivary nuclei of the cerebellum (Mancuso et al., 2013). Cerebellar ataxia is a prominent clinical feature of mtDNA disease and often progressively gets worse (Lax et al., 2012). Here, several of our patients showed signs of cerebellar atrophy and were ataxic, and on testing were impaired in processing speed and motor control. In addition to the cerebellum, reduced cerebral glucose uptake in occipital and temporal regions has been found in mitochondrial disorders (Molnar et al., 2000). Further, lesions and atrophy in the basal ganglia and temporo-parieto-occipital junction have been reported in mitochondrial disorders (Sartor et al., 2002). We found that as a group our patients evidenced worse semantic versus phonemic fluency; showed marked psychomotor slowing; and encoding and proactive interference were relatively intact versus grossly impaired retroactive interference and long-term recall. These findings are consistent with past research indicating that subcortical brain regions are especially vulnerable to mtDNA mutation.

Herein we presented a series of 19 related and unrelated cases with various primary mtDNA mutations in an attempt to identify the nature and severity of cognitive impairment potentially attributable to mitochondrial dysfunction arising from allelic and structural variation in the mitochondrial genome. Pronounced deficits in nonverbal reasoning, visuospatial construction, memory recall, retroactive interference, semantic fluency, and processing speed were evident and consistent with a mitochondrial-based cognitive decline. However, variability in cognitive performance was also noteworthy, suggesting that the phenotypic landscape of cognitive traits linked to primary mtDNA mutations is also heterogeneous. In evaluating patients who present with similar cognitive problems, mitochondrial dysfunction should be considered.

Supplementary Material

Supplementary material is available at Archives of Clinical Neuropsychology online.

Funding

This work was supported by the grant of Scientific and Technological Cooperation Program (TET) [10-1-2011-0058], the Social Renewal Operative Program (TAMOP) [4.2.1B-09/1/KMR-2010-001] and the National Brain Research Program of Hungary to G.I.F. and M.J.M.

Conflict of Interest

None declared.

Acknowledgments

We thank our patients for their consent and cooperation. We also thank Gyorgyi Bathori and Metta Stralendoff for their technical help.

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Author notes

These authors contributed equally to the manuscript.